The scale of the challenge is sobering. DSRCT is an aggressive soft tissue sarcoma in which nests of small round tumour cells are embedded in a dense, fibrous stroma, the very desmoplastic tissue that gives the disease its name. In 90 per cent of patients, tumours have already spread diffusely throughout the abdominal cavity by the time of diagnosis, and half have metastasised beyond the peritoneum to the liver, lungs, lymph nodes or bones. Eighty per cent of cases occur in post-pubertal males, with a peak incidence between the ages of 20 and 24. Current treatment, a punishing combination of intensive multi-agent chemotherapy, cytoreductive surgery and whole-abdomen radiotherapy, has produced no meaningful improvement in survival in 30 years. Even after complete surgical resection, some studies report recurrence or progression in 84 per cent of patients, and up to 70 per cent of surgically treated patients require further procedures.

At the molecular level, DSRCT is a paradox. It is a genomically ‘quiet’ cancer, meaning it carries remarkably few mutations beyond its defining event: a reciprocal translocation between chromosomes 11 and 22 that fuses the EWSR1 gene to WT1, producing an abnormal transcription factor found exclusively in tumour cells. This fusion protein, present in every DSRCT cell, combines the transactivation domain of EWSR1 with the DNA-binding domain of WT1, rewiring gene expression across the genome. Laboratory studies have shown that suppressing the fusion protein halts tumour cell growth entirely, triggering cell-cycle arrest and shrinking xenograft tumours in mice. The workshop participants unanimously ranked EWSR1::WT1 as the highest-priority target, but hitting it directly is extraordinarily difficult because the protein is structurally disordered and buried in the cell nucleus.

One of the most exciting strategies discussed targets the fusion protein through the immune system. The chromosomal breakpoint creates a unique junctional amino acid sequence, a neoantigen that exists only in tumour cells and never in healthy tissue. Using mass spectrometry of HLA molecules, researchers confirmed that this neopeptide is displayed on the cell surface by two globally common HLA variants, HLA-A03 and HLA-A11. Engineered T-cell receptors designed to recognise this peptide have shown complete and durable responses in animal models. The catch is HLA restriction: only around 32 per cent of DSRCT patients worldwide carry the required tissue types, though efforts are under way to broaden coverage, and future iterations may be armoured with immune-stimulating cytokines such as interleukin-18. A parallel technology, peptide-centric chimeric antigen receptors, which are not limited by HLA type, is earlier in development but could eventually offer a wider route to the same target.

Indirect approaches to disabling the fusion protein are already in the clinic. Trabectedin and its analogue lurbinectedin are small molecules that bind the DNA minor groove and disrupt the fusion protein’s activity, and lurbinectedin is now being tested in DSRCT both as a monotherapy and in combination with irinotecan. Beyond the fusion itself, the workshop identified several cell-surface proteins as promising targets, including LRRC15, the somatostatin receptors SSTR3 and SSTR5, NECTIN4, STEAP1 and mesothelin. Each is attractive in principle, but the participants stressed that proteomic validation in DSRCT tissue remains thin. A single case report of a patient with atypical DSRCT achieving a 23-month response to the NECTIN4-targeting antibody-drug conjugate enfortumab vedotin hints at what may be possible, but the panel cautioned that far more expression data are needed before such drugs can be justified for routine investigation.

Some of the most encouraging clinical signals come from drugs already approved for other cancers. Trastuzumab deruxtecan, an antibody-drug conjugate linking a HER2-targeting antibody to a topoisomerase I inhibitor, produced partial responses in nine of 17 DSRCT patients with measurable disease in a single-centre off-label study, with a further eight achieving stable disease. Strikingly, response did not correlate with HER2 expression levels, and preclinical work suggests the drug is active even at low HER2 abundance. Those results have propelled a biomarker-agnostic trial through the Children’s Oncology Group. Other trials now under way include an antibody-drug conjugate against claudin-6, the NTRK3 inhibitor repotrectinib combined with chemotherapy, and the somatostatin analogue pasireotide as maintenance therapy for tumours expressing SSTR2, 3 or 5.

The workshop also prioritised existing clinical assets that could be redeployed. B7-H3, a cell-surface protein expressed in up to 96 per cent of DSRCT tumours but minimally in healthy tissue, was rated a very high priority, with an antibody-drug conjugate carrying a topoisomerase 1 payload considered the optimal modality. Inhibitors of the DNA damage response also ranked highly, because DSRCT cells show high levels of replication stress; a phase I trial of the CHK1/2 inhibitor prexasertib with irinotecan produced partial responses in six of 19 patients. Androgen receptor signalling emerged as potentially ‘low-hanging fruit’, given that hundreds of AR-targeted drugs already exist for prostate cancer and that AR is highly expressed in many DSRCT cases, particularly in males. FGFR4, a direct transcriptional target of the fusion protein, and STEAP1 round out the shortlist, with cell-surface approaches such as CAR T-cells and antibody-drug conjugates favoured over small-molecule inhibitors.

Yet the workshop was candid about the barriers that have kept DSRCT patients waiting. With so few patients, pharmaceutical companies have little financial incentive to run trials, and regulatory frameworks designed for common adult cancers fit poorly. The participants proposed three complementary solutions: international platform trials such as the OCTOPUS master protocol for non-rhabdomyosarcoma soft tissue sarcomas, which can test multiple agents simultaneously and adapt as data emerge; the systematic collection of high-quality off-label and real-world evidence, as demonstrated by the trastuzumab deruxtecan experience; and the inclusion of DSRCT patients in adult trials of relevant targets, for example by adding signal-seeking DSRCT cohorts to prostate cancer studies of androgen receptor inhibitors. Trials in the setting of minimal residual disease, where the chance of altering the disease’s natural history may be greatest, were also flagged as a priority, alongside better tools to detect and characterise the residual cells that seed relapse.

For a disease that has defied progress for a generation, the workshop’s message is one of cautious momentum. The biology of DSRCT, once an impenetrable black box, now offers a defined driver, a tumour-specific neoantigen, a growing list of surface targets and a pipeline of drugs, many already tested in humans, that could be redirected toward these patients. The participants concluded that progress will come from a dual strategy: developing entirely new agents against the EWSR1::WT1 fusion while simultaneously evaluating existing therapeutics in well-designed, internationally harmonised trials that enrol children, adolescents and adults together. If the roadmap is followed, the first generation of DSRCT patients with genuine targeted options may not be far away, turning one of oncology’s most neglected diagnoses into a test case for how science can serve the rarest of the rare.

Subject of Research: Therapeutic target prioritisation and clinical trial strategy for desmoplastic small round cell tumour

Article Title: Paediatric therapeutic development workshop on desmoplastic small round cell tumours

Article References: Paediatric therapeutic development workshop on desmoplastic small round cell tumours. (n.d.). https://doi.org/10.1038/s41416-026-03631-7

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03631-7

Keywords: DSRCT, EWSR1::WT1 fusion, paediatric oncology, sarcoma, T-cell receptor therapy, antibody-drug conjugates, B7-H3, androgen receptor, DNA damage response, rare cancers, drug development, clinical trials

Transfer RNAs have long occupied a quiet corner of molecular biology. These small RNA molecules perform one of the most essential tasks in every living cell: during mRNA translation, they read the genetic instructions carried by messenger RNA and deliver the corresponding amino acids, which are then linked together to build proteins. Because every cell needs its proteins made, tRNAs were historically viewed as housekeeping components — abundant, interchangeable, and largely indifferent to the specific fate of the cell they serve. The new research challenges that view at its foundation. “The discovery opens an entirely new realm of cancer biology that was previously unrecognized,” said Andrew Hsieh, MD, co-corresponding author of the study and a professor and associate director of Fred Hutch’s Human Biology Division. “Historically, tRNAs have been thought to play a bystander role in cell maintenance and disease, but our study shows that tRNAs can actively shape the identity of cancer cells.”

The clinical backdrop for the work is one of the most common and consequential problems in oncology. Prostate cancer is a leading cause of cancer in men, and in its early stages it is typically driven by the androgen receptor, a protein that responds to male hormones and fuels tumor growth. Because of this dependence, the androgen receptor has long been the primary target of standard prostate cancer therapies, and drugs that block its activity are often effective initially. But many tumors do not stay vulnerable. Over time, a substantial fraction of prostate cancers undergo a profound change in cellular identity, shifting to an androgen receptor-independent state in which they no longer rely on the protein that the therapies were designed to suppress. Once tumors make this transition, they become more aggressive, less responsive to treatment, and considerably harder to manage.

Understanding what drives this identity switch has been a central question in prostate cancer research. Scientists have known that genomic mutations and alterations in transcription factor-driven gene expression — changes in which genes are switched on and off — accumulate during cancer progression and can contribute to the emergence of treatment resistance. But Yeon Soo Kim, PhD, first author of the Nature paper and a postdoctoral researcher in Hsieh’s laboratory at Fred Hutch, wanted to probe a layer of regulation that had received far less attention. “We already knew that genomic mutations or transcriptional factor-dependent genetic expression are altered during the cancer progression and can lead to the development of treatment resistance,” Kim explained. “But we wanted to know more about how mRNA translation — also known as protein synthesis — is involved when the disease becomes more aggressive.” Kim’s work on the project was supported by a National Cancer Institute K99/R00 Pathway to Independence Award, a prestigious grant designed to help promising early-career scientists launch independent research careers.

