Macrophages are immune cells that can adopt different functional states within the tumor microenvironment. The review describes a balance between pro-inflammatory M1 macrophages and pro-tumorigenic M2 macrophages. M2 polarization can favor processes associated with tumor progression, whereas M1 polarization is linked in the reviewed evidence to inhibition of tumor growth.

Several non-coding RNAs are linked with M2 polarization in the review. miR-934, lncRNA RPPH1 and circPLCE1 are associated with M2 polarization and metastasis through signaling involving PI3K/AKT, NF-κB and STAT3. Their effects are presented as part of the molecular communication networks that connect colorectal cancer cells with tumor-associated macrophages. The review places these molecules within the broader biological context of tumor progression and metastatic behavior.

Other non-coding RNAs are associated with the M1 state. miR-195-5p and lncRNA GAS5 are described in the reviewed literature as favoring M1 polarization and suppressing tumor growth. The contrast between these molecules illustrates that non-coding RNA activity can be associated with different macrophage states and opposing effects on tumor-related processes. The mechanisms summarized in the review include exosomal transfer, competing endogenous RNA interactions and transcriptional regulation.

Transcriptional regulation provides another level at which these signals can affect cellular behavior. Together, these mechanisms form intricate communication networks between colorectal cancer cells and immune components, including tumor-associated macrophages. The review also discusses the possible translational applications of this biology.

Circulating exosomal non-coding RNAs are presented as candidate biomarkers that could improve diagnostic precision, and ncRNA-regulated macrophage polarization is identified as a possible target for immunomodulatory and precision-treatment strategies. These are research opportunities rather than established clinical benefits. Colorectal cancer remains a major global health burden, with incidence and mortality rates continuing to rise worldwide, according to the review.

The article cites a projection of 3.2 million colorectal cancer cases by 2040 and attributes this expected burden to complex interactions among genetic, environmental and lifestyle factors. The review positions ncRNA signaling within this wider disease context because these molecules may influence tumor-cell behavior, immune evasion, therapeutic resistance and the states of macrophages in the tumor microenvironment. Its central conclusion is that targeting ncRNA-regulated macrophage polarization holds promise for developing next-generation precision therapies and advancing immunomodulatory strategies in colorectal cancer.

That conclusion is a direction for research, not evidence of clinical efficacy. The review’s contribution is to assemble current knowledge about how microRNAs, long non-coding RNAs and circular RNAs relate to macrophage polarization and cancer progression, providing a framework for further investigation of these molecular connections.

Subject of Research: Non-coding RNA regulation of tumor-associated macrophage polarization in colorectal cancer

Article Title: Macrophage polarization and non-coding RNAs in colorectal cancer progression and metastasis

Article References: Nami, M. T., Fattahiyan, I., Eini, P., Eramian, M., & Vanan, A. G. (2026). Macrophage polarization and non-coding RNAs in colorectal cancer progression and metastasis. Medical Oncology, 43(11), Article 350. https://doi.org/10.1007/s12032-026-03482-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03482-5

Keywords: colorectal cancer, non-coding RNAs, tumor-associated macrophages, macrophage polarization, microRNAs, long non-coding RNAs, circular RNAs, cancer metastasis, tumor microenvironment, exosomal biomarkers, Macrophage, polarization

The investigation began with a systematic characterization of the fecal microbiome in mice with surgically induced endometriosis. Using 16S rDNA sequencing of the V3–V4 hypervariable region on an Illumina NovaSeq 6000 platform, the researchers profiled the gut microbiota of endometriosis and control mice during diestrus at day 42 post-model establishment. After quality filtering, 700 amplicon sequence variants were shared between groups, with 583 unique to controls and 536 unique to endometriosis mice. Alpha-diversity indices, including Chao1, Shannon, Pielou’s evenness, and Good’s coverage, did not differ significantly between groups, suggesting that overall species richness and evenness remained intact. However, beta-diversity analysis revealed clear structural separation between groups, confirmed by unweighted UniFrac-based principal coordinates analysis, hierarchical clustering, and analysis of similarities. At the phylum level, endometriosis mice showed reduced Firmicutes abundance and increased Bacteroidota, with a significantly altered Firmicutes-to-Bacteroidota ratio compared to controls. Linear discriminant analysis effect size analysis further delineated taxon-level compositional differences, and indicator species analysis nominated g_Ruminococcus, g_Coprococcus, g_Muribaculum, and g_Duncaniella as candidate endometriosis-associated biomarkers. Functional prediction using PICRUSt2 against the KEGG database identified enrichment of sphingolipid biosynthesis and metabolism pathways in endometriosis mice, hinting that lipid metabolism might be a key functional consequence of the dysbiosis.

