The team built Grubraw as a tool for testing what happens when oxidative metabolism is activated inside cancer cells despite this preference for glycolysis. The enzyme acts at the point where the study’s authors say pyruvate influx is limited, producing pyruvate within the mitochondrial compartment rather than relying on pyruvate transported from outside the cell. In HeLa Kyoto cells, this activity activated oxidative phosphorylation. It also increased the export of extracellular pyruvate, indicating that surplus mitochondrial pyruvate was not simply retained for fuel but was being disposed of through the cell membrane. The study further showed that Grubraw altered major metabolic fluxes in cells supplied with labeled glucose, providing a way to trace how carbon moved through glycolytic, mitochondrial and extracellular pathways.

Grubraw’s effects were not confined to one experimental cell line. The researchers found that its activity modulated metabolism across a series of cancer cell lines, although the supplied article abstract does not specify the full set of lines tested or the magnitude of each response. The broader cellular result was that activating mitochondria increased oxidative metabolism in cancer cells displaying Warburg metabolism. At the same time, Grubraw caused cancer cells to export excess mitochondrial pyruvate, revealing an unexpected route by which the cells controlled carbon flux. Rather than using all of the additional pyruvate to expand mitochondrial energy production, they routed it out of the cell.

Molecular analysis also found that mitochondrial activation through Grubraw suppressed transcription of genes involved in cell-cycle progression, cell proliferation and DNA replication. These gene-expression changes accompanied slower growth in vivo: human melanoma xenografts grew more slowly when the cancer cells’ mitochondria were activated with the chemogenetic system. The experiment therefore connected three measured observations—altered mitochondrial metabolism, reduced expression of growth-related genes and slower xenograft growth—but the abstract does not establish which of these changes was solely responsible for the tumor effect. Nor does the reported work demonstrate that Grubraw is a usable cancer treatment. The evidence comes from engineered cancer cells and mouse xenografts, and the published summary does not describe testing in people, long-term safety, delivery methods or treatment outcomes in human patients.

Subject of Research: Chemogenetic activation of mitochondrial metabolism in cancer cells and melanoma xenografts

Article Title: Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells

Article References: Bass, D. Y., Potekhina, E. S., Ivanenko, A. V., Moshchenko, A. A., Korzhenevskiy, D. A., Nesterenko, A. M., Shevchenko, E. K., Karnaeva, A. E., Zakirova, N. F., Ivanov, A. V., Shimolina, L. E., Shirmanova, M. V., Lyang, O. V., Patsap, O. I., Kudryashova, O. M., Gazizova, G. R., Shagimardanova, E. I., Mariasina, S. S., Ivlev, V. A., … Belousov, V. V. (2026). Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells. Nature Chemical Biology. https://doi.org/10.1038/s41589-026-02350-7

Image Credits: AI Generated

DOI: 10.1038/s41589-026-02350-7

Keywords: chemogenetics, mitochondria, Warburg effect, cancer metabolism, pyruvate, oxidative phosphorylation, melanoma, xenografts, glycolysis, Grubraw, Chemogenetic, activation

The review, led by Professor Kefei Yuan of West China Hospital, Sichuan University, and colleagues, was published online in the Chinese Medical Journal on July 30, 2026. It systematically assembles the latest research on how epigenetic regulation and metabolic reprogramming interact in HCC, organizing a sprawling literature into a coherent framework. “A thorough understanding of how epigenetic modifications and metabolic reprogramming interact in HCC is critical for elucidating the mechanisms underlying hepatocarcinogenesis and developing new treatment approaches against HCC,” explains Prof. Yuan, the corresponding author of the review. “In this article, we systematically introduce the molecular basis of each epigenetic modification, then summarize the latest research progress on epigenetic regulation of metabolism in HCC, trying to link these two frontier fields.”

The central insight of the review is that the relationship between metabolism and epigenetics is bidirectional. Metabolic pathways generate small molecules that serve as substrates or cofactors for epigenetic enzymes. Acetyl-CoA, produced from glucose and lipid metabolism, fuels histone acetylation. S-adenosylmethionine (SAM), a product of one-carbon amino acid metabolism, supplies the methyl groups that decorate DNA and histones. Lactate, the end product of the Warburg effect—the phenomenon in which cancer cells preferentially ferment glucose even in the presence of oxygen—has emerged as a signaling molecule in its own right, driving a newly recognized histone modification called lactylation. In this way, the metabolic state of a cell is written directly into its chromatin, the packaged form of DNA that determines which genes are accessible for transcription.

The reverse direction is equally consequential. Epigenetic modifications alter the expression of metabolic enzymes, reinforcing and amplifying the metabolic phenotype of the tumor. Aberrant methylation of promoters controlling metabolic genes can silence or activate entire pathways, shifting cells toward enhanced glycolysis, increased fatty acid synthesis, or reprogrammed amino acid handling. This feedback loop—metabolites shaping epigenetic marks, epigenetic marks shaping metabolic enzymes—creates a self-reinforcing circuit that locks HCC cells into their malignant state and contributes to the construction of a tumor-promoting microenvironment. The review organizes this crosstalk around five major types of epigenetic modification, each with distinct connections to metabolism.

The first is DNA methylation, which shows bidirectional crosstalk with multiple metabolic pathways. On one side, aberrant methylation of metabolic gene promoters drives changes in glycolysis, lipid synthesis, and amino acid metabolism, effectively rewriting the tumor’s metabolic instruction manual. On the other side, metabolic intermediates such as SAM, derived from one-carbon metabolism, provide the raw material for DNA methylation itself, closing the loop. This means that nutritional state, enzyme availability, and flux through one-carbon metabolism can all influence which genes are silenced or expressed, and those expression changes in turn reshape metabolism further.

The second is RNA methylation, particularly N6-methyladenosine (m6A), the most abundant internal modification of messenger RNA in mammalian cells. The review describes how m6A fine-tunes the expression of metabolic enzymes through a cast of regulatory proteins: “writers” such as METTL3 that install the mark, “erasers” such as FTO that remove it, and “readers” such as YTHDFs and IGF2BPs that interpret it and determine the fate of the modified transcript. This dynamic system controls key metabolic processes in HCC, including glycolysis, lipid synthesis, and amino acid metabolism, allowing tumor cells to adjust enzyme production rapidly in response to shifting conditions without altering the underlying DNA sequence.

The third category is non-coding RNAs, which form a multi-layered regulatory network. MicroRNAs directly target the messenger RNAs of metabolic enzymes, dampening or eliminating their translation. Circular RNAs act as sponges that sequester microRNAs, relieving their inhibitory effects, and some can even encode functional peptides. Long non-coding RNAs operate through yet other mechanisms: they interact with proteins, remodel chromatin, or stabilize metabolic enzymes, thereby influencing metabolic pathways at multiple levels simultaneously. The sheer diversity of these RNA species means that a single metabolic pathway in HCC may be regulated by dozens of non-coding RNAs acting in concert, creating redundancy that can frustrate single-target therapies but also offering multiple points of intervention.

The fourth is histone modification, the family of chemical tags on chromatin proteins that includes methylation, acetylation, lactylation, phosphorylation, and ubiquitination. These modifications integrate metabolic signals directly into transcriptional programs. Histone acetylation depends on acetyl-CoA derived from glucose and lipid metabolism, meaning that a cell burning sugar at high rates is chemically primed to open up its genes. Histone methylation depends on SAM from amino acid metabolism, linking nitrogen and one-carbon metabolism to gene expression. Perhaps most striking is lactylation, an emerging modification in which lactate—the very molecule produced by the Warburg effect—is attached to histones, directly coupling glycolytic flux to gene regulation. The review also flags RNA editing as a fifth mechanism, predominantly adenosine-to-inosine (A-to-I) editing mediated by the enzyme ADAR1, which contributes to metabolic reprogramming by altering key genes involved in polyamine metabolism and oxidative stress responses.

What elevates this review beyond a descriptive catalog is its therapeutic framing. The epigenetic-metabolism axis, the authors argue, represents a promising target for drug development. Preclinical studies have shown that targeting DNA methyltransferases, histone modifiers, or non-coding RNAs can reverse metabolic reprogramming and suppress tumor growth. Inhibitors of DNMT1, a DNA methyltransferase, and of histone methyltransferases have demonstrated anti-tumor effects in HCC models. Meanwhile, nanoparticle-mediated delivery of small interfering RNAs targeting metabolic enzymes has shown efficacy in reducing tumor burden in preclinical settings. “Given that epigenetic mechanisms drive metabolic reprogramming essential for HCC survival and drug resistance, targeting this axis theoretically could overcome chemoresistance,” notes Prof. Yuan. “However, promising preclinical candidates have not yet advanced to clinical trials, underscoring the need for further interdisciplinary research.”