Kim focused on a specific step in the translation process: the moment when a tRNA molecule reads the biological information encoded in a messenger RNA and delivers the amino acid that it carries, allowing amino acids to be joined into a growing protein chain. It is a step that happens billions of times in every cell, and it depends on a large family of tRNAs, each tuned to recognize particular codons and deliver particular amino acids. Rather than treating this machinery as uniform background noise, Kim and her colleagues asked whether individual tRNAs might be differentially deployed as prostate cancer cells change their identity — and whether those differences might matter.

To answer that question, the team assembled evidence across multiple model systems. They examined prostate cancer cell lines grown in the laboratory, mouse models of the disease, and tumor samples taken from patients. Across all of these systems, a consistent pattern emerged. A specific transfer RNA, known as tRNA1Arg(UCU), was present at high levels in androgen receptor-dependent prostate cancer cells — the treatment-sensitive state — but was markedly diminished in tumors that had become less dependent on the androgen receptor and resistant to therapy. The consistency of the pattern across cell lines, animal models and human tissue suggested that the tRNA was not an incidental byproduct of disease progression but a feature closely tied to the cancer’s state.

The most striking result came from the next set of experiments, which tested whether the correlation ran in a causal direction. When the researchers supplied the specific tRNA to treatment-resistant tumors, the tumors reverted to a state in which they were once again sensitive to therapies targeting the androgen receptor. In other words, restoring a single RNA molecule appeared to push aggressive, drug-resistant cancer cells back toward the vulnerable identity they had abandoned. “We found that we can shift the cell state between androgen receptor-dependent to an androgen receptor-independent state with a single tRNA,” Kim said. “This is important because changes in cell identity are a major reason prostate cancers become resistant to treatment. We found that this tRNA can influence whether cells remain in a drug-sensitive state or transition to one that is more aggressive.”

The implications extend well beyond the prostate. Changes in cellular identity — sometimes described as lineage plasticity — are increasingly recognized as a common route by which cancers evade targeted therapies across many tumor types. Lung cancers and breast cancers, among others, are known to undergo identity switches after treatment, allowing them to survive in forms that existing drugs no longer recognize. “In this study we used prostate cancer as an archetype to study tRNA dependent state changes, but we think it’s just the beginning,” said Kim, who plans to pursue this line of research when she establishes her own laboratory. “We can apply this approach to any type of disease models or other types of cancers that undergo identity switches after treatment, such as lung and breast cancers.” If tRNA dosage proves to be a general lever for controlling cell state, it could open a new chapter in precision oncology, one in which the translation machinery itself becomes a therapeutic target.

Kim and Hsieh are already exploring how the tRNA could be harnessed in the clinic, both as a biomarker and as a therapeutic target for aggressive prostate cancer. As a biomarker, measuring levels of tRNA1Arg(UCU) in tumor samples could potentially help clinicians determine whether a patient’s cancer remains dependent on the androgen receptor and therefore likely to respond to receptor-targeted therapies, guiding more precise treatment decisions. As a therapeutic target, the finding raises the possibility of developing interventions that restore or mimic the tRNA’s activity in resistant tumors, effectively reversing resistance rather than simply escalating treatment. Microscopy work published alongside the study illustrates the principle visually: human prostate cancer tissue with high amounts of the tRNA, revealed by dark purple and pink staining, was associated with tumors that depended on the androgen receptor for growth and were sensitive to therapies aimed at it.

The research was a collaborative effort spanning institutions. Co-corresponding author Tao Pan, PhD, of the University of Chicago brought expertise in tRNA biology to the project, and Hsieh — who holds the Larry and Virginia Gordon Endowed Chair in Prostate and Bladder Cancer Research at Fred Hutch and is also a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine — contributed his laboratory’s focus on translation control in cancer. The study was funded by multiple grants from the National Institutes of Health, including the Pacific Northwest Prostate Cancer SPORE, and by the U.S. Department of Defense, with additional funding from the Prostate Cancer Foundation and the American Cancer Society. For a field that has long treated tRNAs as anonymous couriers, the message of the new work is hard to ignore: the machinery of protein synthesis may hold keys to cancer’s identity, and with them, new ways to unlock drug resistance.

Subject of Research: tRNA-mediated regulation of cell identity and drug resistance in prostate cancer

Article Title: Key driver of aggressive prostate cancer identified, suggesting new way to reverse drug resistance

Article References: Key driver of aggressive prostate cancer identified, suggesting new way to reverse drug resistance. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: prostate cancer, transfer RNA, tRNA1Arg(UCU), androgen receptor, drug resistance, mRNA translation, protein synthesis, cell identity, Fred Hutch Cancer Center, Nature, precision oncology, lineage plasticity

The research, led by Shaon Basu and Markus Ralser at Charité Universitätsmedizin Berlin and the Francis Crick Institute, together with a team at AstraZeneca, focused on degraders of the androgen receptor, a transcription factor that drives treatment-resistant prostate cancer. First-line therapies for prostate cancer typically block androgen receptor signaling with antagonist drugs, but tumors inevitably acquire mutations at the androgen receptor locus, rendering the drugs ineffective and the disease lethal. Degraders promise a way around this resistance by directly destroying the receptor inside tumor cells. Despite this promise, no androgen receptor degrader has yet demonstrated improved efficacy over standard treatment with an acceptable safety profile, echoing the fate of first-generation bromodomain degraders that failed in cancer patients because of dose-limiting toxicity.

The team’s strategy began with a technological foundation: a fast, scalable proteomic workflow capable of monitoring how thousands of proteins respond to drug treatment in a 96-well plate format. HepG2 cells, a well-established model for screening liver toxicity, were cultivated and treated with liquid-handling robots, and their proteins were digested into peptides and analyzed by data-independent acquisition mass spectrometry on two platforms, using scanning SWATH acquisition on a Sciex TripleTOF 6600 and dia-PASEF acquisition on a Bruker timsTOF HT. Neural network-based processing with the DIA-NN software, benchmarked against a hepatocarcinoma-specific spectral library, quantified thousands of proteins per sample with minimal batch effects and low technical variance, making the approach suitable for industrial-scale screening.

To validate the platform, the researchers exposed HepG2 cells to 78 FDA-approved drugs whose targets span human, bacterial and fungal proteins. Forty-seven of these compounds, particularly those with favorable safety profiles, triggered no significant proteomic response. The remaining 31 induced measurable changes, and the proteomes faithfully reflected each drug’s mechanism of action: methotrexate altered less than one percent of the proteome while its primary target, dihydrofolate reductase, ranked among the most upregulated proteins, whereas the chemotherapy doxorubicin reshaped seven percent of the proteome in a pattern consistent with DNA damage. Intriguingly, the dominant proteomic signatures often corresponded to off-target rather than on-target interactions, including disruption of ribosomal translation, endoplasmic reticulum stress and mitochondrial dysfunction. The antifungal clotrimazole, for example, induced broad rearrangements driven by xenobiotic response proteins and mitochondrial impairment despite the absence of its fungal target in human cells. A principal component analysis cleanly separated compounds with narrow therapeutic windows, such as chemotherapeutics and immunosuppressants, from safer drugs.

With the platform validated, the team turned to the central question: what off-target effects do experimental androgen receptor degraders produce? Because HepG2 cells do not express the androgen receptor, any proteomic response to these compounds must reflect off-target engagement. The researchers profiled a library of 204 structurally unique androgen receptor degraders, including clinically advanced candidates such as bavdegalutamide (ARV-110) and an AstraZeneca compound referred to as compound 1, alongside control degraders targeting BRD4, CDK4 and CDK9. The screening campaign generated 2,113 proteomic samples reaching depths of roughly 4,000 proteins each. The results were striking: despite the absence of their intended target, several androgen receptor degraders perturbed up to 57 percent of the proteome, with an average of 19 percent of proteins differentially expressed, a far stronger response than that elicited by the FDA-approved drug library. Notably, degraders targeting proteins actually expressed in HepG2 cells, such as BRD4, produced responses that partly reflected the biology of their targets, confirming that the platform can distinguish on-target from off-target signatures.

The off-target responses clustered according to chemical structure. Degraders recruiting the cereblon E3 ligase, particularly those using phthalimide derivatives and achiral DHU warheads, produced the broadest perturbations, while those recruiting the von Hippel-Lindau ligase produced the weakest. Crucially, the toxicity was not inherent to the recruiter alone: lenalidomide by itself elicited no proteomic response, while other cereblon ligands induced moderate or strong changes. Functional enrichment analysis pointed decisively at the mitochondrial compartment, with pathways involving mitochondrial protein-containing complexes responding in a dose-dependent manner. When the researchers tested whether the compounds impaired respiration by culturing cells in galactose medium, which forces cells to rely on mitochondrial ATP production, several cereblon-recruiting degraders reduced viability in a dose-dependent fashion. Compound 1 showed a half-maximal inhibitory concentration of 0.73 micromolar in galactose medium, while its constituent building blocks, lenalidomide and an androgen receptor-binding analog of enzalutamide, were inactive above 20 micromolar, indicating a gain-of-function toxicity arising from the assembled degrader molecule.