To translate these compositional shifts into metabolic consequences, the team performed non-targeted liquid chromatography-mass spectrometry metabolomics on peritoneal lavage fluid from endometriosis and control mice. Partial least-squares discriminant analysis revealed clear separation between the metabolic profiles of the two groups, and a 200-permutation test confirmed model robustness without overfitting. Applying thresholds of fold change greater than or equal to 1.2 or less than or equal to 1/1.2, p less than 0.05, and variable importance in projection greater than or equal to 1, the researchers identified 26 upregulated and 2 downregulated metabolites in the endometriosis group. Among these, LysoPC(16:0) exhibited one of the largest fold-changes, highlighted in a heatmap of the top 28 differential metabolites. KEGG pathway enrichment of the full differential metabolite set identified glycerophospholipid metabolism, choline metabolism, linoleic acid metabolism, and unsaturated fatty acid biosynthesis among the top 20 enriched pathways, placing LysoPC(16:0) within a broader lipid metabolic reprogramming of the peritoneal cavity. Spearman’s correlation analysis between significantly altered genera and differential metabolites revealed that multiple genera, including g_Muribaculum, g_Mucispirillum, g_Ruminococcus, and g_Lactiplantibacillus, showed significant positive correlations with peritoneal LysoPC(16:0), suggesting a potential microbiota-metabolite link that demanded causal testing.

The researchers then turned to fecal microbiota transplantation to establish causality. Mice were rendered pseudo-germ-free by a seven-day antibiotic cocktail regimen containing vancomycin, ampicillin, metronidazole, and neomycin sulfate before endometriosis model establishment. Beginning on day 1 after model establishment and repeated every three days, mice were gavaged with sterile phosphate-buffered saline, fecal suspension from control mice, or fecal suspension from endometriosis mice. Peritoneal LysoPC(16:0) was significantly higher in recipients of endometriosis-donor feces than in either control group. These mice also developed heavier lesions and showed a greater proportion of CD206-positive macrophages, a canonical M2 marker, in peritoneal lavage fluid compared with control recipients. These results demonstrated that endometriosis-associated gut microbiota is sufficient to elevate peritoneal LysoPC(16:0) and promote peritoneal M2 macrophage accumulation, thereby facilitating lesion growth. The finding represents a critical advance because it moves beyond correlation to demonstrate that the altered microbiota itself carries the pro-endometriotic signal, with the lipid metabolite serving as the functional mediator between gut dysbiosis and pelvic immune remodeling.

To dissect the cellular mechanism, the team isolated bone marrow-derived macrophages from the femurs and tibias of eight-week-old C57BL/6N mice, cultured them with macrophage colony-stimulating factor for seven days, and stimulated them under multiple conditions. Flow cytometry showed that 50 micromolar LysoPC(16:0) significantly augmented IL-4-induced CD206 expression, confirming that the metabolite promotes M2 polarization in vitro. In a Transwell co-culture assay, mouse endometrial stromal cells placed in the upper chamber migrated significantly more when co-cultured with IL-4 plus LysoPC(16:0)-stimulated macrophages in the lower chamber than with either negative control or IL-4-alone conditions. Additionally, a phagocytosis assay using phycoerythrin-conjugated microspheres demonstrated that LysoPC(16:0)-treated macrophages exhibited enhanced particle uptake over two hours, consistent with prior reports that lysophosphatidylcholine promotes macrophage phagocytic activity. These in vitro findings established that LysoPC(16:0) directly reshapes macrophage phenotype and function, with downstream consequences for endometrial stromal cell migration, a pivotal step in ectopic lesion formation.