The authors are candid about the gaps that remain. The specific effects of metabolites such as cholesterol, ethanol, and alpha-ketoglutarate on DNA methylation require further exploration, a question with direct relevance given that alcohol exposure and lipid dysregulation are major risk factors for liver disease. The relationship between histone modifications and amino acid metabolism remains unclear, as does the role of ketone body metabolism in histone acetylation and the involvement of histone demethylases in metabolic reprogramming. These unresolved questions define the research agenda for the field. What is already clear, however, is that the epigenetic-metabolic crosstalk in HCC is not a side effect of cancer but a central organizing principle of it—a bidirectional network in which every metabolic choice a tumor cell makes is recorded in its chromatin, and every epigenetic mark reshapes its metabolism. Untangling that loop, the review suggests, may be the key to therapies that do not merely attack liver cancer cells but dismantle the regulatory logic that sustains them.

Subject of Research: The bidirectional crosstalk between epigenetic regulation and metabolic reprogramming in hepatocellular carcinoma

Article Title: New review in Chinese Medical Journal illuminates the crosstalk between epigenetics and metabolism in hepatocellular carcinoma

Article References: New review in Chinese Medical Journal illuminates the crosstalk between epigenetics and metabolism in hepatocellular carcinoma. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: hepatocellular carcinoma, epigenetics, metabolic reprogramming, DNA methylation, RNA methylation, m6A, non-coding RNAs, histone modification, lactylation, Warburg effect, cancer metabolism, Chinese Medical Journal

The team focused on a subtlety of gene architecture that is often overlooked. Most human protein-coding genes do not have a single transcription start site, or TSS, but several: the analysis uncovered 57,461 start sites mapped to 16,302 genes, meaning roughly three options per gene, with more than three-quarters of genes carrying at least two. Because these alternative start sites usually sit upstream of the same start codon, switching between them typically leaves the final protein untouched. Yet every nucleotide transcribed between the start site and the codon costs the cell phosphate bonds, so the choice of where RNA polymerase fires is, in energy terms, anything but free.

The researchers call the region between a transcription start site and the start codon a measure of futile transcription distance. When a cell uses a start site very close to the codon, the wasted stretch is short. When it fires from a far-flung upstream site, it transcribes thousands of extra bases — including introns — that code for nothing. Strikingly, the data showed that the human genome has evolved to keep most start sites tightly clustered: about 60 percent of all mapped TSSs lie within one kilobase of their start codon, and successive start sites within a gene showed strong constraints on how much farther apart they could drift. The authors interpret this clustering as the footprint of evolutionary pressure to minimize pointless transcription.

To test whether cancer disrupts this design, the team mined cap analysis of gene expression (CAGE) data from the FANTOM5 project, comparing 476 cancer samples with 1,255 non-cancer samples, and then validated the results using an independent technique called PRO-cap on 110 cancer and 305 non-cancer samples. CAGE and PRO-cap both capture the capped 5′ ends of freshly initiated RNA molecules, providing a direct readout of how often each start site is deployed. By combining these deployment frequencies with the distances to each gene’s start codon, the researchers computed an energy cost coefficient for every gene and, ultimately, for entire transcriptomes.

The result was unambiguous: the aggregated energy cost of the cancer promoterome was roughly 10 to the power of 0.5 — a little over threefold — higher than that of non-cancer samples, an excess confirmed by both technologies after correction for sequencing depth. At the level of individual genes, the aggregated cost coefficient was significantly higher in cancers across 15,861 genes. In other words, cancer cells do not merely transcribe more; they transcribe more wastefully, pushing polymerase to fire from start sites that saddle the cell with longer, more expensive upstream transcripts.

But the deregulation proved far more strategic than simple sloppiness. Using Shannon entropy to quantify how randomly start sites were deployed, the researchers found two contrasting behaviors coexisting in cancer. For most genes, particularly those at distant upstream positions, start site deployment became highly stochastic — scattered, unregulated, and gene-function agnostic, effectively leaking transcription from sites that healthy cells keep silent. Yet for a specific subset of genes, cancers did the opposite: deployment became more deterministic, tightly concentrated on the most proximal, energy-cheap start sites. That subset was overwhelmingly enriched for genes driving biosynthesis, nucleotide metabolism, cell proliferation, and the cell cycle — the very engines of the cancer phenotype.

This duality, the authors argue, reflects selection acting on energy economics. A gene that must be expressed at high volume in a rapidly dividing cell profits enormously from shaving thousands of wasted bases off every transcript. The genome apparently anticipated this: biosynthetic and proliferation genes already carry start sites that sit unusually close to their start codons, a layout the researchers suggest may have first evolved to support the rapid cell divisions of early embryogenesis under metabolic constraint. Incipient cancer cells appear to co-opt this pre-existing economy, and even recruit chromatin-regulatory genes — whose deregulated deployment could rewire the epigenome — to lock in the cost-saving configuration.

The study also proposes an evolutionary interpretation of transcriptional noise itself. If start sites are clustered proximally, then purely random deployment of them actually saves energy, because the dice fall most often on the short transcripts. The authors suggest the human transcription start site landscape has been shaped to make stochasticity cheap, and that healthy cells exploit this, maintaining higher gene-space entropy with lower overall cost. Cancer breaches that threshold in two directions at once: embracing expensive randomness at distant start sites while carving out tightly regulated, low-cost proximal deployment for hallmark genes. The combined parameter the team built from effective futile transcription distance and compound entropy turned out to be the single strongest classifier of cancer from non-cancer samples in their functional analyses.

The findings carry caveats the authors themselves acknowledge. The observed patterns could partly be downstream consequences of MYC-driven transcriptional amplification, elevated RNA polymerase II activity, or the metabolic reprogramming of specific tumor types, rather than a truly universal hallmark — and the magnitude of the cost excess varied across tissue types, with brain cancers a notable exception in the CAGE data. Even so, the near-universal direction of the effect across heterogeneous sample pools, replicated across two independent technologies, suggests that transcriptional energy waste deserves a place alongside the Warburg effect and glutamine addiction as a metabolic signature of malignancy.

Beyond cancer biology, the work hints at a general principle: where a gene begins is not an accident of genome annotation but a calibrated trade-off between regulatory flexibility and metabolic cost. If future experiments confirm the causal chain — that relaxing start site selection precedes and enables malignant transformation — then the transcriptional start site landscape could become a diagnostic window onto a tumor’s energetic state, and perhaps even a therapeutic target. For now, the message is vivid enough: in cancer, even the silent stretches of RNA carry a bill, and the cell has learned to make someone else pay it.

Subject of Research: Deregulated transcription start site deployment and futile transcription energetics in cancer

Article Title: Gene functions determine stochastic or adaptive futile transcription in cancers through deregulated start site deployments

Article References: Satish, A. L., Kumar, P., Morbia, I., & Singh, U. (2026). Gene functions determine stochastic or adaptive futile transcription in cancers through deregulated start site deployments. Frontiers in Bioinformatics, 6, Article 1883461. https://doi.org/10.3389/fbinf.2026.1883461

Image Credits: AI Generated

DOI: 10.3389/fbinf.2026.1883461

Keywords: transcription start sites, futile transcription, cancer metabolism, CAGE, PRO-cap, gene expression, Shannon entropy, promoterome, Warburg effect, energy cost, biosynthesis, cell proliferation

The review’s central provocation is that the famous Warburg effect, the observation that cancer cells preferentially ferment glucose into lactate even in the presence of oxygen, is an incomplete map of tumor metabolism. Tumors, the authors emphasize, are far more metabolically diverse than the Warburg model suggests. Cancer cells possess a dual capacity: many can oxidize glucose through fully functional mitochondria via oxidative phosphorylation, or OXPHOS, while simultaneously running glycolysis. Strikingly, some cells occupy hybrid states in which both pathways operate concurrently, feeding energy production and biomass synthesis at the same time. Systems-level modeling and gene-signature approaches, such as quantifying downstream targets of AMPK and HIF-1, now provide tools to measure where a given tumor sits on this glycolytic-to-oxidative spectrum.

This plasticity is not a biochemical curiosity; it is clinically consequential. Hybrid glycolysis/OXPHOS phenotypes are specifically associated with metastasis and therapy resistance, and coexisting cell populations within a single tumor can reverse their energetic control, switching between sugar fermentation and oxygen-based respiration in response to environmental cues or drug pressure. The mechanistic wiring involves oncogenic and stress-responsive pathways converging on shared glycolytic effectors. The enzymes HK2, PKM2 and LDHA are targets of both c-Myc and hypoxia-inducible factors, while PI3K–AKT–mTOR signaling drives nutrient uptake and anabolic growth and AMPK guards the energy balance. Because these circuits interact, a single tumor can harbor genuinely different metabolic states in its oxygen-starved core versus its well-perfused margin, complicating any therapy that blocks just one pathway.