To pinpoint the molecular mechanism, the team applied machine learning to the proteomic data. Univariate linear regression linking protein expression changes to galactose toxicity revealed that nine of the ten best-fitting proteins localized to mitochondria, and four of these were subunits of electron transport chain complex I, the NADH dehydrogenase that initiates the proton gradient driving ATP synthesis. The complex I protein NDUFA5 showed the strongest relationship, with a coefficient of determination of 0.57. A second-pass gradient-boosted decision tree model, refined through Shapley additive explanations analysis and retrained on top features, achieved a cross-validation area under the precision-recall curve of 80 percent, with complex I proteins dominating the feature importance rankings. Biochemical validation followed: compound 1 reduced oxygen consumption in HepG2 cells, and in assays using bovine heart mitochondrial membranes it potently inhibited NADH oxidation through the complex I-III-IV axis with an IC50 of 0.2 micromolar, roughly 100-fold more potent than lenalidomide and 45-fold more potent than enzalutamide, while leaving complex II activity untouched. The degrader, in other words, was a selective complex I inhibitor.

The most consequential step came next. Because the toxicity was not inherent to the recruiter chemistry, the researchers reasoned that proteomics could identify degraders lacking complex I engagement. Their trained models assigned compound 1 a predicted toxicity score of 91 out of 100, comparable to known hepatotoxins such as troglitazone, but attributed far lower scores of 47 and 35 to two close structural analogs, compounds 2 and 3, which differed only in the linker region and carried a 7-methoxy modification on the lenalidomide moiety. Experimentally, the analogs induced no complex I proteomic signature, did not impair mitochondrial respiration, and showed a complex I IC50 of 6.5 micromolar versus 0.2 micromolar for compound 1. In primary human hepatocytes, compound 1 caused acute cell death at 2.7 micromolar, whereas compounds 2 and 3 were tolerated above 20 micromolar. The analogs also lost the unwanted degradation of the cereblon neosubstrates IKZF3 and SALL4, proteins linked to bone marrow and developmental toxicity, likely owing to the methoxy modification.

Safety gains did not come at the expense of efficacy. All three compounds inhibited proliferation of androgen receptor-positive prostate cancer cell lines, but only compound 1 suppressed androgen receptor-negative lines, suggesting improved selectivity for the refined analogs. Compound 3 degraded the androgen receptor as effectively as compound 1 in LNCaP cells and dose-dependently suppressed prostate-specific antigen expression. It also displayed favorable pharmacokinetics, with low clearance in human liver microsomes and rat hepatocytes and 50 percent oral bioavailability in mouse. RNA sequencing confirmed that compound 3 modulated androgen response signaling similarly to enzalutamide while reducing MYC oncogenic signaling and G2/M checkpoint pathways, consistent with cell-cycle arrest, and without perturbing oxidative phosphorylation at any time point.

The decisive test came in vivo. In a C4-2 xenograft model of castration-resistant prostate cancer in immunocompromised mice, three days of oral dosing with compound 3 at 30 milligrams per kilogram reduced androgen receptor protein levels in tumors by more than 70 percent. Over 28 days of treatment, compound 3 achieved 56 percent tumor growth inhibition, compared with just 15 percent for enzalutamide at 50 milligrams per kilogram, and both treatments were well tolerated with no significant body weight loss. The study establishes that systematic, high-throughput proteomics paired with interpretable machine learning can trace unwanted proteomic signatures back to specific chemical features, here a linker region, and guide the rational design of safer, more selective degraders. As polypharmacological modalities such as degraders and antibody-drug conjugates continue to enter the clinic, the authors argue that this proteome-guided framework offers a versatile route to de-risk drug development before candidates ever reach patients.

Subject of Research: Proteome-guided discovery and mitigation of toxicity mechanisms in androgen receptor-targeted protein degraders

Article Title: Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity

Article References: Basu, S., Yu, J. S. L., Bosak, J., Bagal, S. K., Crafter, C., Fallan, C., Lemke, O., Freiwald, A., White, M. E. H., Vernardis, S. I., Messner, C. B., Michaloglou, C., Pryde, K., Ramos-Montoya, A., Regan, S., Rodrigo-Brenni, M., Roth, S., Ruffilli, C., Mülleder, M., … Ralser, M. (2026). Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity. Nature Chemical Biology. https://doi.org/10.1038/s41589-026-02347-2

Image Credits: AI Generated

DOI: 10.1038/s41589-026-02347-2

Keywords: proteomics, targeted protein degradation, PROTAC, androgen receptor, prostate cancer, mitochondrial toxicity, complex I, machine learning, drug discovery, hepatotoxicity, cereblon, mass spectrometry

Prostate cancer is the archetypal lineage-dependent malignancy. Its growth hinges on the androgen receptor (AR), which is why androgen deprivation therapy and second-generation AR pathway inhibitors such as enzalutamide, apalutamide and darolutamide form the backbone of advanced disease treatment. Yet resistance is nearly universal. Tumors frequently shed their AR dependence through a process called lineage plasticity, transdifferentiating into neuroendocrine-like states that no longer respond to AR-targeted drugs. Genetic loss of TP53, PTEN or RB1 can drive this transition, but the translational mechanisms, the events at the level of protein synthesis, that permit such phenotypic flexibility have remained largely unknown.

To find them, the team performed unbiased small RNA sequencing using a multiplex platform capable of quantifying full-length tRNAs, their fragments and selected chemical modifications. They applied this technique to an engineered model in which LNCaP prostate adenocarcinoma cells were pushed into a lineage-plastic state through RB1 knockdown and overexpression of mutant TP53, MYCN, ASCL1, SRRM4, NR0B2, BCL2 and mutant KRAS. Among 49 tRNA isoacceptor families surveyed, only tRNAArg(UCU) was significantly downregulated during the transition, with a log2 fold change of roughly minus 0.34 and a false discovery rate of 2.42 x 10-25 in one analysis. Within the five tRNAArg(UCU) isodecoders, molecules sharing the same anticodon but differing in body sequence, tRNA1Arg(UCU) was the most abundant and the only one substantially decreased. Northern blotting and quantitative PCR confirmed the reduction in both LNCaP and C4-2B cells, and the decline was not accompanied by changes in tRNA fragmentation or chemical modification, indicating a specific loss of the mature molecule.

The correlation with lineage identity was striking. Across nine prostate cancer cell lines, tRNA1Arg(UCU) abundance showed a strong positive correlation with AR activity (Pearson’s r = 0.85, P = 0.0034) and a negative correlation with the neuroendocrine markers ENO2 and SCN3A. In the LTL331 patient-derived xenograft model, which transdifferentiates from adenocarcinoma to neuroendocrine prostate cancer after castration, tRNA1Arg(UCU) levels fell in a stepwise fashion from pre-castration through castration to relapse. The researchers then developed an in situ hybridization assay to visualize the tRNA directly in patient tissue. In specimens from 56 patients in the University of Washington rapid autopsy cohort, AR-positive tumors expressed significantly higher levels of tRNA1Arg(UCU) than neuroendocrine-positive tumors, and tRNA abundance correlated positively with AR activity and negatively with the neuroendocrine marker ELAVL4.

Crucially, the tRNA was not merely a passive marker. Using inducible short hairpin RNAs, the team reduced tRNA1Arg(UCU) levels by 25 to 50 percent in LNCaP and C4-2B cells. The knockdown was specific, leaving other tRNAArg(UCU) isodecoders untouched. The consequence was a coordinated shift in cell identity: AR pathway genes declined at both RNA and protein levels, while neuron-related gene programs rose. Cells depleted of the tRNA became significantly more resistant to enzalutamide, apalutamide and darolutamide, yet more sensitive to alisertib, an Aurora kinase A inhibitor with activity in neuroendocrine prostate cancer. In mice, the team generated animals haploinsufficient for n-Trtct2, the gene encoding tRNA1Arg(UCU), crossed onto the MYC-driven Hi-Myc prostate cancer model. Organoids derived from these mice showed a threefold increase in resistance to AR inhibition, and after surgical castration, haploinsufficient mice developed significantly enlarged prostates, with 25 percent exhibiting high-grade prostatic intraepithelial neoplasia compared with none of the controls.

Most remarkably, the process proved reversible. Re-expressing tRNA1Arg(UCU) in lineage-plastic cells restored AR pathway gene expression, suppressed neuroendocrine markers and resensitized the cells to AR-targeted therapies. Overexpression of other arginine tRNA isodecoders or isoacceptors had no such effect, underscoring the exquisite specificity of this single molecule. In LNCaP-abl cells, a subline that spontaneously evolved androgen insensitivity after prolonged culture in androgen-depleted medium, restoring tRNA1Arg(UCU) enhanced AR signaling and improved enzalutamide sensitivity. In the TRAMP transgenic mouse model, which normally progresses toward neuroendocrine tumors, crossing in a tRNA1Arg(UCU) overexpression allele reduced the incidence of premalignant glands after castration. Together, these experiments demonstrate that lineage dependency in prostate cancer can be toggled by modulating one tRNA species.

The team then asked how tRNA1Arg(UCU) is regulated. Mining the ENCODE database of transcription factor binding, they identified 11 DNA-binding proteins that occupy the TRR-TCT1-1 genomic locus encoding the tRNA. Four of these were downregulated during lineage transition, and functional screening pinpointed two: TARDBP, a DNA- and RNA-binding protein best known for its role in amyotrophic lateral sclerosis, and ZSCAN29, a zinc-finger protein. Silencing either factor reduced tRNA1Arg(UCU) expression, and their occupancy, measured by CUT&RUN profiling, declined selectively at the TRR-TCT1-1 locus during lineage plasticity. The locus carried the highest enrichment of the H3K4me3 histone mark among all six TRR-TCT isodecoder genes, and this mark, along with RNA polymerase III occupancy, was lost specifically at TRR-TCT1-1 during the lineage switch. TARDBP and ZSCAN29 appear to maintain RNA polymerase III recruitment at this chromatin-primed locus, and their expression correlated with tRNA1Arg(UCU) levels in patient specimens. This work provides one of the first demonstrations of isodecoder-specific transcriptional control of tRNA genes in cancer, extending tRNA regulation beyond canonical RNA polymerase III mechanics.