In vivo, the researchers administered daily intraperitoneal injections of LysoPC(16:0) to endometriosis mice for two weeks. Mice treated with the metabolite developed larger lesions than vehicle controls, whereas mice treated with AACOCF3, a phospholipase A2 inhibitor that suppresses endogenous LysoPC(16:0) production, showed smaller lesions and a lower proportion of peritoneal CD206-positive macrophages relative to endometriosis controls. To determine whether PPARγ signaling underlies the M2-polarizing activity of LysoPC(16:0), the team used GW9662, a selective PPARγ antagonist. In bone marrow-derived macrophages, LysoPC(16:0) significantly augmented IL-4-induced CD206-positive polarization, and this was substantially reduced by GW9662 pretreatment. In vivo, LysoPC(16:0)-t mice developed heavier lesions and showed a higher proportion of peritoneal CD206-positive macrophages than vehicle controls, and GW9662 co-administration significantly reduced both parameters. To assess whether these findings extend beyond a single genetic background, the researchers repeated the experiment in BALB/c mice using a four-group design, and the directional results were consistent with those in C57BL/6N mice across all outcome measures, confirming that the LysoPC(16:0)–PPARγ–M2 axis is not strain-specific but operates across genetically distinct backgrounds.

A key mechanistic advance of the study is the identification of IL-10 as the downstream effector through which LysoPC(16:0)-polarized M2 macrophages promote lesion progression. Reverse transcription quantitative polymerase chain reaction demonstrated that LysoPC(16:0) significantly upregulated Il10 messenger RNA in IL-4-primed macrophages in a PPARγ-dependent manner, placing IL-10 transcription within the LysoPC(16:0)–PPARγ cascade. The functional importance of IL-10 was confirmed in vivo: neutralizing IL-10 in LysoPC(16:0)-supplemented endometriosis mice with an anti-mouse IL-10 neutralizing antibody significantly reduced lesion weight compared with isotype controls. To formally establish that peritoneal macrophages are causally required rather than incidental bystanders, the researchers co-administered clodronate liposomes to deplete macrophages in LysoPC(16:0)-treated endometriosis mice. At day 14, clodronate-treated mice showed markedly fewer F4/80-positive cells in peritoneal lavage fluid and significantly lower lesion weights than empty liposome controls, despite equivalent LysoPC(16:0) exposure. Macrophage depletion therefore abolished the pro-endometriotic effect of LysoPC(16:0), demonstrating that peritoneal macrophages are required mediators of the metabolite-driven lesion growth.

To provide preliminary cell-based evidence relevant to human endometriosis, the researchers employed two complementary human models. THP-1 monocytes were differentiated into macrophages by phorbol 12-myristate 13-acetate treatment, rested for 24 hours, and stimulated under four conditions: negative control, IL-4/IL-13, IL-4/IL-13 plus LysoPC(16:0), and IL-4/IL-13 plus LysoPC(16:0) plus GW9662. LysoPC(16:0) significantly increased the proportion of CD206-positive cells compared with IL-4/IL-13 alone, and GW9662 reversed this effect, recapitulating the PPARγ-dependent polarization observed in murine macrophages. Conditioned medium was then collected from THP-1 macrophages stimulated under six conditions, including IL-10 neutralization with an anti-human IL-10 antibody or a human IgG1 isotype control. Primary endometrial stromal cells were isolated from ectopic lesions of five patients with surgically and histologically confirmed endometriosis, aged 26 to 37 years with a median age of 33, all with rAFS stage III–IV disease. Conditioned medium from LysoPC(16:0)-stimulated macrophages promoted significantly greater stromal cell migration than conditioned medium from IL-4/IL-13-alone conditions across all five patient samples, and this enhancement was substantially reduced by GW9662 or IL-10 neutralization but not by the isotype control. The consistency of the conditioned medium effect across five independent patient specimens, each tested under all six conditions in parallel, provides preliminary evidence that the axis identified in murine models is also operative in human cells.