Within that heterogeneity, some tumors are strikingly dependent on mitochondrial respiration. Preclinical development of complex I inhibitors has flagged acute myeloid leukemia, subsets of lymphoma, glioblastoma, triple-negative breast cancer, melanoma and pancreatic ductal adenocarcinoma as OXPHOS-reliant contexts. Melanoma is the canonical example: PGC-1α-driven mitochondrial oxidative metabolism is described as essential for the growth and survival of a defined subset of human melanomas, a biologically grounded metabolic subtype that could, in principle, be identified in surgical specimens and used to stratify patients. The review argues that this phenotype-aware view, rather than an assumption of uniform glycolytic dependence, should anchor future translational studies.

Mitochondrial DNA adds another layer of vulnerability and opportunity. Unlike nuclear DNA, mtDNA is not protected by histones, making it exceptionally susceptible to oxidative damage generated inside the mitochondrial matrix. Mutations in genes encoding respiratory chain complexes I, III and IV appear across cancers and can reshape metabolism in ways that enhance tumorigenesis and adaptation. Crucially, the functional impact of any mutation depends on heteroplasmy, the proportion of mutant to wild-type genomes in each cell, so a mutation list alone cannot predict metabolic behavior. Yet mtDNA features may soon guide treatment: in a 2024 study of 308 patients with mismatch repair–deficient colorectal cancer, higher tumor mitochondrial DNA copy number correlated with better disease-free and overall survival, and those patients appeared to derive greater benefit from adjuvant chemotherapy. Because mtDNA copy number can be measured in resected tissue, it is an attractive perioperative biomarker, though the authors stress it still requires prospective validation.

The therapeutic record is humbling, and the review does not soften it. Metformin, the widely repurposed respiratory inhibitor, failed in the phase III MA.32 trial: adding it to standard therapy did not improve invasive disease–free survival in unselected early breast cancer, and it produced more grade 3 nonhematological toxicities and poorer adherence. Intriguingly, metformin did measurably lower CA 15-3 and estradiol levels, proof that biomarker modulation does not guarantee survival benefit without proper patient selection. More dramatic still is the story of IACS-010759, a potent, selective complex I inhibitor that entered phase I trials in relapsed or refractory acute myeloid leukemia and advanced solid tumors. Dose-limiting lactate elevation and neurotoxicity produced a narrow therapeutic index, no recommended phase 2 dose could be established, target inhibition was modest, and the trials were discontinued. Meanwhile, devimistat, a lipoate analog targeting two TCA cycle enzyme complexes, failed to improve survival when added to modified FOLFIRINOX in metastatic pancreatic cancer in the phase III AVENGER 500 trial.

Apoptosis targeting tells a sharper two-sided tale. Venetoclax, a BH3 mimetic that selectively neutralizes the anti-apoptotic protein BCL-2, transformed outcomes in acute myeloid leukemia: in the phase 3 VIALE-A trial, azacitidine plus venetoclax extended overall survival in previously untreated patients ineligible for intensive chemotherapy. That is clinical proof of principle that manipulating mitochondrial apoptotic priming can work. But translation to solid tumors has faltered, exemplified by the randomized phase II VERONICA trial, in which venetoclax plus fulvestrant did not significantly improve clinical benefit rate or progression-free survival in ER-positive, HER2-negative metastatic breast cancer. Broader BCL-2 family inhibition carries its own liabilities, with navitoclax’s thrombocytopenia a recurring dose-limiting concern, and venetoclax-associated events such as tumor lysis syndrome would complicate perioperative timing.

What elevates this review beyond a standard mechanism summary is its surgical framing. The authors propose that resected tumors become maps rather than samples: mass spectrometry imaging could chart metabolites across anatomically defined regions such as tumor core, invasive margin, hypoxic zones and adjacent healthy tissue, while matched single-cell sequencing and spatial transcriptomics would link those metabolic landscapes to specific malignant, stromal and immune cell populations. Integrating such data with histopathology, treatment exposure and outcomes could identify glycolytic, OXPHOS-dependent and metabolically plastic subpopulations associated with response, resistance or recurrence, and reveal cells that switch fuel sources after therapy and thereby seed relapse. Timing matters too: because postoperative recovery demands a metabolic shift from catabolism to repair, broad mitochondrial inhibition around surgery could interfere with healing and would need careful scheduling alongside nutritional status and wound recovery.

The immune dimension adds a final twist. Mitochondrial fitness is essential for antitumor T cells: OXPHOS and complex III-derived reactive oxygen species support NFAT signaling, IL-2 production and antigen-specific expansion, while the tumor microenvironment’s hypoxia and nutrient deprivation suppress PGC-1α-driven mitochondrial biogenesis in CD8-positive T cells, pushing them toward terminal exhaustion. Restoring mitochondrial fitness can reinvigorate these cells, so any therapy intended to cripple tumor mitochondria must spare those of infiltrating lymphocytes. Meanwhile, mtDNA released into the cytosol or extracellular space activates cGAS–STING, TLR9 and inflammasome pathways, linking mitochondrial injury to innate immunity, and mitochondria-targeted sensitizers that release damage-associated molecular patterns are being explored for immunogenic cell death. Early clinical signals include a phase I dose-escalation trial of an engineered mitochondrial vaccine in advanced solid tumors, registered with objective response rate endpoints but no outcomes yet reported, and preclinical work showing that the mitochondria-targeted antioxidant MitoQ radiosensitizes MDA-MB-231 but not MCF7 breast tumors, prevented recurrence and metastasis in mouse models at nanomolar concentrations that spared nonmalignant cells, and has a defined response signature for bulk biopsies.

The synthesis that emerges is deliberately unsentimental: mitochondrial vulnerabilities are a context-dependent opportunity, not a universal off switch. The authors call for metabolic phenotype classification, biomarker-guided patient selection and rational combinations, with pharmacodynamic readouts such as the rise in mitochondrial-to-genomic DNA ratio observed during complex I inhibition, and continued development of increasingly precise mitochondrial genome editors whose off-target edits have been reduced by more than 99 percent in preclinical systems. The near-term payoff is unlikely to be a single metabolic drug; it will more likely be a workflow in which a surgical specimen is spatially profiled, a tumor’s hybrid metabolic state is quantified, and a mitochondria-directed intervention is timed and combined accordingly. If that vision holds, the organelle once dismissed as an evolutionary passenger in cancer may become the anatomical and therapeutic reference point of multimodal oncology.

Subject of Research: Mitochondrial metabolic plasticity, hybrid glycolysis/OXPHOS states, and biomarker-guided therapeutic targeting in surgical oncology

Article Title: Mitochondrial metabolic plasticity in cancer: hybrid bioenergetic states and translational targeting in surgical oncology

Article References: Chattopadhyay, D., Rajendran, R. L., Mubin, N., Tendulkar, D., Singh, T. D., Ghosh, S., Jha, S. K., Gangadaran, P., & Ahn, B.-C. (2026). Mitochondrial metabolic plasticity in cancer: hybrid bioenergetic states and translational targeting in surgical oncology. Experimental Biology and Medicine, 251, Article 11244. https://doi.org/10.3389/ebm.2026.11244

Image Credits: AI Generated

DOI: 10.3389/ebm.2026.11244

Keywords: mitochondria, cancer metabolism, OXPHOS, glycolysis, Warburg effect, metabolic plasticity, mitochondrial DNA, surgical oncology, OXPHOS inhibitors, venetoclax, tumor microenvironment, biomarkers

Wilms tumor, also known as nephroblastoma, arises in the developing kidney and accounts for the vast majority of pediatric renal malignancies. More than 90 percent of children are diagnosed with the favorable-histology form, but outcomes vary considerably across patient cohorts. The picture is far grimmer for the 5 to 10 percent of cases classified as high-risk—including metastatic blastemal-type tumors, diffuse anaplastic disease, chemotherapy-refractory tumors, and multiply relapsed cancers—which carry survival rates below 50 percent even after aggressive multimodal therapy. Survivors of intensive radiochemotherapy frequently endure severe long-term side effects that diminish their quality of life. These realities have long motivated researchers to search for molecular vulnerabilities that could enable more individualized and less toxic treatments.

The new study began with a well-known hallmark of cancer: metabolic reprogramming. Tumor cells preferentially break down glucose into lactate even when oxygen is abundant, a phenomenon called the Warburg effect, leading to lactate buildup in the tumor microenvironment. Previous metabolomics work had already flagged elevated lactate as a signature distinguishing Wilms tumor tissue from normal kidney tissue, and a retrospective cohort study showed that higher lactate dehydrogenase activity independently predicts increased recurrence risk in pediatric patients. The research team confirmed these patterns directly, analyzing 52 pairs of Wilms tumor specimens and matched adjacent normal tissues collected at Qilu Hospital of Shandong University. Tumor tissues contained significantly less glucose and significantly more lactate than their normal counterparts, consistent with hyperactive glycolysis.