How does a single tRNA change cell fate? The answer lies in codon optimality. tRNA1Arg(UCU) decodes the AGA arginine codon, and the researchers built fluorescent reporters to show that translational capacity at AGA codons dropped roughly fourfold in lineage-plastic cells and was restored by tRNA addback. Polysome RNA sequencing, which separates ribosome-bound messenger RNAs by density to measure translation efficiency genome-wide, revealed that AGA codons were enriched among efficiently translated transcripts in adenocarcinoma cells, lost that enrichment in lineage-plastic cells, and regained it upon tRNA restoration. Among the translationally upregulated targets were five components of the SWI/SNF chromatin remodeling complex, and the team focused on SMARCC2, whose protein levels fell during lineage transition despite unchanged mRNA. A codon-switching experiment confirmed the mechanism: replacing SMARCC2’s AGA codons with synonymous CGC codons rendered the protein insensitive to lineage state. Silencing SMARCC2 in tRNA-restored cells reversed the AR pathway reactivation and restored enzalutamide resistance, establishing SMARCC2 as a key translational mediator through which tRNA1Arg(UCU) sustains lineage fidelity.

The clinical implications are substantial. In the rapid autopsy cohort, patients with the lowest tRNA1Arg(UCU) abundance had significantly shorter time to first bone metastasis, shorter survival after starting androgen deprivation therapy, shorter survival after developing androgen independence, and shorter overall survival overall. In mouse models, tRNA depletion led to a fourfold increase in metastatic burden following intracardiac injection of luciferase-labeled cells. The authors caution that the clinical associations are retrospective and that prospective studies will be needed to validate tRNA isodecoders as biomarkers of AR-targeted therapy resistance. But the therapeutic horizon is already visible: adeno-associated virus delivery of suppressor tRNAs has restored protein function in models of mucopolysaccharidosis type I, and lipid nanoparticle-based tRNA delivery has re-expressed CFTR in cystic fibrosis epithelia. Such platforms could, in principle, be adapted to restore tumor-suppressive tRNAs like tRNA1Arg(UCU), reprogramming lineage dependency and resensitizing tumors to existing therapies. For a disease in which treatment resistance remains the central clinical challenge, the idea that a single RNA adaptor molecule holds a master key to cellular identity is a genuinely paradigm-shifting proposition.

Subject of Research: Regulation of prostate cancer lineage plasticity and therapy resistance by tRNA dosage

Article Title: tRNA dosage regulates lineage dependency and resistance in prostate cancer

Article References: Kim, Y. S., Arora, S., Young, D., Tsou, A., Shiuan, A., Wladyka, C. L., Rudoy, D., Kim, J. Y., Waters, J. A., Schuster, S. L., Coleman, I. M., Kapur, M., Sobczyk, M., Katanski, C. D., Bayat Tork, A. M., Zhang, W., Nelson, P. S., Ha, G., Haffner, M. C., … Hsieh, A. C. (2026). tRNA dosage regulates lineage dependency and resistance in prostate cancer. Nature. https://doi.org/10.1038/s41586-026-11153-8

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11153-8

Keywords: prostate cancer, transfer RNA, lineage plasticity, androgen receptor, therapy resistance, neuroendocrine prostate cancer, translation, SMARCC2, TARDBP, ZSCAN29, RNA polymerase III, codon optimality

The prostate is not just a bag of secretory cells. It is a composite tissue in which a fibromuscular stroma, packed with collagen, elastic fibers, smooth muscle, blood vessels, nerves and immune cells, wraps around and actively regulates the glandular epithelium. When that stroma stiffens with excess collagen, a process called fibrosis, the epithelial cells above it can lose their normal growth controls, a shift implicated in benign prostatic hyperplasia and in the reactive stroma that surrounds prostate tumors. Prostate cancer remains one of the most common malignancies worldwide, with roughly 1.4 million new cases recorded in 2020, making any strategy that softens or reorganizes the stromal matrix of considerable clinical interest.

Mycophenolate mofetil was developed to block lymphocyte proliferation after transplantation. Once in the body it is hydrolyzed into mycophenolic acid, a potent, selective and reversible inhibitor of inosine monophosphate dehydrogenase, an enzyme essential to the de novo synthesis of guanosine nucleotides. Lymphocytes depend heavily on this pathway, which is why the drug works as an immunosuppressant. But fibroblasts rely on the same guanosine-dependent machinery to proliferate, migrate and adhere, and mycophenolic acid also downregulates cytoskeletal proteins such as vinculin, actin and tubulin while cutting collagen output and boosting matrix metalloproteinase expression. The result, the researchers reasoned, could be a pharmacologically induced softening of fibrotic tissue, and the rat prostate offered an ideal, hormone-sensitive testing ground.

The team, led by Luiz Roberto Falleiros Junior of São Paulo State University and collaborators at the Federal University of Goiás, UNICAMP and the Faculty of Medicine of São José do Rio Preto, gave adult male Wistar rats 30 milligrams per kilogram of the drug daily by gavage for either 7 or 30 days, with a saline-treated control group for comparison. They then subjected the ventral prostate to an unusually thorough battery of analyses: stereological point counting to quantify each tissue compartment, histochemical stains for collagen I, collagen III and elastic fibers, polarization microscopy to assess collagen aggregation, and immunohistochemistry for matrix metalloproteinases 2 and 13, the inhibitor TIMP-1, the androgen receptor, both estrogen receptors, proliferation and apoptosis markers, smooth muscle actin and macrophages. Mast cells were counted with toluidine blue, and lesions were graded using standard rodent prostate pathology criteria.

The first phase of remodeling emerged within a week. After just 7 days of treatment, the area occupied by collagen III, the thin reticular fibers that form a supportive network beneath the epithelium, had dropped significantly, and elastin fibers had diminished as well. This early matrix disassembly coincided with a marked rise in matrix metalloproteinase 2, an enzyme expressed in the non-muscular stroma that not only degrades basement membrane components but also activates other, more aggressive MMPs in the stromal cascade and participates in elastolysis. Because collagen III helps anchor and polarize epithelial cells, its loss had immediate consequences upstairs: epithelial cells showed reduced androgen receptor expression, less proliferation as measured by phosphohistone H3, and more apoptosis, revealed by activated caspase-3, in both the epithelium and the stroma.

The second phase unfolded over the following weeks. By 30 days, the drug had turned its attention to collagen I, the thick, highly birefringent fiber type that organizes stromal cells and orients the smooth muscle layer. Polarization microscopy showed reduced collagen aggregation, indicating a softer extracellular matrix, and this breakdown tracked with a surge in matrix metalloproteinase 13, or collagenase 3, detected in luminal epithelial cells and in the smooth muscle layer. At the same time the muscular stroma thinned, the non-muscular stroma expanded, and blood vessel density increased, a pattern consistent with matrix softening and with MMP-13’s known association with angiogenesis. Notably, TIMP-1, the natural brake on the metalloproteinases, showed no significant change at either time point, leaving the remodeling enzymes essentially unchecked.

The immune system turned out to be a scheduled participant rather than a bystander. Degranulated mast cells, which release their own matrix-degrading enzymes when they discharge their granules, rose early and remained elevated through 30 days, while intact mast cells plummeted. Macrophages, identified by the F4/80 marker, increased only at the later time point and formed clusters in the periglandular stroma of treated animals, alongside a rise in inflammatory foci. The authors interpret this sequence as successive waves of immune involvement: mast cells kick off extracellular matrix degradation, and macrophages arrive later to phagocytose the debris and clear the way for tissue reorganization. Inflammatory cells also stained positive for TIMP-1, hinting at a more complex regulatory dialogue than the simple enzyme-inhibitor balance alone.

Perhaps the most provocative finding concerns the androgen axis. Androgen receptor levels in the epithelium fell sharply at both time points, and the incidence of high-grade prostatic intraepithelial neoplasia, a precancerous lesion that depends on androgen signaling, dropped at 30 days, while simple hyperplasia increased. The authors propose a mechanistic explanation drawn from prior work: mycophenolic acid activates the aryl hydrocarbon receptor, which interferes with androgen receptor transcription, and it also impairs androgen receptor phosphorylation through the MAPK8/9 pathway, blocking the nuclear translocation the receptor needs to function. The researchers are careful to note that their two-endpoint design cannot establish causality, and that the rise in hyperplasia shows the drug did not restore normal glandular homeostasis but rather redirected the epithelium toward a proliferative pattern lacking pre-neoplastic features.

The study’s authors go further, proposing that the compartment-specific measurements they tracked, including the collagen I to III ratio, MMP2 and MMP13 immunolabeling, smooth muscle area and microvascular density, could serve as pharmacodynamic readouts of antifibrotic efficacy in future studies, much as circulating collagen turnover markers have been used to identify responders in other fibroproliferative diseases. They also raise, explicitly as an untested hypothesis, the possibility that antifibrotic interventions like mycophenolate mofetil could restrain androgen-dependent lesions in conditions such as benign prostatic hyperplasia. Validating that idea, they caution, would require established hyperplasia models, dose-response protocols, intermediate time points, paired tissue and serum measurements, long-term follow-up, and a careful weighing of the systemic immunosuppression the drug inevitably causes. Biometric data offered reassurance in the short term, with no differences in body or prostate weight between treated and control animals.