The researchers acknowledge several limitations that place practical bounds on these conclusions. The bacterial taxa ultimately responsible for LysoPC(16:0) production were not isolated at the species level, as several candidate genera are obligate anaerobes whose cultivation requires dedicated infrastructure. Confirming a direct strain-metabolite relationship will require single-strain gnotobiotic colonization. The link between LysoPC(16:0) and PPARγ was established pharmacologically with GW9662, consistent with earlier reports that structurally related lysophospholipids can act as PPARγ ligands, but direct biophysical evidence of binding, such as co-crystallography or surface plasmon resonance, was not obtained. Likewise, IL-10 was identified as the principal downstream effector, but transforming growth factor beta and other M2-associated cytokines were not systematically profiled, and how IL-10 signaling drives endometrial stromal cell migration, whether through JAK-STAT3, PI3K-AKT, or another route, remains to be worked out. The translational component relied on a monocyte-derived cell line and primary stromal cells from five patients, a cohort that cannot capture the clinical heterogeneity of endometriosis across disease stage, lesion subtype, or symptom severity. Despite these limitations, the findings carry potential clinical relevance that warrants further exploration. Elevated peritoneal LysoPC(16:0) and altered microbiota composition could be evaluated as candidate biomarkers for endometriosis in future clinical studies, and the phospholipase A2–LysoPC(16:0)–PPARγ–IL-10 cascade offers multiple candidate intervention points for preclinical exploration. As the work is primarily based on murine models and cell-based human systems, its findings should be interpreted as preclinical mechanistic evidence, with clinical applicability to be established in future patient studies.

Subject of Research: Intestinal microbiota-associated LysoPC(16:0) promotes endometriosis via PPARγ-mediated M2 macrophage polarization and IL-10 secretion

Article Title: Intestinal microbiota-associated LysoPC(16:0) promotes endometriosis via PPARγ-mediated M2 macrophage polarization and IL-10 secretion

Article References: Li, N., Yuan, M., Jin, X., Jiao, X., Wang, S., Zhong, Z., Guan, H., Le, X., Ren, Q., Liu, Y., Dong, X., Li, Q., Wang, M., & Wang, G. (2026). Intestinal microbiota-associated LysoPC(16:0) promotes endometriosis via PPARγ-mediated M2 macrophage polarization and IL-10 secretion. iScience, 29(11), Article 117917. https://doi.org/10.1016/j.isci.2026.117917

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117917

Keywords: Intestinal, microbiota-associated, LysoPC, promotes, endometriosis, PPAR, mediated, macrophage, polarization, IL-10, secretion, scientific research

The cochlea, it turns out, has a robust local immune system of its own. Cochlear resident macrophages are found in several strategic locations, including the spiral ligament, the spiral ganglion — where the cell bodies of auditory neurons live — and in close association with the blood-labyrinth barrier, the specialized vascular gate that shields the inner ear from systemic circulation. These cells express well-known macrophage markers such as IBA1, MHCII, CD163, and CD68, and have been documented in non-diseased human temporal bone samples, underscoring that they carry out normal physiological functions as well as pathological ones. At rest, they adopt a ramified form, extending elaborate branching processes that continuously survey the local microenvironment for debris, damaged cells, and threats to homeostasis. A specialized population known as perivascular-resident macrophage-like melanocytes sits directly within the blood-labyrinth barrier, where they help regulate its permeability.

When injury, noise exposure, or aging strikes, these cells undergo a dramatic transformation. They retract their processes, adopt an ameboid morphology, and acquire phagocytic capacity — the ability to engulf and digest cellular debris. Functionally, they exist along a continuum between two canonical states: M1 classically activated macrophages, which drive pro-inflammatory responses, and M2 alternatively activated macrophages, which promote tissue homeostasis and resolution of inflammation. The morphological landscape is not uniform across the cochlea. In the spiral ganglion, macrophages resemble microglia, the resident immune cells of the brain, extending long processes that contact auditory neurons and surrounding glia. Along the basilar membrane, apical macrophages tend to retain a more quiescent appearance while basal cells adopt an activated phenotype — a pattern that becomes more prominent with age and may reflect the base-to-apex progression of cochlear degeneration characteristic of presbycusis.

The neuroprotective significance of these cells was demonstrated through selective depletion experiments. When researchers administered PLX5622, a CSF-1 receptor inhibitor, to eliminate cochlear macrophages, mice undergoing cochlear implantation showed significantly greater spiral ganglion neuron degeneration compared to animals with intact macrophage populations — and the same acceleration occurred in unoperated control ears. These findings establish that cochlear macrophages are active neuroprotective agents, tempering inflammatory responses and sustaining neuronal integrity under both physiological and stressed conditions. Macrophages also engage directly with Schwann cells, the glial architects of auditory neuron myelination, releasing a context-dependent repertoire of secreted signals — pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6, alongside anti-inflammatory and neurotrophic factors like IL-10 and IGF-1 — that directly influence Schwann cell proliferation and regeneration.