Lactate, once dismissed as a mere metabolic waste product, is now understood to be a versatile molecule that serves as an energy substrate, a signaling agent, and—critically—an epigenetic regulator. In 2019, researchers first identified histone lactylation as a novel epigenetic modification that directly modulates gene transcription on chromatin. Since then, histone lactylation has been implicated in immune evasion, metabolic reprogramming, and therapeutic resistance across many cancers. The process is enzyme-dependent: the acetyltransferase p300 acts as a writer that deposits lactyl groups onto histones, while HDAC1-3 and sirtuins serve as erasers that remove them. Because these same enzymes also manage histone acetylation, the two modifications share overlapping machinery, raising the possibility that lactylation plays an important but overlooked role in Wilms tumor biology.

Using immunohistochemistry and western blotting on the clinical specimens, the team found that pan-lysine lactylation and H3K18 lactylation were the most prominently elevated modifications in tumor tissue. Survival analysis showed that only high levels of these two marks correlated with significantly poorer event-free survival among the 52 patients studied. To probe function, the researchers manipulated lactylation levels in two Wilms tumor cell lines, WiT49 and WT-CLS1, using sodium lactate to raise intracellular lactate and the glycolysis inhibitors 2-deoxy-D-glucose and oxamate to lower it. The results were striking: boosting lactylation enhanced cell proliferation and migration in a dose-dependent manner, while suppressing lactylation markedly reduced these malignant behaviors.

To identify the genes controlled by H3K18 lactylation, the team integrated public ChIP-seq datasets with RNA-sequencing data from 126 Wilms tumor patients in the TARGET database. Cross-referencing genes bound by the H3K18la mark with genes upregulated in tumors yielded 302 candidates, which were then filtered through Cox regression analyses of patient survival data. Three genes emerged with independent prognostic significance: PSRC1, RFXAP, and GLRX3. Only PSRC1, however, responded specifically to changes in lactylation levels—its mRNA rose with sodium lactate treatment and fell with oxamate. Chromatin immunoprecipitation experiments confirmed that H3K18la was robustly enriched at the PSRC1 promoter in Wilms tumor cells, and that the writer enzyme p300 was required for this deposition. Importantly, the closely related acetylation mark H3K18ac remained unchanged across all treatments, demonstrating that p300 regulates PSRC1 specifically through lactylation rather than acetylation.

PSRC1 itself proved to be a potent oncogenic driver. The protein, also known as DDA3, is a mitotic regulator previously implicated in small cell lung cancer, breast cancer, and hepatocellular carcinoma. In Wilms tumor, high PSRC1 expression predicted poorer overall survival, with area under the curve values of 0.71 to 0.73 for one-, three-, and five-year survival predictions, and multivariate analysis confirmed it as an independent prognostic risk factor. Mechanistically, the team discovered that PSRC1 acts as a molecular competitor: it binds directly to the kinase domain of AKT through its proline-rich P-X-X-P domain spanning amino acids 103 to 246, thereby blocking the tumor suppressor PTEN from binding AKT and dephosphorylating it. Co-immunoprecipitation, mass spectrometry, immunofluorescence, and molecular docking—all supporting a stable interaction with a binding free energy of minus 28.4 kilocalories per mole—confirmed the competitive binding model. The consequence is sustained activation of the AKT/mTOR pathway, which stabilizes the HIF-1α protein, a master transcription factor that promotes glycolysis and tumor growth.

The final piece of the puzzle closed the loop. HIF-1α, stabilized by PSRC1-driven AKT signaling, was found to bind directly to a hypoxia response element within the PSRC1 promoter, further amplifying PSRC1 transcription. Dual-luciferase reporter assays demonstrated that hypoxia increased promoter activity only when the response element was intact, and HIF-1α knockdown blunted this activation. The result is a positive feedback circuit: H3K18 lactylation activates PSRC1, PSRC1 activates AKT/mTOR/HIF-1α signaling, and HIF-1α returns to boost PSRC1 expression, creating an escalating cycle of oncogenic signaling. Animal experiments corroborated the entire axis in vivo. In nude mouse xenograft models, PSRC1 knockdown slowed tumor growth and reduced lung metastatic burden, while PSRC1 overexpression accelerated growth, promoted lung colonization, and partially reversed the tumor-suppressive effects of oxamate, which was administered daily at 500 milligrams per kilogram.

The therapeutic implications are considerable, though tempered by practical challenges. The authors highlight three promising intervention points: inhibiting lactate production with agents such as oxamate, which has shown antitumor activity and low toxicity in preclinical models but suffers from poor membrane permeability that nanoparticle delivery could overcome; targeting the writer enzyme p300 with inhibitors such as CCS1477, which has advanced to phase I/II clinical trials in other cancers; and disrupting the feedback loop itself through AKT/mTOR inhibitors, peptide inhibitors designed to block the PSRC1-AKT interaction interface, or HIF-1α inhibitors. Each strategy faces hurdles, including systemic toxicity, the heightened safety requirements of pediatric oncology, and the risk that single-target inhibition will be undermined by the very feedback loop the study describes. The authors also note limitations: the clinical cohort was relatively small, genetically engineered animal models were not used, and the identity of the eraser enzymes that remove H3K18 lactylation in Wilms tumor remains unknown.

Nevertheless, the study represents the first demonstration of a histone lactylation-driven feedback circuit in Wilms tumor and bridges three previously separate domains—metabolic reprogramming, epigenetic modification, and oncogenic signaling. By showing that a metabolic byproduct can be converted into a durable transcriptional program that fuels cancer progression, the work adds Wilms tumor to the growing list of malignancies shaped by lactylation and provides a molecular rationale for combining metabolic inhibitors with signaling blockade. For the children with high-risk disease who currently face the bleakest odds, such rational combination strategies may ultimately offer a path toward more effective and less toxic therapy.

Subject of Research: Histone H3K18 lactylation and the PSRC1/AKT/HIF-1α feedback loop in Wilms tumor progression

Article Title: Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop

Article References: Wang, Y., Gao, H., Zhang, B., Li, X., Li, D., Cao, A., & Sun, F. (2026). Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop. Advanced Science, 13(56), Article e76579. https://doi.org/10.1002/advs.76579

Image Credits: AI Generated

DOI: 10.1002/advs.76579

Keywords: Wilms tumor, histone lactylation, H3K18la, PSRC1, AKT signaling, HIF-1α, p300, PTEN, Warburg effect, epigenetics, pediatric cancer, metabolic reprogramming

The centerpiece of the new work is the pyruvate dehydrogenase complex, or PDHc, a multi-enzyme assembly that sits at one of the most consequential crossroads in cellular metabolism. Glycolysis in the cytoplasm converts glucose into pyruvate, and the fate of that pyruvate determines which metabolic program the cell will run. When PDHc is active, it catalyzes the oxidative decarboxylation of pyruvate into acetyl-coenzyme A, which then feeds the tricarboxylic acid cycle, or TCA cycle, inside mitochondria, driving the production of NADH and FADH2 that power oxidative phosphorylation. When PDHc is inhibited, pyruvate is instead reduced to lactate, the TCA cycle slows, and the cell becomes dependent on glucose fermentation and on the diversion of glycolytic intermediates into biosynthetic pathways that support rapid proliferation. PDHc activity is therefore a metabolic master switch, and its regulation is a matter of life and death for a growing tumor.

The canonical off switch for PDHc is phosphorylation. Pyruvate dehydrogenase kinase 1, or PDK1, attaches phosphate groups to the E1 alpha subunit of the complex, PDHE1α, and this inhibitory mark suppresses the enzyme’s decarboxylase activity. Pharmaceutical efforts to reverse this blockade have centered on dichloroacetate, or DCA, a small molecule that inhibits PDK enzymes and thereby restores PDHc flux. What has remained less clear is how tumor cells recruit and amplify PDK1 activity in the first place, and whether noncoding RNAs, a class of regulatory molecules long suspected of shaping cancer metabolism, participate directly in this process. The new study provides a striking answer to both questions.

The researchers began with an observation that challenges the traditional division of labor between proteins and RNAs: PDHE1α, an enzyme long considered a purely metabolic protein, can bind RNA. Among the transcripts that associate with it is SNHG15, a long noncoding RNA that has previously been implicated in the progression of several cancers but whose metabolic functions were poorly defined. This RNA-protein interaction suggested that a noncoding transcript might physically insert itself into the machinery that governs mitochondrial fuel oxidation, a possibility the team pursued through a series of mechanistic experiments in hepatocellular carcinoma cells.

The mechanism that emerged is a scaffold model of metabolic control. According to the authors’ analysis, SNHG15 facilitates the interaction between phosphoglycerate kinase 1, PGK1, a glycolytic enzyme, and PDK1, and it simultaneously promotes the association between PDK1 and its substrate, PDHE1α. In effect, the RNA acts as a molecular matchmaker, bringing the kinase into proximity both with its upstream activator and with the enzyme it phosphorylates. The consequence is increased phosphorylation of PDK1 itself and of PDHE1α, which suppresses the catalytic activity of the pyruvate dehydrogenase complex. With PDHc throttled back, pyruvate oxidation into the TCA cycle declines, glycolysis accelerates, and lactate production rises, the classic biochemical signature of the Warburg phenotype.