What makes the study resonate beyond urology is its demonstration that a stroma-targeted drug reached the epithelium through hormone signaling, placing fibrotic status and androgen responsiveness on connected axes of prostatic homeostasis. If the two remodeling windows the team identified hold up in larger and longer studies, clinicians may one day time antifibrotic therapy against measurable tissue benchmarks rather than trial and error, and the humble immunosuppressant in every transplant pharmacy may find a second career as a precision instrument for softening the scarred landscapes where prostate disease takes root.

Subject of Research: Antifibrotic effects of mycophenolate mofetil on stromal remodeling and collagen dynamics in the rat prostate

Article Title: Stromal Remodeling and Collagen Dynamics under Antifibrotic Conditions in the Rat Prostate

Article References: Falleiros Junior, L. R., Ruiz, T. F. R., Grigio, V., Bicalho-Silva, S., Colleta, S. J., de Souza, L. G., Ferrato, L. J., Vilamaior, P. S. L., da Silveira Antoniassi, T., Spessoto, L. C. F., Taboga, S. R., & Facio Junior, F. N. (2026). Stromal Remodeling and Collagen Dynamics under Antifibrotic Conditions in the Rat Prostate. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02221-5

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02221-5

Keywords: mycophenolate mofetil, prostate, fibrosis, collagen, matrix metalloproteinases, stroma, androgen receptor, mast cells, macrophages, extracellular matrix, rat model, antifibrotic therapy

The study, published on 27 July 2026 in the journal Energy & Environment Nexus by Mei Ma’s team at the Chinese Academy of Sciences, is notable for its unusually comprehensive scope. Rather than measuring a handful of known chemicals, the team assessed the total biological activity of wastewater samples using effect-based tools that capture the combined action of entire chemical mixtures. This matters because oxidation and photochemical reactions during advanced treatment can generate transformation products whose biological properties differ sharply from those of their parent compounds. Some of these byproducts may be cytotoxic, genotoxic, or endocrine-disrupting, yet routine chemical analysis—built to detect known target compounds—can miss their combined effects entirely.

The researchers worked at a typical wastewater treatment plant in Tianjin, China, supplemented by two pilot-scale treatment systems. Samples were collected from 11 locations spanning the full treatment train: the plant inlet, preliminary sedimentation, anaerobic-anoxic-oxic (A2O) biological treatment, secondary sedimentation, ultraviolet disinfection, ozonation, coagulation, and biological activated carbon filtration. Organic compounds were isolated from each sample using solid-phase extraction, concentrating the dissolved chemistry so that even trace activity could be measured.

The heart of the method lay in a panel of recombinant yeast assays. Each assay carried a human hormone receptor—estrogen receptor alpha, androgen receptor, or thyroid receptor beta—wired to a reporter system, allowing the team to quantify both receptor-agonistic effects, in which chemicals mimic a hormone, and receptor-antagonistic effects, in which chemicals block a hormone from acting. Bioactivity was expressed as equivalent concentrations of reference chemicals, giving the results a tangible toxicological meaning. Crucially, the team also derived an effect-based trigger value of 7.97 micrograms of flutamide equivalents per liter for androgen receptor-antagonistic activity, providing a benchmark against which treated effluents could be judged.

For estrogenic activity, the treatment train performed largely as intended. Estrogen receptor-agonistic activity was prominent in untreated and preliminarily treated wastewater but declined progressively through the plant, falling below the detection limit after secondary sedimentation. Estrogen receptor-antagonistic activity followed a similar trajectory, dropping from 58.4 micrograms per liter in the influent to roughly 7.8 to 9.2 micrograms per liter after treatment. These results confirm that conventional biological treatment, particularly the A2O process, removes most detectable estrogen-linked endocrine activity before water ever reaches the advanced polishing stages.

Thyroid-related activity told a similar, though slightly more complicated, story. Thyroid receptor-antagonistic activity fell dramatically from 0.56 milligrams per liter to 0.0085 milligrams per liter through the main plant. In the pilot systems, ozonation—and ozonation followed by biological activated carbon filtration—further suppressed this activity, demonstrating that oxidative processes can genuinely help control certain endocrine endpoints. Yet coagulation, a standard physicochemical step, produced a slight rebound in thyroid receptor antagonism. The researchers suggest this may occur because residual endocrine-disrupting chemicals compete with other organic matter during removal, escaping the coagulation process while bulk organic material is stripped away.

The most alarming findings concerned the androgen receptor. No androgen receptor-agonistic activity was detected anywhere in the treatment train—good news in itself—but antagonistic activity, which can interfere with male hormone signaling, was present throughout. The A2O biological process reduced it markedly, from 156.6 to 12.4 micrograms of flutamide equivalents per liter, a roughly twelvefold decrease that brought the effluent comfortably below the trigger value. What happened next undermined that progress. Both ultraviolet irradiation and ozonation increased anti-androgenic activity, pushing the treated effluents above the newly established threshold of 7.97 micrograms per liter. Even biological activated carbon filtration applied after ozonation did not fully reverse the increase.

The researchers propose a chemical explanation for this counterintuitive result. Advanced oxidation and UV-driven photochemistry rarely mineralize organic contaminants completely; instead, they transform parent compounds into partially degraded products through reactions such as hydroxylation, dealkylation, decarboxylation, and deamination. These transformation products may retain or acquire the ability to bind and block the androgen receptor, even as the original pollutants disappear from chemical inventories. In other words, a treatment plant can appear to be succeeding by every conventional metric—removing parent pollutants, reducing chemical oxygen demand, eliminating pathogens—while its effluent grows biologically more hazardous along a specific endocrine pathway.

The broader implication is that treatment performance cannot be judged solely by pollutant removal or by measuring a single biological endpoint. UV irradiation and ozonation remain valuable technologies for pathogen control and contaminant degradation, and the study does not argue for abandoning them. Instead, it calls for optimizing their operating conditions and downstream treatment configurations to prevent the formation or persistence of hazardous transformation products. It also argues for embedding multi-endpoint, effect-based monitoring into routine wastewater management, so that risks invisible to chemical analysis—such as mixture effects that simultaneously activate or inhibit different hormone receptors—can be detected before reclaimed water is discharged or reused.

As water reuse expands from arid regions into mainstream urban planning, the study offers a timely reminder that purification is not the same as safety. Effect-based trigger values like the one derived for anti-androgenic activity could become a template for regulators seeking to balance purification efficiency against ecological and human health protection. For now, the message for engineers and water utilities is clear: the cleanest-looking effluent is not necessarily the safest, and the next generation of wastewater reclamation systems must be designed with the full spectrum of hormone receptor activity in view.

Subject of Research: Endocrine-disrupting effects of transformation products formed during advanced wastewater treatment

Article Title: Advanced wastewater treatments may intensify hidden endocrine risks

Article References: Advanced wastewater treatments may intensify hidden endocrine risks. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: wastewater treatment, endocrine disruption, ozonation, ultraviolet irradiation, androgen receptor, estrogen receptor, thyroid receptor, water reclamation, transformation products, effect-based monitoring, A2O treatment, flutamide equivalents

The androgen receptor belongs to the family of nuclear hormone receptors that bind DNA only when their ligand is present. Once activated by dihydrotestosterone, the potent form of testosterone, the receptor docks onto thousands of genomic sites called androgen receptor binding sites and switches nearby genes on or off. Where the receptor lands is not random. In prostate cancer, a so-called pioneer factor called FOXA1 prises open the chromatin and guides the receptor to its targets. But whether the same rulebook applies in neurons was unknown. To find out, the team turned to SH-SY5Y cells, a human neuroblastoma-derived line widely used as a model of neuronal biology, and used chromatin immunoprecipitation sequencing, or ChIP-seq, to chart every place the androgen receptor bound across the genome.

The results were striking. In these neuronal cells, the genes nearest to androgen receptor binding sites were overwhelmingly involved in axonogenesis, forebrain development and synapse organization, and androgen treatment shifted the expression of genes tied to nervous system and synaptic function. When the researchers scanned the DNA sequences underneath the binding peaks for recognizable motifs, the strongest hit was not a familiar nuclear receptor pattern but the binding motif of the GATA family of transcription factors, with GATA3 standing out. GATA3 is a lineage-defining factor in the immune system and in neurons, and the team confirmed that it physically associates with the androgen receptor through co-immunoprecipitation and immunofluorescence. ChIP-seq showed that GATA3’s own binding signal was enriched precisely at the receptor’s peaks, a molecular handshake suggesting the two proteins operate as a collaborative complex.

The collaboration proved functionally essential. When the researchers knocked down GATA3 with siRNA, androgen-driven induction of neuronal genes collapsed, and the receptor’s own protein levels dropped as well, though overexpression of the receptor could partially rescue the loss. Reporter assays drove the point home: a luciferase construct carrying a neuronal androgen receptor binding enhancer from the HAND2 gene lost its androgen responsiveness when the GATA3 motif within it was mutated. Perhaps most tellingly, when SH-SY5Y cells were coaxed to differentiate with retinoic acid, androgen treatment and receptor overexpression both lengthened the cells’ neurites and boosted NeuN, a canonical neuronal marker, but silencing GATA3 blunted these effects. In other words, GATA3 is not a passive bystander; it helps maintain androgen receptor protein and enables the hormone to push cells toward a mature neuronal identity.