The pathophysiology of age-related hearing loss, the review argues, develops from low-grade chronic inflammation known as inflammaging. In mouse models of presbycusis, activated macrophages were observed in the cochlea prior to detectable hair cell damage and were concentrated near hair cells that subsequently degenerated — suggesting that macrophage activation may drive, rather than simply accompany, sensory cell loss. RNA sequencing of cochlear tissue from mouse models revealed a transcriptionally distinct expansion of pro-inflammatory macrophage populations, and analysis of human temporal bone samples from older donors showed a markedly increased proportion of activated macrophages in the auditory nerve and lateral wall, two structures whose integrity is central to auditory function. In the blood-labyrinth barrier, the number of perivascular-resident macrophage-like melanocytes decreased in aged ears, but a larger proportion of the remaining cells were activated — pointing to both macrophage loss and dysfunction as contributors to age-related pathology.

Several molecular signaling pathways govern this delicate balance. The fractalkine pathway, in which the chemokine CX3CL1 is constitutively expressed on spiral ganglion neurons and hair cells and binds exclusively to the CX3CR1 receptor on immune cells, has emerged as a critical regulator. Disrupting this pathway in knockout mice leads to increased spiral ganglion neuron loss accompanied by elevated IL-1β expression, impaired spontaneous ribbon synapse recovery after noise exposure, and diminished macrophage recruitment after selective hair cell damage. The JAK/STAT pathway, particularly STAT3, promotes M2 polarization in multiple tissues. The PI3K/Akt pathway is involved in both M1 and M2 phenotypes, with downregulation of different AKT isoforms favoring opposite polarization states. The mTOR pathway, inhibited by rapamycin, has been implicated in age-related neuroinflammation, and newer evidence suggests that overactivation secondary to dysregulated upstream activators may lead to sensorineural hearing loss. The MAPK pathway, typically activated downstream of toll-like receptor signaling, is also involved in macrophage activation and polarization.

The broader inflammatory environment in the aging cochlea is further destabilized by a failure of oxidative stress regulation. Mechanisms that clear reactive oxygen species are progressively weakened, lowering the threshold for activation of downstream inflammatory cascades. Chief among these is the NLRP3 inflammasome, a multi-protein complex whose overactivation is implicated in both neurodegenerative disorders and age-related hearing loss. NLRP3 activation follows a two-step process — an initial priming signal followed by activation triggered by pathogen- or damage-associated molecular patterns — leading to caspase-1 activation, release of pro-inflammatory cytokines IL-1β and IL-18, and pyroptotic cell lysis that floods the local microenvironment with inflammatory mediators. Priming can be driven by upstream pathways including TLR9/NF-κB signaling, which elevates expression of IL-6 and TNF-α. Dysregulation of the complement cascade represents an additional amplifying mechanism: complement factor B-deficient mice exhibit progressive hearing loss, spiral ganglion neuron loss, and myelin sheath damage despite structurally intact hair cells — implicating this pathway in glial function and myelination independently of sensory cell pathology.

Therapeutic strategies aimed at rebalancing macrophage polarization are showing promise in preclinical models. Concurrent inhibition of IL-1 and TNF-α using anakinra and etanercept, respectively, protected hearing thresholds in noise-exposed mice. Blockade of IL-6 signaling reduced macrophage activation and improved spiral ganglion neuron survival. Minocycline administration partially preserved hair cells by attenuating macrophage activation following cochlear injury. On the pro-regenerative side, local administration of soluble fractalkine to noise-exposed mice restored synaptic integrity and hearing thresholds — but only in the presence of macrophages. When macrophages were depleted following noise exposure, synaptic and neuronal loss was exacerbated; upon reintroduction, previously depleted mice recovered hearing thresholds, restored ribbon synapses, and preserved spiral ganglion neurons. Mesenchymal stem cells have been shown to suppress pro-inflammatory microglial activation while enhancing neuroprotective states, in part through activation of the fractalkine pathway, and can push macrophage differentiation toward the M2 anti-inflammatory phenotype across multiple organ systems.