This reprogramming is not merely a correlative curiosity; the study connects it directly to malignant behavior. In cell models, SNHG15-driven suppression of the TCA cycle promoted the glycolytic flux that fuels hepatocellular carcinoma progression. The team then extended the findings into xenograft models, in which tumor cells are implanted into experimental animals. Tumors with elevated SNHG15 grew more aggressively, and biochemical analysis of those tumors revealed increased lactate production alongside heightened phosphorylation of both PDK1 and PDHE1α, confirming that the RNA-protein phosphorylation axis operates in living tumors and not only in culture dishes.

Perhaps the most therapeutically compelling result came when the researchers administered dichloroacetate to the xenograft-bearing animals. DCA, which inhibits pyruvate dehydrogenase kinases and thereby releases the brake on PDHc, significantly reversed the oncogenic effects of SNHG15. Tumor growth was blunted, and the metabolic markers of the Warburg state receded. This pharmacological rescue is important because it demonstrates causality: if blocking PDK1 activity negates the tumor-promoting effects of the RNA, then the RNA’s oncogenic power flows substantially through that kinase, and the PGK1-PDK1-PDHE1α axis becomes a defined, druggable vulnerability rather than a loose correlation.

The study also broadens the conceptual repertoire of long noncoding RNA biology. LncRNAs have typically been cast as regulators of gene expression, modulating transcription, chromatin state, or messenger RNA stability. Here, SNHG15 acts instead at the level of enzyme activity, functioning post-translationally by organizing protein-protein interactions. The finding that PDHE1α itself is an RNA-binding protein adds to a growing recognition that core metabolic enzymes moonlight as participants in RNA-based regulatory networks, blurring the boundary between the genome’s informational layer and its metabolic machinery. In this view, noncoding RNAs can serve as intracellular scaffolds that rewire enzyme kinetics on demand, offering tumors a rapid and reversible means of adapting their metabolism to the demands of proliferation.

For hepatocellular carcinoma specifically, the clinical implications are worth weighing carefully. Liver cancer is frequently diagnosed at advanced stages and remains among the leading causes of cancer mortality worldwide, and metabolic vulnerabilities have long been proposed as therapeutic entry points. The SNHG15-PDK1-PDHE1α pathway offers several potential intervention surfaces: targeting the RNA itself with antisense or degrading strategies, disrupting its interaction with PDHE1α or PGK1, or inhibiting PDK1 pharmacologically, an approach already tested clinically with DCA in various contexts. The authors position the PGK1-PDK1-PDHE1α axis as a candidate target for clinical intervention, and the xenograft data with DCA provide an early proof of principle, though the gap between animal models and human therapy remains substantial and will require validation in patient-derived systems and ultimately clinical trials.

As with any study, important questions remain open. The precise structural basis of the SNHG15-PDHE1α interaction, the determinants of SNHG15 overexpression in liver tumors, and the relationship between this metabolic scaffold function and any other roles the RNA may play in HCC cells all await further definition. The work was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province and related institutional funds, and the authors declare no competing interests. What the study establishes, however, is a clear mechanistic narrative: a long noncoding RNA can hijack a phosphorylation cascade at the glycolysis-mitochondria junction, silence the TCA cycle, and push liver cancer cells into the fermentative metabolism on which their growth depends, and that same cascade can be chemically disarmed. In doing so, it adds a new layer to the metabolic playbook of hepatocellular carcinoma and offers researchers a concrete molecular handle on one of cancer’s oldest and most stubborn adaptations.

Subject of Research: Metabolic reprogramming of hepatocellular carcinoma by the lncRNA SNHG15 through PDK1 and PDHE1α phosphorylation

Article Title: SNHG15 inhibits the tricarboxylic acid cycle and promotes HCC progression by facilitating the phosphorylation of PDK1 and PDHE1α

Article References: Chen, H., Wang, Y., Chong, W., Wang, X., Wang, L., Zhang, J., Zhao, X., & Wang, C. (2026). SNHG15 inhibits the tricarboxylic acid cycle and promotes HCC progression by facilitating the phosphorylation of PDK1 and PDHE1α. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03380-9

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03380-9

Keywords: hepatocellular carcinoma, SNHG15, long noncoding RNA, pyruvate dehydrogenase complex, PDK1, PDHE1α, PGK1, TCA cycle, glycolysis, Warburg effect, dichloroacetate, cancer metabolism

The biological centerpiece of this framework is metabolic reprogramming, one of the updated Hallmarks of Cancer. Head and neck squamous cell carcinoma cells rely heavily on aerobic glycolysis, the so-called Warburg effect, burning through enormous quantities of glucose and converting it to lactate even in the presence of oxygen. This inefficient ATP generation might seem like a design flaw, but it allows rapid proliferation and creates a continuous drain on the body’s nutrient supply. The lactate released by tumors does not simply disappear; it enters the Cori cycle, forcing the liver to spend energy converting it back into glucose through gluconeogenesis. The result is a futile substrate loop that raises resting energy expenditure and contributes to the hypermetabolic state long observed in cancer patients.

The review emphasizes that the tumor behaves, in the authors’ framing, as a metabolic sink. Glucose, lipids, and amino acids are redirected from skeletal muscle, liver, and adipose tissue toward the growing malignancy. Cytokine-driven activation of proteolytic pathways in muscle triggers the breakdown of contractile proteins and the release of glutamine and other amino acids that can be funneled into tumor metabolism. Meanwhile, tumor-derived factors such as parathyroid hormone-related protein promote lipolysis and the browning of white adipose tissue, converting energy stored in fat into heat rather than usable fuel. These processes, the authors stress, do not directly nourish the tumor; instead, they force the host to mobilize substrates in a losing attempt to maintain homeostasis, producing thermogenic inefficiency and accelerating energy wasting.

Chronic systemic inflammation amplifies this catabolic storm. Elevated circulating levels of interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta are commonly found in head and neck cancer patients and correlate with weight loss, sarcopenia, and poorer clinical outcomes. Interleukin-6 has been strongly linked to loss of body mass and adipose tissue depletion, while tumor necrosis factor-alpha enhances ubiquitin-proteasome-mediated protein degradation and impairs glucose transport in peripheral tissues. Within skeletal muscle, activation of the myostatin/SMAD signaling pathway suppresses protein synthesis and accelerates atrophy. Together, these mechanisms create a self-perpetuating loop in which inflammation sustains catabolism, tissue wasting further fuels inflammatory signaling, and the patient’s metabolic reserve erodes progressively, often before any anticancer therapy has begun.

This model explains a clinical observation that has long puzzled oncologists: many patients lose weight and muscle mass early in the disease course, even when their oral intake appears adequate, and caloric supplementation alone frequently fails to prevent muscle loss or cachexia. The internationally accepted GLIM criteria for diagnosing malnutrition already recognize inflammation as a key etiologic driver, requiring at least one phenotypic criterion such as weight loss or reduced muscle mass alongside an etiologic criterion such as reduced intake or disease-related inflammation. The new review goes further, arguing that in head and neck cancer the inflammatory and metabolic components dominate, and that nutritional impairment should be viewed as a dynamic, tumor-driven process rather than a simple caloric deficit.

Translating this biology into measurable clinical tools is where the review makes its most distinctive contribution. Sarcopenia, the progressive loss of skeletal muscle, is one of the most clinically relevant manifestations of cancer-related metabolic derangement. Because patients with head and neck cancer rarely undergo routine abdominal imaging, cross-sectional muscle assessment at the level of the third cervical vertebra has emerged as a validated surrogate for whole-body muscle mass. The resulting C3 skeletal muscle index can identify muscle depletion that body mass index misses entirely, and it carries prognostic weight: sarcopenia has been consistently associated with poorer overall survival, increased treatment-related toxicity, and reduced quality of life, making it a robust biomarker rather than a mere byproduct of treatment intolerance.

On the metabolic side, functional imaging offers a window into the tumor’s glycolytic appetite. Total lesion glycolysis, derived from 18F-FDG PET scans, integrates tumor volume with metabolic activity to reflect the overall glucose consumption of the malignancy. High values have been associated with aggressive tumor biology, greater inflammatory burden, and adverse oncologic outcomes. Crucially, recent prospective data in locally advanced head and neck squamous cell carcinoma showed that higher tumor metabolic activity measured by total lesion glycolysis was significantly associated with reduced skeletal muscle mass at the third cervical vertebra, elevated inflammatory markers, and impaired nutritional status at the start of treatment. This provides clinical validation of the biological model: tumor-driven hypermetabolism and inflammation translate into measurable deterioration of body composition and nutritional reserve.