Digging deeper into the epigenetic landscape, the team found that androgen receptor binding sites in the neuronal cells overlapped heavily with super-enhancers, the dense clusters of acetylated histone H3K27 that mark the genes most critical to a cell’s identity. Among the receptor-regulated super-enhancer genes were NFIX and HAND2, transcription factors that govern inhibitory interneuron function and neurogenesis, as well as KLF7 and NEFL, both required for axonal growth. The picture that emerges is of the androgen receptor plugging into the very enhancer network that defines what a neuron is, amplifying the transcriptional programs that keep neurons wired and communicative.

The crucial question was whether this architecture holds in actual human brains, and what happens to it with age and disease. Using postmortem temporal lobe gray matter from the Brain Bank of the Tokyo Metropolitan Institute for Geriatrics and Gerontology, the researchers performed ChIP-seq for the androgen receptor in five elderly male donors: two controls with no or minimal Alzheimer’s pathology and three Alzheimer’s patients spanning moderate to advanced disease. In the control brains, thousands of reproducible receptor binding sites were detected, validated with two different antibodies targeting the receptor’s N-terminal and C-terminal domains. Motif analysis revealed that, alongside the receptor’s own motif, the peaks were enriched for binding sites of NRF1 and SP1, neuron-associated factors, as well as AP-1 family motifs, and ChIP-seq confirmed that NRF1, SP1, GATA3 and the AP-1 component Fra-1 all co-occupied the receptor’s binding regions in vivo.

Then came the disease-related twist. Public transcriptome datasets and the team’s own clinical samples showed that GATA3 and GATA4 expression declines with aging and is further reduced in Alzheimer’s brains, while Fra-1, an AP-1 family factor, rises with both age and disease. In the two most advanced Alzheimer’s samples, the number of detectable androgen receptor binding sites plummeted, and the sites that did appear were largely divergent, found in regions where binding was negligible in control brains. Motif analysis of these disease-specific peaks pointed instead to the STAT family of transcription factors, and indeed STAT3 and STAT5 proteins were elevated in Alzheimer’s tissue and interacted more strongly with the androgen receptor. Because inflammatory response genes, including STAT3, were the most significantly upregulated category in the Alzheimer’s samples, the authors propose that inflammation-driven transcription factors hijack or displace the receptor’s normal collaborative partners, diverting its binding landscape in advanced disease.

The consequences for neuronal genes were severe. RNA sequencing showed that genes bound by the androgen receptor, whether alone or together with GATA3 or Fra-1, were significantly enriched among the genes downregulated in Alzheimer’s brains. Among these were genes tied to mitochondrial ATP synthesis and the proteasome, pathways with well-established protective roles against Alzheimer’s pathology. In control brains, receptor binding was enriched at the promoters of such genes; in advanced disease, that enrichment largely vanished. Notably, receptor binding was preserved in the brains of aged men without Alzheimer’s, despite their naturally reduced androgen levels, which suggests that the collapse of androgen signaling in disease is driven less by hormone depletion than by the disintegration of the transcription factor network that anchors the receptor to chromatin.

To test causality, the team forced expression of Fra-1 in the SH-SY5Y neuronal model. The effect was dramatic: the receptor’s binding profile reshaped itself around the new factor, Fra-1’s motif replacing GATA3’s as the dominant feature at binding sites, and histone acetylation at key neuronal enhancers, exemplified by the NEFL and KLF7 loci, was suppressed. Cells overexpressing Fra-1 lost their neuron-like morphology and failed to induce NeuN, and neuron-specific genes near the remodeled binding sites were downregulated. Reporter assays indicated that Fra-1 represses enhancer activity through a mechanism that depends on intact GATA3 motifs, hinting that Fra-1 displaces GATA3 from shared genomic sites. The authors are careful to note the study’s limitations, including the small number of brain donors, the possibility that neuronal loss contributes to reduced binding signals, and the need for single-cell analyses to confirm which cell types drive the observed shifts. Even so, the model they propose is compelling: the integrity of the androgen receptor’s collaborative transcription factor network, rather than hormone levels alone, may determine how well androgen signaling protects the aging brain, and restoring or protecting factors like GATA3, or countering the inflammatory STAT and AP-1 drift, could open new therapeutic avenues for slowing Alzheimer’s progression.

Subject of Research: Dysregulation of neuronal androgen receptor transcription factor signaling in aging and Alzheimer's disease

Article Title: Dysregulation of neuronal androgen receptor signaling by divergent collaborative transcription factors in Alzheimer’s disease

Article References: Takayama, K., Suzuki, Y., Saito, Y., Suzuki, T., Tsutsumi, S., Aburatani, H., & Inoue, S. (2026). Dysregulation of neuronal androgen receptor signaling by divergent collaborative transcription factors in Alzheimer’s disease. iScience, 29(10), Article 117731. https://doi.org/10.1016/j.isci.2026.117731

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117731

Keywords: androgen receptor, Alzheimer's disease, GATA3, transcription factors, super-enhancers, ChIP-seq, Fra-1, STAT3, neurons, aging brain, epigenetics, testosterone

Researchers at Fudan University Shanghai Cancer Center, writing in the journal Holistic Integrative Oncology, have assembled a comprehensive transcriptional landscape of prostate cancer progression by re-analyzing single-cell RNA sequencing data from 44 patient samples drawn from three prospective clinical trials. Their meta-cohort captured three clinically distinct stages of the disease: 13 samples of localized, treatment-naïve prostate cancer; 25 samples of hormone-sensitive prostate cancer obtained while patients were actively undergoing androgen deprivation therapy; and 6 samples of metastatic castration-resistant prostate cancer, collected from metastatic lesions in the prostate, lymph nodes, bladder, bone, and liver. The hormone-sensitive samples were particularly valuable, having been obtained 13 to 15 weeks after the initiation of a standardized ADT regimen, offering a snapshot of tumor cells in the act of adapting to therapeutic pressure rather than merely before or after it.

The technical challenge at the heart of the study was to reliably distinguish malignant epithelial cells from the benign cells that surround them within each tumor. The team applied a battery of quality-control filters, excluding cells with more than 25 percent mitochondrial gene expression, cells with fewer than 500 detected genes, and potential doublets exhibiting co-expression of incompatible lineage markers. Epithelial cells were identified by high expression of canonical markers such as EPCAM and KRT18, together with the absence of immune or stromal markers. The researchers then turned to inferCNVpy, a computational tool that infers single-cell copy number variation profiles by comparing each epithelial cell against a reference baseline built from 800 immune cells and 800 stromal cells. Clusters showing large-scale copy number aberrations consistent with genomic instability were classified as malignant, while those lacking such patterns were deemed normal. After these stringent steps, the final analytical dataset comprised 35,365 malignant tumor cells from 39 samples: 13 treatment-naïve, 22 hormone-sensitive, and 4 castration-resistant.

The first major finding concerns what happens inside tumor cells during the early months of ADT. Comparing malignant cells from hormone-sensitive samples with those from localized, untreated tumors, the researchers documented extensive transcriptional remodeling. Canonical androgen-responsive genes, including KLK3, the gene encoding the widely used clinical biomarker prostate-specific antigen, were significantly downregulated, confirming that the therapy was doing precisely what it was designed to do: suppressing androgen receptor signaling. Gene set enrichment analysis showed that the hallmark androgen response pathway was markedly suppressed in tumor cells under ADT, consistent with the known pharmacological effects of the treatment.

But the suppression of androgen signaling was only part of the story. In a finding with potentially far-reaching clinical implications, the team observed that ADT induced the activation of immune-associated transcriptional programs within the malignant cells themselves. Hallmark interferon-alpha and interferon-gamma response pathways were significantly enriched, alongside pathways involved in antigen processing and presentation. Over-representation analysis of the most upregulated genes in hormone-sensitive tumor cells further highlighted biological processes related to leukocyte differentiation, humoral immune response, and inflammatory signaling. In parallel, apoptosis-related pathways were significantly enriched, reflecting therapy-induced cellular stress and diminished survival signaling. Crucially, these immune programs were detected within the tumor cells themselves, independent of immune cell infiltration, indicating a direct transcriptional response of malignant cells to androgen deprivation rather than a secondary effect of a changing tumor microenvironment.

This observation aligns with a growing body of evidence suggesting that hormonal therapy can transiently enhance tumor immunogenicity. Prior work has shown that androgen receptor inhibition can increase the expression of major histocompatibility complex class I molecules on prostate cancer cells, potentially making them more visible to the immune system. The new single-cell data provide tumor-cell-intrinsic molecular support for this idea and carry an important practical implication: the timing of combination strategies that pair ADT with immune checkpoint inhibitors may matter enormously. If androgen deprivation opens a transient window of heightened immune visibility in tumor cells, then delivering immunotherapy during that window, rather than after resistance has fully established itself, could maximize therapeutic benefit. Clinical trials are already exploring this logic in metastatic castration-sensitive disease, and the new findings add molecular granularity to the rationale.