Perhaps the most striking finding is that macrophages must be modulated, not eliminated. Complete macrophage depletion appears to worsen outcomes: spiral ganglion neuron degeneration accelerates, synaptic repair fails, and hearing loss deepens. The evidence firmly argues against broad immunosuppressive strategies and in favor of dampening pathological M1 activity while preserving or enhancing M2 neuroprotective and pro-repair functions essential to cochlear homeostasis. Timing of intervention is likely as important as target choice. Macrophage activation and shifts toward pro-inflammatory states have been documented in both animal models and human temporal bone specimens prior to significant hair cell or neuronal loss, suggesting that the immunological changes driving structural degeneration precede — and may be necessary for — that degeneration to occur. Even subclinical hearing loss leaves an immunological footprint: cochlear macrophages exposed to low-level noise leading to temporary threshold shifts exhibited activation and reduced phagocytic capacity, pointing to macrophage priming whereby repeated insults condition the immune system toward exaggerated responses to subsequent stressors.

The broader implications extend beyond hearing. Age-related hearing loss has been independently associated with cognitive decline and increased risk of dementia, though the direction and mechanism of this relationship remain incompletely understood. Given that many of the inflammatory cascades implicated in cochlear macrophage dysregulation are shared with Alzheimer’s disease, Parkinson’s disease, and related disorders — including complement activation, NLRP3 inflammasome signaling, and microglial priming — therapeutic strategies developed for the cochlea may have direct translational relevance to the brain and vice versa. Emerging evidence suggests that cochlear macrophages and central nervous system microglia share transcriptional programs and signaling pathways, offering a valuable first roadmap for inner ear therapeutics derived from neurodegeneration research. The cochlear macrophage, the review concludes, stands at the intersection of protection and pathology in age-related hearing loss — and a more complete understanding of the signals governing this balance offers promise not only for preserving hearing, but for uncovering shared mechanisms of immune-driven neurodegeneration across the nervous system.

Subject of Research: science

Article Title: The cochlear macrophage in presbycusis: inflammaging, neuroinflammation, and targets for therapeutic modulation

Article References: Al-Asad, R. K., & Kempfle, J. S. (2026). The cochlear macrophage in presbycusis: inflammaging, neuroinflammation, and targets for therapeutic modulation. Frontiers in Cellular Neuroscience, 20, Article 1930209. https://doi.org/10.3389/fncel.2026.1930209

Image Credits: AI Generated

DOI: 10.3389/fncel.2026.1930209

Keywords: presbycusis, age-related hearing loss, cochlear macrophages, inflammaging, neuroinflammation, fractalkine, NLRP3 inflammasome, complement cascade, microglia, neurodegeneration, cochlear, macrophage

BP-1, chemically known as 2,4-dihydroxybenzophenone, belongs to a family of hydroxylated benzophenone compounds used as ultraviolet absorbers and photostabilizers in cosmetic formulations. Because these products are applied directly to the skin and often remain there for hours in leave-on preparations, dermal uptake is a realistic exposure route. The molecule is small, with a molecular weight of 214.22 grams per mole and moderate lipophilicity, and safety assessments by the Scientific Committee on Consumer Safety suggest it has a low to moderate potential for dermal absorption. Worryingly, human biomonitoring studies have detected BP-1 in maternal serum, amniotic fluid, and fetal and cord blood samples, indicating that the compound crosses biological barriers that many toxicologists once assumed were protective.

Structurally, BP-1 carries phenolic hydroxyl groups on aromatic rings, features that allow it to interact with hormone-responsive cellular systems. Previous work has shown that the position and number of these hydroxyl substituents influence the estrogenic activity of benzophenone derivatives, and some members of the family also exhibit anti-androgenic activity. Earlier studies established that BP-1 induces estrogen-like responses in estrogen receptor-positive breast cancer models, including changes in estrogen-responsive transcription, cell proliferation, cell cycle gene expression, and metastasis-associated genes. Beyond endocrine disruption, BP-1 has been linked to intracellular reactive oxygen species accumulation, impaired antioxidant defenses, and mitochondrial and nuclear injury, raising the possibility of DNA damage and genomic instability.

To move beyond these tumor-cell-intrinsic effects, the research team, led by investigators at the Fourth Affiliated Hospital of Hebei Medical University, assembled a multi-layered analytical pipeline. They merged three breast cancer transcriptomic datasets from the Gene Expression Omnibus database, corrected batch effects, and identified 1,549 differentially expressed genes between tumor and normal tissue. Weighted gene co-expression network analysis then pinpointed a module of 85 genes most strongly associated with breast cancer, yielding a combined set of 1,597 breast cancer-related genes. In parallel, they predicted BP-1’s molecular targets using three databases, ChEMBL, the Similarity Ensemble Approach, and SwissTargetPrediction, which together yielded 107 BP-1-associated targets. Fifteen of these overlapped with the breast cancer gene set, forming the candidate pool for deeper interrogation.