The authors are careful to acknowledge the limitations of the current evidence base. The studies linking PET-derived metabolic parameters with nutritional impairment remain limited in number and observational in design, and external validation in larger prospective cohorts is still needed. Methodological heterogeneity in PET acquisition protocols, lesion segmentation strategies, and cutoff values complicates comparisons across studies, and standardized imaging protocols and universally accepted thresholds for C3-based muscle assessment have not yet been fully established. Metabolic imaging biomarkers should therefore be considered complementary tools alongside conventional nutritional and body composition assessment rather than stand-alone diagnostic markers. In practice, the review advocates a multimodal approach combining clinical nutritional evaluation, C3-derived muscle assessment when available, inexpensive and widely accessible inflammatory markers such as C-reactive protein and the neutrophil-to-lymphocyte ratio, and metabolic imaging parameters in patients already undergoing PET imaging.

The therapeutic implications are perhaps the most consequential part of the framework. If malnutrition is an immune-metabolic syndrome, then early nutritional intervention should aim not merely to increase calories but to modulate systemic inflammation and preserve functional body composition. Current European Society for Clinical Nutrition and Metabolism guidelines support early nutritional intervention as a cornerstone of multidisciplinary care in head and neck oncology, and intervention appears most effective during the pre-cachectic or early cachectic phases, when metabolic alterations remain potentially reversible. Immunonutrition enriched with arginine, omega-3 fatty acids, and nucleotides has shown promising effects, including improvement of the CD4/CD8 T-cell balance and accelerated postoperative recovery, but the evidence remains heterogeneous, and the authors caution that adequately powered randomized trials are needed before routine use beyond current guideline indications can be recommended.

Patients with locally advanced disease, high tumor metabolic burden, marked systemic inflammation, and early muscle depletion are especially vulnerable, as are those with advanced age, HPV-negative tumors, extensive smoking histories, dysphagia, or treatment with concurrent chemoradiotherapy. For these individuals, the review argues, nutritional management should prioritize preservation of lean body mass over weight maintenance alone, with adequate protein and energy provision embedded in integrated supportive care that includes pain control and oncologic treatment planning. Nutritional support alone is unlikely to fully reverse the underlying immune-metabolic alterations, but early recognition of high-risk features could shift the paradigm from reactive nutritional rescue to proactive metabolic management. By uniting tumor metabolism, systemic inflammation, and imaging-based body composition into a single conceptual framework, the Naples team offers oncologists a way to identify vulnerable patients before cachexia takes hold, and a biological rationale for treating the tumor’s metabolic sabotage, not just the patient’s empty plate, as the true target of nutritional care in head and neck cancer.

Subject of Research: Tumor-driven immune-metabolic mechanisms of cancer-related malnutrition in head and neck squamous cell carcinoma

Article Title: Beyond reduced intake: tumor metabolism and immune dysregulation drive cancer-related malnutrition in head and neck squamous cell carcinoma (HNSCC)

Article References: Zurlo, V., Piccirillo, A., Marciano, M. L., Pontone, M., Rampetta, F. R., Perri, E., & Perri, F. (2026). Beyond reduced intake: tumor metabolism and immune dysregulation drive cancer-related malnutrition in head and neck squamous cell carcinoma (HNSCC). Supportive Care in Cancer, 34(10), Article 1056. https://doi.org/10.1007/s00520-026-11115-w

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11115-w

Keywords: head and neck cancer, cancer-related malnutrition, sarcopenia, tumor metabolism, Warburg effect, systemic inflammation, immunonutrition, total lesion glycolysis, C3 skeletal muscle index, cachexia, PET imaging, nutritional intervention

The biological logic behind this approach rests on one of the most fundamental hallmarks of cancer: metabolic reprogramming. Tumor cells do not simply grow faster than normal cells; they rewire their entire chemical economy. They devour glucose at extraordinary rates, preferentially fermenting it into lactate even when oxygen is plentiful, a phenomenon known since the 1920s as the Warburg effect. They become addicted to glutamine, which feeds carbon and nitrogen into the tricarboxylic acid cycle and into the synthesis of nucleotides needed for rapid DNA replication. They ramp up de novo lipid synthesis to build membranes for dividing cells, and they scavenge fatty acids from neighboring adipocytes when supplies run short. Each of these rewired pathways alters the types and concentrations of metabolites released into bodily fluids, and those changes can be read out through liquid biopsy, the minimally invasive sampling of blood that can be repeated over the course of treatment.

Plasma and serum have emerged as the optimal sample types for this kind of analysis, and the review quantifies just how dominant they have become. In a survey of recent lung cancer metabolomics studies, plasma or serum accounted for roughly 54 percent of samples analyzed by nuclear magnetic resonance spectroscopy, around 62 percent of those analyzed by gas chromatography-mass spectrometry, and approximately 65 percent of those analyzed by liquid chromatography-mass spectrometry, with tissue samples making up only a small fraction in each case. The reasons are practical as much as scientific. Blood draws are minimally invasive, easily repeatable, and capable of capturing metabolic features of both primary tumors and metastases, something a single tissue needle biopsy, limited by tumor heterogeneity, often cannot achieve.

The technical machinery behind plasma metabolomics has advanced considerably. The two workhorse platforms remain nuclear magnetic resonance and mass spectrometry, each with distinct trade-offs. NMR requires minimal sample preparation and delivers rapid, quantitative, highly reproducible measurements, but it suffers from relatively low sensitivity and high cost. Mass spectrometry, in its capillary electrophoresis, gas chromatography, and liquid chromatography variants, offers far greater sensitivity and specificity. Among these, LC-MS has become the preferred method for untargeted metabolomics because it can identify a wide variety of metabolites at very low concentrations. Capillary electrophoresis-mass spectrometry excels at polar and charged species such as amino acids, nucleotides, and small organic acids, and recent innovations including sheathless interfaces have boosted its sensitivity while improved throughput has made it more practical than its earlier reputation suggested.

Beyond the established platforms, the review highlights a wave of emerging techniques that push detection limits dramatically lower. High-resolution mass spectrometry, particularly Fourier transform ion cyclotron resonance, offers exceptional resolution for precise mass determination. The parallel accumulation-serial fragmentation approach, integrated with trapped ion mobility spectrometry, markedly improves peak capacity and identification depth, allowing researchers to exploit low-abundance ions in complex samples. On the NMR side, a technique called PRISE-NUS-HSQC uses probe-induced sensitivity enhancement to break through the micromolar detection ceiling that has long limited conventional NMR. Meanwhile, the molecule-resolvable surface-enhanced Raman spectroscopy method, known as MORE SERSome, combines laser desorption and ionization mass spectrometry with SERS to identify dominant metabolic molecules in serum with label-free molecular resolution. A separate technique, Catch and Display for Liquid Biopsy, enables digital counting of biomarkers on individual extracellular vesicles. Together these advances lay a technical foundation robust enough for clinical deployment.

Yet the field’s Achilles heel is metabolite instability, and the review is unusually candid about it. Metabolites in liquid samples can degrade and transform rapidly after collection, and complex matrices like plasma are vulnerable to minor metabolic fluctuations. Delayed centrifugation of whole blood significantly alters levels of glucose, potassium, and aspartate aminotransferase. Non-refrigerated storage leads to substantial degradation of specific serum and plasma components within short periods, and excessive freeze-thaw cycles can markedly change biomarker profiles. The authors point to standardized operating procedures as critically important: widely accepted protocols now call for fasting at least eight hours before blood collection, using EDTA as the anticoagulant, processing samples within thirty minutes, storing plasma at minus eighty degrees Celsius, and thawing on ice before analysis. Without such discipline, the accuracy and reproducibility that clinical medicine demands simply cannot be achieved.

The mechanistic core of the review explains why specific metabolites carry prognostic information at all. Glucose uptake in tumor cells is driven by glucose transporter 1 and hexokinase under the regulation of the PI3K-AKT signaling pathway, with mutations in p53, HIF-1 alpha, Kras, and c-Myc further amplifying glycolytic enzyme expression. The resulting lactate does more than fuel tumors; it chemically modifies histones through lactylation, reprogramming gene expression, and it converts anti-inflammatory type I macrophages into tumor-promoting type II macrophages while suppressing CD8 T cell and NK cell activity through glucose depletion and NFAT inhibition. Glutamine metabolism follows a similarly intricate logic, with transporter overexpression through SLC1A5, SLC7A5, and related carriers sustaining mTORC1 activation, while SLC7A11 suppresses ferroptosis to promote tumor progression. In osimertinib-resistant non-small cell lung cancer cells, AMPK pathway activation increases glutamine uptake via ASCT2, directly linking metabolic rewiring to drug resistance.