The second major finding shifts the focus to the endgame of the disease. When the researchers compared malignant cells from metastatic castration-resistant samples with those from localized, treatment-naïve tumors, they uncovered a strikingly different transcriptional profile, one dominated by genes involved in protein synthesis, mitochondrial function, and oncogenic signaling. Among the most prominently upregulated genes were ribosomal proteins such as RPL41 and RPSA, mitochondrial-encoded genes including MT-ND1 and MT-ND3, and FOLH1, the gene that encodes prostate-specific membrane antigen, or PSMA, a clinically important diagnostic and therapeutic target in advanced prostate cancer. These changes collectively point to an enhanced biosynthetic and metabolic capacity in castration-resistant tumor cells, a cellular state geared toward rapid growth under hostile conditions.

Pathway-level analysis crystallized this picture around a single dominant theme: MYC. Gene set enrichment analysis identified significant enrichment of MYC target gene sets in castration-resistant tumor cells, while androgen response pathways remained significantly downregulated relative to treatment-naïve samples. Over-representation analysis supported the same conclusion through an independent statistical route. To guard against the possibility that the finding was an artifact of their particular cohort, the researchers validated it in an independent dataset, GSE264573, and again found higher hallmark MYC pathway scores in tumor cells from castration-resistant samples compared with castration-sensitive ones. Together, these converging lines of evidence position MYC-driven transcriptional programs as a central feature of tumor cell adaptation in castration-resistant disease.

The emphasis on MYC is biologically coherent with prior mechanistic studies. In localized prostate cancer, MYC has been reported to cooperate with RAS signaling to promote bone metastasis and castration resistance, and a MYC/RAS co-activation signature has demonstrated predictive value across clinical cohorts. In neuroendocrine prostate cancer, an aggressive variant marked by loss of androgen receptor signaling, MYC activation has been associated with neuroendocrine differentiation, and alisertib, an Aurora-A kinase inhibitor that disrupts N-MYC stabilization, has shown clinical activity in a subset of neuroendocrine prostate cancer patients. Still, the authors are careful to note the limits of translation. MYC is not yet an established clinical biomarker in prostate cancer, its activity is not reliably captured by any single genomic alteration, and further studies are required to validate it as a robust prognostic and predictive tool. Moreover, other pathways, including PI3K/AKT signaling, may also contribute to castration resistance even if they were not prominently enriched in this dataset, reflecting the biological heterogeneity of metastatic disease, in which different tumors may rely on different dominant escape routes. The MYC-associated program identified here likely represents one major transcriptional state within a subset of patients rather than a universal mechanism.

The study also carries a molecular rationale for PSMA-targeted medicine. The significantly higher expression of FOLH1 in castration-resistant tumor cells provides single-cell-level support for the clinical efficacy of PSMA-directed therapies, most notably lutetium-177 PSMA-617 radioligand therapy, which has transformed the management of metastatic castration-resistant disease. The authors acknowledge the limitations inherent in their design: the number of castration-resistant samples was small, a constraint that reflects the genuine difficulty of obtaining metastatic specimens suitable for single-cell analysis, and functional validation will be needed to establish causal relationships between the observed transcriptional states and resistance. The analysis also did not systematically link tumor-cell changes to immune infiltration, clonal expansion, or T-cell receptor dynamics, information not available in the underlying dataset. Even so, by defining a transcriptional roadmap that spans from treatment-naïve disease through early hormonal therapy to full castration resistance, the study highlights two actionable features of tumor cell adaptation: a transient immune activation during ADT that could be exploited with timed immunotherapy combinations, and MYC-driven programs in resistant disease that may point toward new biomarker and drug development strategies aimed at delaying or preventing the emergence of lethal, treatment-resistant prostate cancer.

Subject of Research: Single-cell transcriptomic evolution of prostate cancer cells during androgen deprivation therapy and progression to castration resistance

Article Title: Single-cell analysis reveals tumor cell evolution from ADT-naïve to castration-resistant prostate cancer

Article References: Wei, Y., Wu, J., Wang, B., Gu, W., Qin, X., Dai, B., Lin, G., Gan, H., Wan, F., Zhu, Y., & Ye, D. (2026). Single-cell analysis reveals tumor cell evolution from ADT-naïve to castration-resistant prostate cancer. Holistic Integrative Oncology, 5(1), Article 39. https://doi.org/10.1007/s44178-026-00261-0

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00261-0

Keywords: prostate cancer, single-cell RNA sequencing, androgen deprivation therapy, castration resistance, MYC signaling, PSMA, FOLH1, interferon response, tumor evolution, immunotherapy timing, androgen receptor, metastatic cancer

Spinal and bulbar muscular atrophy, or SBMA, is an X-linked hereditary condition that affects only males, typically manifesting between the third and fifth decades of life. It arises from an expansion of CAG trinucleotide repeats in the first exon of the androgen receptor gene. While healthy individuals carry between 9 and 36 repeats, patients carry more than 37, with up to 72 repeats reported. This expansion is translated into an abnormally long polyglutamine tract in the receptor protein, placing SBMA among the CAG/polyglutamine family of neurodegenerative diseases. The global prevalence is estimated at roughly 2.58 per 100,000 males, but the true figure is likely far higher, since population studies suggest a four-fold prevalence of carriers of pathological CAG repeats, many of whom never develop symptoms.

The disease mechanism is intimately tied to male hormones. In the absence of testosterone, the androgen receptor is held in the cytoplasm by chaperone proteins such as HSP90, HSP40 and HSP70, which keep the ligand-binding pocket in a high-affinity conformation. When testosterone or its metabolite dihydrotestosterone binds, the receptor dissociates from its chaperones, dimerizes, exposes its nuclear localization signal and moves into the nucleus to regulate transcription. In the mutant receptor, the elongated polyglutamine tract disrupts these processes, promoting misfolding and aggregation in both neuronal and muscle tissues. This toxic gain of function depletes the cell’s protein quality control machinery and alters transcription, ultimately driving the loss of lower motor neurons in the brainstem and spinal cord and the progressive wasting of skeletal muscle.

Crucially, the androgen receptor gene does not produce just one protein. Alternative use of start codons generates multiple isoforms. The canonical full-length receptor, AR-B, is translated from the first AUG codon and contains the polyglutamine tract within its N-terminal domain. A second AUG codon, located downstream of the CAG repeat, drives production of AR-A, an 87-kilodalton isoform that lacks the first 188 amino acids of the N-terminal domain, including the entire polyglutamine tract. First described in 1994 in human genital skin fibroblasts, AR-A has remained poorly characterized, largely because available antibodies cannot easily distinguish the two isoforms. In androgen-responsive tissues, AR-B predominates at a ratio of roughly 10:1, with AR-A generally accounting for less than 20 percent of total receptor.

The research team, led by investigators at the University of Milan together with collaborators in Italy, France and the United States, set out to map where AR-A is expressed and to determine whether it behaves like its toxic mutant counterpart. Using western blot analysis of tissues from wild-type mice at one, three and six months of age, they found that AR-B is abundant in the testis, prostate, skeletal muscle, heart, brainstem and spinal cord, whereas AR-A was detectable only in the spinal cord and brainstem. In these neural tissues, the AR-A to AR-B ratio was notably elevated. Extending the analysis to a knock-in mouse model carrying 113 glutamine repeats in the androgen receptor, the researchers observed a statistically significant increase in the AR-A to AR-B ratio in the spinal cord and brainstem of the diseased animals, hinting that the shorter isoform may be part of an endogenous response to the pathology.

The team then compared the biochemical behavior of AR-A, AR-B and the mutant polyglutamine-expanded receptor in NSC-34 motor neuron-like cells. Under basal conditions, all three isoforms showed diffuse cytoplasmic localization, indicating that the missing 188 amino acids do not disrupt the receptor’s native conformation or its interaction with chaperones. Upon treatment with dihydrotestosterone, AR-B translocated completely into the nucleus, while the mutant receptor formed large aggregates and only partially entered the nucleus. Strikingly, AR-A translocated fully into the nucleus and formed no aggregates whatsoever, confirming that the absence of the polyglutamine tract is both necessary and sufficient for normal behavior. In transcriptional assays using a luciferase reporter driven by androgen response elements, AR-A activated gene expression at levels comparable to the mutant receptor, roughly 60 to 70 percent of full-length AR-B activity, likely reflecting the partial loss of the N-terminal AF-1 activation domain.

Filter retardation assays revealed that while the mutant receptor accumulated abundant high-molecular-weight oligomeric species upon androgen treatment, AR-A formed very few such species under any condition. The researchers also dissected the degradative pathways acting on AR-A: the inactive monomeric form was cleared primarily by the proteasome, whereas the activated dimeric form was preferentially degraded by autophagy, mirroring the pattern previously established for the full-length receptor. Phosphorylation analysis added another layer of complexity. AR-A was phosphorylated at serine 25, the counterpart of serine 215 in AR-B, more than 15-fold in response to androgen, compared with a 3.3-fold increase at the corresponding site in AR-B. This heightened phosphorylation, possibly due to greater accessibility of the exposed N-terminus to the kinase Akt, appears to modulate AR-A function, since the coactivator PRMT6 failed to enhance AR-A transcriptional activity but strongly boosted a phosphorylation-defective S25A mutant.