Lipid metabolism adds another layer of prognostic significance. Most cancer cells upregulate de novo lipogenesis through the ATP-citrate lyase, acetyl-CoA carboxylase, and fatty acid synthase pathway, and in lung cancer, bidirectional crosstalk between adipocytes and tumor cells establishes a metabolic symbosis in which cancer cells induce lipolysis and internalize released fatty acids via CD36 and FATP1 transporters. Elevated CD36 expression correlates with poor prognosis and metastasis in several cancers, while high expression of ALDH1L2 promotes chemoresistance in small cell lung cancer by inhibiting lipid peroxidation. Within the tumor microenvironment, PD-1 signaling suppresses phospholipid synthesis in CD8 T cells, promoting their ferroptosis, and the lipid metabolite 25-hydroxycholesterol accumulates in tumor-associated macrophages, reinforcing an immunosuppressive phenotype associated with poor survival in lung squamous cell carcinoma.

The clinical payoff is already visible in early trials. Combining the glycolysis inhibitor 2-deoxy-D-glucose with docetaxel enhanced chemotherapy efficacy in non-small cell lung cancer and thyroid cancer, though the authors note the sample size was small and larger validation is needed. In advanced renal cell carcinoma, the glutaminase inhibitor telaglenastat combined with everolimus extended progression-free survival compared with everolimus alone in the randomized ENTRATA trial. The fatty acid synthase inhibitor TVB-2640 enhanced paclitaxel efficacy in advanced solid tumors including KRAS-mutant lung cancer, with serum FASN metabolite levels serving as pharmacodynamic markers of pathway engagement. In small cell lung cancer, elevated serum lactate and lactate dehydrogenase levels were associated with reduced benefit from immunotherapy, suggesting lactate itself can predict therapeutic response. At the 2023 World Conference on Lung Cancer, a multi-omics classifier combining metabolomics, proteomics, and transcriptomics from peripheral blood demonstrated strong performance in detecting lung cancer across all stages.

The authors are careful about what remains undone. No consensus guidelines currently endorse metabolomics-based biomarkers for lung cancer, and existing expert statements emphasize potential while calling for large-scale, multicenter clinical validation. Metabolic patterns vary across tumor subtypes and disease stages, meaning prognostic analyses must account for factors such as the pronounced differences in carnitine, amino acid, and lipid profiles between early and late-stage non-small cell lung cancer, and the distinct N-acyl ethanolamine biosynthesis alterations separating adenocarcinoma from squamous cell carcinoma. Still, the trajectory is clear. With standardized sample handling protocols in place, detection technologies capable of resolving ever-lower metabolite concentrations, and clinical trials already testing whether metabolic pathway activity predicts treatment benefit, plasma metabolomics is positioned to move from the research bench toward the oncology clinic, where a routine blood draw could one day help determine which patients need more aggressive therapy and which can be spared it.

Subject of Research: Plasma metabolomics detection technology and its clinical applications in lung cancer and other malignancies

Article Title: Advances in plasma metabolomics detection technology and its clinical applications in lung cancer and other malignancies

Article References: He, Y., Guo, J., Gao, P., Li, Z., Wang, W., & Chen, K. (2026). Advances in plasma metabolomics detection technology and its clinical applications in lung cancer and other malignancies. Holistic Integrative Oncology, 5(1), Article 33. https://doi.org/10.1007/s44178-026-00248-x

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00248-x

Keywords: plasma metabolomics, liquid biopsy, lung cancer, non-small cell lung cancer, metabolic reprogramming, Warburg effect, mass spectrometry, nuclear magnetic resonance, glutamine metabolism, lactate, lipid metabolism, biomarkers

RNA editing is one of biology’s most elegant post-transcriptional tricks. Enzymes called adenosine deaminases acting on RNA, or ADARs, chemically convert adenosine bases in RNA molecules into inosine. Because the cell’s molecular machinery reads inosine as guanosine, this edit can rewrite the sequence of an RNA transcript without touching the underlying DNA. For protein-coding messenger RNAs, that can mean a subtly altered protein. But for microRNAs, the short non-coding strands that silence genes by binding to messenger RNA targets, an edit in the seed region, the critical stretch of about six to eight nucleotides that determines target recognition, can completely rewire which genes the microRNA represses.

The team focused on miR-376a-3p because it belongs to the miR-376 cluster, a family of microRNAs already known to be heavily edited in human tissues and previously implicated in cancers ranging from glioblastoma to prostate and esophageal tumors. Earlier work had shown that attenuated editing of miR-376a promotes invasiveness in glioblastoma cells, while edited versions of related microRNAs can either suppress or promote tumor growth depending on context. What remained unclear was what editing does to this particular microRNA in thyroid cancer, a disease often described as clinically inert but which nonetheless affects a growing number of patients worldwide.

To answer that question, the researchers first measured editing levels in papillary thyroid carcinoma (PTC) tissues and found them significantly elevated compared with non-cancerous thyroid tissue. They then hunted for the enzyme responsible. Among the ADAR family members, ADAR2, encoded by the gene ADARB1, emerged as the principal editor driving the modification of miR-376a-3p in PTC cells, and its activity was found to contribute to the carcinogenic process itself. That detail matters because it links a specific editing enzyme, a specific edited microRNA, and a specific cancer type into one coherent mechanistic chain.

The functional experiments were extensive. Using RT-qPCR, Western blotting, and immunohistochemistry, the team quantified microRNA and gene expression in patient tissues and cell lines. They then probed cancer-relevant behaviors with a battery of assays: CCK-8 and colony formation tests for proliferation, 5-ethynyl-2′-deoxyuridine (EdU) incorporation to track DNA synthesis, wound healing and Transwell assays to measure migration and invasion, and flow cytometry to profile cell death and cell-cycle effects. Across these readouts, a clear pattern emerged: the unedited, wild-type miR-376a-3p restrained malignant behavior, while the edited version, ed-miR-376a-3p, encouraged it. In other words, the same molecule, differing by a single inosine, played opposite roles depending on its editing state.

The molecular explanation lies in a target swap. MicroRNAs silence genes by base-pairing with complementary sequences in target messenger RNAs, and even one changed base in the seed region can abolish old partnerships and create new ones. Using dual-luciferase reporter assays, which test whether a microRNA can directly bind and suppress a predicted target sequence, the researchers showed that editing caused miR-376a-3p to lose its interaction with KPNA4, a gene previously linked to malignant phenotypes in papillary thyroid cancer, while simultaneously acquiring HOXD10 as a novel target. HOXD10 is a homeobox transcription factor with well-documented tumor-suppressive functions in multiple cancers, including earlier evidence of its silencing in thyroid tumors with BRAF V600E mutations.

With HOXD10 newly in its crosshairs, ed-miR-376a-3p suppresses the expression of this tumor suppressor, and the downstream consequence is metabolic. The team measured glycolytic activity through four independent readouts: glucose consumption, lactate production, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR). Cancer cells famously favor glycolysis, the rapid fermentation of glucose into lactate even in the presence of oxygen, a phenomenon known as the Warburg effect, to fuel their growth. The experiments showed that ed-miR-376a-3p enhances glycolysis in PTC cells by downregulating HOXD10, thereby supplying the energy-hungry tumor with a more aggressive metabolic program.

This study adds to a growing body of evidence that A-to-I editing of microRNAs is a powerful and underappreciated layer of gene regulation in cancer. Recent work has documented edited microRNAs influencing tumor growth in esophageal squamous cell carcinoma, lung adenocarcinoma, and hepatocellular carcinoma, with editing sometimes restraining and sometimes accelerating disease. What makes the new finding particularly striking is the completeness of the mechanism: an elevated editing enzyme, a confirmed editing event in patient tumors, a demonstrated target switch verified by direct binding assays, and a metabolic endpoint that ties the whole cascade to tumor biology. Each link in the chain was tested experimentally rather than inferred from correlation alone.

The clinical implications are tantalizing, though the authors and the field caution that translating editing biology into therapy remains a distant goal. If editing levels of miR-376a-3p reliably mark more aggressive tumors, they could serve as biomarkers helping clinicians stratify patients with papillary thyroid cancer, most of whom have excellent prognoses but a subset of whom experience recurrence or metastasis. More ambitiously, the ADAR2-miR-376a-3p-HOXD10 axis offers multiple potential intervention points: inhibiting the editing enzyme, neutralizing the edited microRNA, or restoring HOXD10 function. None of these strategies is yet available in the clinic, and the study’s data, while mechanistically thorough, derive from cell lines, patient samples, and animal models conducted under approved ethical protocols rather than from therapeutic trials.

For now, the significance of the work is conceptual as much as practical. It underscores that the genome’s final instructions are not fixed at DNA but negotiated at the RNA level, one edited base at a time. A microRNA that polices tumor growth in its canonical form can become a metabolic saboteur after a visit from ADAR2, and the difference between the two states is a single inosine that most conventional genomic analyses would never register. As RNA editing maps of human tumors grow more detailed, findings like this one suggest that the editing landscape may hold both explanatory power for cancer’s origins and untapped opportunities for its treatment, particularly in cancers like papillary thyroid carcinoma that have long been dismissed as too quiet to reveal their secrets.