The most striking findings emerged when the two isoforms were co-expressed. Because AR-A can heterodimerize with the mutant receptor, the researchers tested different ratios of the two proteins. Co-expression of AR-A reduced the formation of insoluble mutant receptor aggregates across micro-aggregates, macro-oligomeric species and detergent-insoluble mature forms, as quantified by filter retardation assays and a flow cytometric technique called FloIT. Fluorescence microscopy showed that cells co-expressing both isoforms had a 90 percent reduction in the average number of aggregates per cell, dropping from about 179 to fewer than 24, and a 35 percent reduction in the proportion of aggregate-bearing cells. Photobleaching experiments revealed that the remaining aggregates were far more dynamic: fluorescence recovery rose from 34 percent to 49 percent, with a 15 percent increase in the mobile fraction. This suggests that AR-A keeps mutant receptor assemblies in a liquid-like condensate state, preventing their maturation into rigid insoluble inclusions and facilitating clearance by the cell’s degradative systems. Importantly, AR-A exerted no dominant-negative effect on transcription, and heterodimers retained roughly the same activity as mutant homodimers.

Finally, the team validated these results in vivo using a fruit fly model of SBMA in which expression of the mutant receptor in the eye causes progressive degeneration. Flies expressing AR-A alone showed no eye degeneration, confirming the isoform’s inherent harmlessness. When AR-A was co-expressed with the mutant receptor, neurodegeneration was reduced by 50 percent, and filter retardation assays of fly eye tissue confirmed a significant reduction in high-molecular-weight aggregates. The authors propose that strategies to redirect translation from the first AUG codon to the second, or to deliver AR-A directly through viral vectors, antisense oligonucleotides or small molecules, could boost the isoform’s protective presence in affected cells without suppressing androgen signaling. Such an approach would avoid the endocrine, cardiovascular, metabolic and behavioral side effects that plague current androgen-deprivation strategies, including leuprorelin, bicalutamide and antisense-based receptor knockdown. The researchers caution that their findings rest on cellular and fly models, and that validation in human induced pluripotent stem cell-derived motor neurons and muscle cells, followed by mammalian in vivo studies, will be essential before AR-A induction can advance toward the clinic. They also note that modulating full-length receptor transcription through AR-A may hold relevance beyond SBMA, potentially informing therapeutic design in androgen-responsive cancers such as prostate cancer.

Subject of Research: The protective role of the alternative androgen receptor isoform AR-A in spinal and bulbar muscular atrophy

Article Title: The alternative androgen receptor isoform A mitigates toxicity of polyglutamine-elongated mutant androgen receptor in spinal and bulbar muscular atrophy

Article References: Chierichetti, M., Andreotti, R., Tedesco, B., Ferrari, V., Cornaggia, L., Pramaggiore, P., Cozzi, M., Mohamed, A., Magdalena, R., Piccolella, M., Boarolo, G., Crippa, V., Rusmini, P., Galbiati, M., Rinaldi, C., Anderson, E. N., Pandey, U. B., Pennuto, M., Cristofani, R., & Poletti, A. (2026). The alternative androgen receptor isoform A mitigates toxicity of polyglutamine-elongated mutant androgen receptor in spinal and bulbar muscular atrophy. Journal of Advanced Research, 88, 959-976. https://doi.org/10.1016/j.jare.2026.01.051

Image Credits: AI Generated

DOI: Not provided

Keywords: spinal and bulbar muscular atrophy, Kennedy's disease, androgen receptor, AR-A isoform, polyglutamine, protein aggregation, motor neurons, neurodegeneration, autophagy, proteasome, gene therapy, Drosophila model

The concept underlying the study is intracrinology, the science of hormone conversion occurring within individual cells rather than through circulating endocrine signals. Many steroid hormones reach tissues in inactive precursor forms and are activated locally by specific enzymes. For years this process has been exploited therapeutically in prostate cancer, where blocking intratumoral androgen synthesis is a mainstay of treatment. Whether ovarian tumors similarly produce bioactive androgens in their own microenvironment, and particularly whether they can generate the potent 11-oxygenated androgens derived from adrenal steroid precursors, has remained largely unexplored.

To address this gap, the team first interrogated two independent public HGSOC cohorts, examining how the expression of key androgen-metabolizing enzymes and the androgen receptor (AR) correlated with tumor site, chemotherapy response, and patient survival. The analysis revealed striking differences between primary and metastatic tumors and between chemo-sensitive and chemo-resistant disease. Critically, the expression patterns carried prognostic weight: higher intratumoral levels of HSD11B2, HSD17B2, and AR were associated with improved survival, whereas elevated expression of PAPSS1 and PAPSS2, enzymes that supply the activated sulfate donor used in steroid sulfonation, together with HSD17B4, predicted poorer outcomes. These findings position the local steroid-processing machinery as a genuine clinical axis rather than a biochemical curiosity.

The researchers then moved into controlled laboratory experiments, examining six HGSOC cell lines and one normal ovarian epithelial cell line. Using quantitative gene expression measurements alongside direct steroid metabolism assays, they incubated the cells with classic androgen precursors such as androstenedione and dehydroepiandrosterone, as well as with 11-oxyandrogen precursors including 11β-hydroxy-androstenedione and 11-keto-androstenedione, and tracked what products emerged by liquid chromatography-tandem mass spectrometry.

The results revealed a sharp asymmetry. Classic androgen precursors underwent only limited conversion to bioactive androgens in the HGSOC cells, and, importantly, the cells could not generate 11-oxyandrogens on their own. In contrast, when supplied with 11-oxyandrogen precursors, chemo-sensitive HGSOC cell lines efficiently converted them into 11-keto-testosterone, a potent agonist of the androgen receptor. Chemo-resistant cell lines and the normal ovarian epithelial control line lacked this capability. The implication is provocative: tumors that can complete this final metabolic step may effectively hijack abundant adrenal steroids, which circulate at concentrations far exceeding those of testosterone, and turn them into a locally active androgenic fuel source.

To understand what such androgen exposure actually does to the cancer cells, the team turned to untargeted transcriptomic and metabolomic profiling in the AR-positive OVSAHO cell line, exposing it to potent classic androgens and to their 11-oxygenated counterparts. The transcriptional response was dominated by stress-adaptive and proliferative programs. In other words, rather than simply accelerating division, the steroids appeared to push the cells toward a protective, resource-mobilizing state that could help them survive hostile conditions such as chemotherapy.

The metabolomic data added a layer of mechanistic detail. Exposure to 11-keto-dihydrotestosterone, the most potent 11-oxyandrogen, triggered widespread metabolic reprogramming, including measurable depletion of amino acids, glutathione, and nucleotide sugar metabolites. Glutathione is the cell’s principal antioxidant defense, so its consumption suggests an oxidatively taxed state, while the drain on nucleotide sugars hints at disruption of glycosylation and energy metabolism. Paradoxically, these demanding shifts were associated with a trend toward reduced cell proliferation, indicating that potent androgen signaling imposes costs on tumor cells even as it activates adaptive programs.

That tension between adaptation and vulnerability is where the therapeutic opportunity lies. If androgen-driven metabolic reprogramming depletes antioxidant reserves and alters nucleotide pools, then tumor cells caught in that state may be primed to respond to agents that push oxidative stress or DNA damage further, including platinum chemotherapy, poly(ADP-ribose) polymerase inhibitors, or other molecularly targeted drugs. The study’s authors frame these steroid-induced cellular vulnerabilities as potentially synergistic with existing HGSOC treatments, and the prognostic signatures they identified, particularly the opposing effects of HSD11B2, HSD17B2, and AR versus PAPSS1/2 and HSD17B4, could help identify which patients carry tumors with active androgen circuits worth targeting.

The study also highlights a technical achievement worth noting. Combining classical molecular biology with untargeted metabolomics based on nuclear magnetic resonance and mass spectrometry allowed the Slovenian team to follow steroids and their downstream metabolic consequences in the same experimental system, rather than inferring signaling from gene expression alone. This integrated view matters because intratumoral steroid metabolism is a moving target: the abundance of an enzyme tells you only part of the story, and the actual flux of substrate to product, visible only through direct measurement, determines whether a pathway is clinically relevant.

For patients, the immediate significance is caution tempered by hope. No new treatment emerges from this study directly, and the cell line findings will need validation in larger clinical cohorts and model systems before they change practice. But the work reframes HGSOC as more than a disease of genomic instability and estrogen signaling. It suggests that some ovarian tumors are active endocrine organs in miniature, capable of importing adrenal androgen precursors and converting them into potent receptor ligands, and that this capacity marks a clinically meaningful axis tied to chemotherapy sensitivity and survival. As researchers begin testing whether blocking the enzymes that generate 11-keto-testosterone, or exploiting the metabolic weaknesses it creates, can improve outcomes, the humble steroid molecule may take its place alongside PARP inhibition and immunotherapy in the evolving treatment landscape of ovarian cancer.

Subject of Research: Intratumoral androgen and 11-oxyandrogen metabolism and androgen receptor signaling in high-grade serous ovarian cancer

Article Title: Local androgen and 11-oxyandrogen metabolism and signaling emerges as a novel prognostic and therapeutic axis in high-grade serous ovarian cancer

Article References: Gjorgoska, M., Pečnik, K., Marolt, N., Plavec, J., & Rižner, T. L. (2026). Local androgen and 11-oxyandrogen metabolism and signaling emerges as a novel prognostic and therapeutic axis in high-grade serous ovarian cancer. Cancer Cell International. https://doi.org/10.1186/s12935-026-04453-6

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04453-6

Keywords: high-grade serous ovarian cancer, androgens, 11-oxyandrogens, 11-keto-testosterone, androgen receptor, intracrinology, steroid metabolism, chemotherapy resistance, metabolomics, transcriptomics, biomarkers, drug targets