Subject of Research: ADAR2-mediated A-to-I RNA editing of miR-376a-3p and its role in papillary thyroid cancer tumorigenesis

Article Title: A-to-I editing modifies the target and role of miR-376a-3p in papillary thyroid cancer

Article References: Yan, X., Mao, X., Zhu, C., Lv, G., Geng, X., Wu, W., Ding, Y., Qin, S., Wang, X., Li, Y., & Fang, L. (2026). A-to-I editing modifies the target and role of miR-376a-3p in papillary thyroid cancer. 3 Biotech, 16(9), Article 400. https://doi.org/10.1007/s13205-026-04984-9

Image Credits: AI Generated

DOI: 10.1007/s13205-026-04984-9

Keywords: A-to-I RNA editing, miR-376a-3p, ADAR2, papillary thyroid cancer, HOXD10, KPNA4, glycolysis, microRNA, RNA modification, tumor suppressor, oncogene, Warburg effect

The biological starting point is a mismatch between how tumors and immune cells process fuel. Most cancers exhibit the Warburg effect, a heavy reliance on aerobic glycolysis even in the presence of oxygen, which generates abundant lactate, promotes extracellular acidosis, and drives redox imbalance. This metabolic environment contributes to T-cell exhaustion, creating what the review describes as a negative feedback loop between tumor metabolic plasticity and immune suppression. Modern therapies, whether checkpoint inhibitors or cytotoxic drugs, often fail not because they cannot reach the tumor, but because the tumor’s metabolic adaptations and the immunosuppressive microenvironment they create blunt sustained responses.

The ketogenic diet intervenes by sharply reducing circulating glucose and insulin while raising ketone bodies, principally β-hydroxybutyrate and acetoacetate. For glycolysis-dependent tumor cells, this creates metabolic stress: glycolytic flux falls, lactate production drops, and the flow of glycolytic intermediates into the pentose phosphate pathway is restricted, depleting the nucleotide and NADPH pools needed for DNA synthesis and antioxidant defense. Ketogenic feeding also downregulates key glycolytic enzymes such as pyruvate kinase M2 and has been shown to increase mitochondrial reactive oxygen species in tumors. Cells already stressed by hypoxia, oncogenic signaling, or replication stress may then be pushed closer to the threshold at which chemotherapy- or radiation-induced damage becomes lethal.

Crucially, the review emphasizes that this selectivity is relative rather than absolute. Normal tissues and immune cells possess greater metabolic flexibility and can switch from glucose to fatty acid and ketone oxidation. Tumors with low levels of ketolysis enzymes, such as succinyl-CoA:3-ketoacid CoA transferase, cannot efficiently use β-hydroxybutyrate or acetoacetate as oxidative fuels and remain dependent on glycolytic substrates. Some tumors, however, retain functional ketolytic pathways and can adapt to ketosis, which limits the metabolic selectivity hypothesis. The diet’s benefits, the authors argue, are most likely in tumors that are highly glucose-dependent yet cannot compensate through ketone oxidation, and patient selection will therefore hinge on characterizing each tumor’s metabolic phenotype.

Ketone bodies are not merely fuel. β-hydroxybutyrate acts as a signalling metabolite with two notable functions: it engages the hydroxycarboxylic acid receptor 2 to dampen NF-κB and NLRP3 inflammasome-mediated inflammation, and it functions as an endogenous inhibitor of class I histone deacetylases, opening chromatin and altering transcriptional programs toward stress resistance and, in some contexts, anti-tumor states. Acetyl-CoA generated during ketolysis can feed into the citric acid cycle and support histone acetylation in immune cells, directly linking metabolism to gene expression. Experimental work shows that activated CD8-positive T cells can oxidize ketones to boost mitochondrial membrane potential and TCA-cycle flux, and that impairing ketone oxidation enzymes compromises T-cell proliferation and anti-tumor activity.

On the immune side, the diet may address one of the central barriers to durable immunotherapy responses: T-cell exhaustion. In the glucose-starved tumor microenvironment, activated T cells normally compete with glycolytic tumor cells and lose effector function. Under ketogenic conditions, metabolically flexible cytotoxic lymphocytes can sustain themselves through oxidative phosphorylation, and experimental studies suggest reductions in exhaustion markers such as PD-1, TIM-3, and LAG-3 in some settings. The diet may also re-polarize tumor-associated macrophages from immunosuppressive M2-like toward inflammatory M1-like phenotypes, and by lowering lactate and acidosis it may relieve metabolic suppression of dendritic cell antigen presentation. Effects on regulatory T cells are less predictable, since Treg maintenance depends on fatty acid oxidation and local nutrient composition, so ketosis may shift the nutrient competition between Tregs and effector CD8-positive cells rather than uniformly favoring one population.

These immunometabolic effects provide a mechanistic rationale for combining the diet with checkpoint inhibitors and adoptive cell therapies. Preclinical models have shown that ketogenic interventions can improve responses to PD-1 blockade, potentially converting immunologically cold tumors into more therapy-responsive states. For CAR-T therapy in solid tumors, where hypoxia, nutrient deprivation, and chronic antigen stimulation undermine engineered T-cell survival, ketogenic states could enhance oxidative metabolism and mitochondrial robustness, promoting memory-like T-cell states that sustain long-term responses. The review also explores synergy with targeted agents: reduced insulin and IGF-1 signaling may complement PI3K/Akt/mTOR inhibitors, and combinations with metformin or IDH inhibitors are biologically plausible, though evidence for clinically meaningful benefit remains preliminary.

A third layer of the framework involves the gut microbiome. By altering nutrient availability, the ketogenic diet changes microbial community composition and metabolite production, including short-chain fatty acids such as butyrate and propionate, which support epithelial barrier integrity, promote T-cell differentiation, and inhibit histone deacetylases. Certain bacterial taxa are associated with improved T-cell activation and better outcomes during anti-PD-1 therapy, raising the possibility that diet-induced microbiome remodeling could influence immunotherapy response. The authors stress, however, that direct proof linking ketogenic microbiome changes to improved cancer treatment outcomes remains preclinical, and connections between specific microbial shifts and therapy response have not been established as causal.

The clinical evidence base lags well behind the mechanistic story. Human studies to date, largely small prospective trials, pilot studies, and retrospective observations in glioblastoma, breast cancer, and gastrointestinal tumors, have consistently demonstrated that the diet reliably changes systemic metabolism, lowering glucose and insulin signaling and raising blood ketones when nutritional ketosis is achieved. Evidence for anti-tumor efficacy, however, is inconsistent, with some reports of disease stabilization and others showing no tumor control benefit. Adherence is a major obstacle, particularly in patients experiencing anorexia, nausea, or weight loss, and nutritional ketosis itself is a non-uniform exposure, with patients on ostensibly identical diets achieving different β-hydroxybutyrate levels. The review calls for future trials to report objective measures of ketosis, dietary composition, caloric and protein intake, and predefined metabolic targets, and to develop biomarker-guided approaches that identify which tumors are metabolically vulnerable.

The overarching message is one of calibrated optimism. The ketogenic diet should not be viewed as inherently anti-carcinogenic, nor as a substitute for established cancer therapies; current evidence does not support its use as an independent curative treatment. Instead, its greatest promise may lie in creating a coordinated biological environment, low glucose and insulin, elevated ketone signalling, preserved T-cell mitochondrial fitness, reduced dysfunctional inflammation, remodeled microbiome metabolites, and altered chromatin states, in which susceptible tumors become more sensitive to the therapies already in clinical use. Until large, controlled prospective trials clarify optimal patient selection, protocols, and long-term safety, the authors conclude, ketogenic strategies should remain carefully supervised adjunctive approaches within an emerging field of precision metabolic oncology.

Subject of Research: Ketogenic diet as an immunometabolic sensitization strategy in cancer therapy

Article Title: Ketogenic diet as a systems-level immunometabolic sensitization strategy in cancer therapy: integrating metabolism, immune reprogramming, microbiome dynamics, and epigenetic regulation

Article References: Mannan, M. S., Khan, M. W., Haseeb Khan, M. A., Javed, A., Hussain, S. M., & Adil, H. (2026). Ketogenic diet as a systems-level immunometabolic sensitization strategy in cancer therapy: integrating metabolism, immune reprogramming, microbiome dynamics, and epigenetic regulation. Medical Oncology, 43(11), Article 297. https://doi.org/10.1007/s12032-026-03425-0

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03425-0

Keywords: ketogenic diet, cancer metabolism, immunotherapy, beta-hydroxybutyrate, tumor microenvironment, gut microbiome, epigenetic regulation, T-cell exhaustion, Warburg effect, checkpoint inhibitors, nutritional ketosis, precision oncology