The decisive step came from machine learning. The team applied four independent feature-selection algorithms, least absolute shrinkage and selection operator regression, support vector machine recursive feature elimination, XGBoost, and Boruta, to the 15 candidates. Only one gene survived all four filters: PLAUR, the gene encoding the urokinase-type plasminogen activator receptor, or uPAR. Single-cell RNA sequencing of a breast cancer dataset revealed that PLAUR was prominently expressed in macrophage, epithelial, and fibroblast clusters, with macrophages standing out as a key site of expression. Virtual overexpression of PLAUR in disease-derived single cells, simulated through the scTenifoldNet framework, perturbed genes involved in peptidase regulation, focal adhesion, cell-substrate junctions, and collagen-containing extracellular matrix, processes intimately tied to invasion and metastasis.

Molecular docking predicted that BP-1 binds uPAR with a binding energy of minus 6.9 kilocalories per mole, forming hydrogen bonds, pi interactions, and van der Waals contacts within the protein’s binding pocket. A 100-nanosecond molecular dynamics simulation confirmed the stability of this complex: the root-mean-square deviation plateaued between 0.6 and 0.9 nanometers, the radius of gyration held steady at roughly 2.2 to 2.4 nanometers, and the free energy landscape displayed a prominent low-energy basin. In the TCGA breast cancer cohort, PLAUR expression was markedly higher in tumors than in normal tissue, with an area under the receiver operating characteristic curve of 0.885, and high-PLAUR tumors were enriched in immune and inflammatory signaling, antigen processing, and cell migration pathways.

With the computational evidence in hand, the researchers turned to the laboratory. They differentiated human THP-1 monocytes into macrophages and exposed them to BP-1 at 1 and 10 micromolar concentrations, both well below the compound’s half-maximal inhibitory concentration of 118.5 micromolar in these cells. Within 48 hours, the macrophages underwent a striking transformation. Western blotting showed that uPAR protein expression increased with BP-1 concentration. Immunofluorescence revealed a decline in CD86, a marker of inflammatory M1 macrophages, and a rise in CD206, a hallmark of the alternatively activated M2 phenotype. At the messenger RNA level, CD163, CD206, and TGFB1 all increased, while CD86 and tumor necrosis factor decreased. Enzyme-linked immunosorbent assays confirmed that the treated macrophages secreted more interleukin-10 and transforming growth factor beta 1, both signature cytokines of the M2-like, tumor-supportive state.

The critical experiment followed. The team collected conditioned medium from BP-1-treated macrophages and applied it to two estrogen receptor-positive breast cancer cell lines, MCF-7 and T-47D. The results were unambiguous. EdU incorporation assays showed a significant increase in DNA synthesis, colony formation assays demonstrated enhanced long-term proliferative capacity, and Transwell and wound healing assays revealed accelerated migration. In MCF-7 cells, Matrigel-coated invasion assays showed a heightened ability to breach extracellular matrix barriers. Western blotting then uncovered the molecular signature underlying these behaviors: the epithelial marker E-cadherin decreased, while the mesenchymal markers N-cadherin and vimentin and the transcription factor Snail all increased, a classic epithelial-mesenchymal transition profile. Crucially, when the researchers added BP-1 directly to conditioned medium from untreated macrophages, the proliferative and motility effects persisted, but the EMT-related protein changes did not appear, suggesting that the macrophage secretome, rather than the chemical alone, drives the transition program.

The mechanism likely centers on TGF-beta 1, which the BP-1-treated macrophages secreted at elevated levels. Upon binding its receptor, TGF-beta 1 triggers phosphorylation of SMAD2/3, which associates with SMAD4 and induces EMT-related transcription factors such as Snail, which in turn represses E-cadherin. TGF-beta 1 also activates non-SMAD pathways, including MAPK, PI3K/AKT, and Rho GTPases, that govern cytoskeletal organization and cell motility. Previous studies have shown that macrophage-conditioned medium can induce TGF-beta-dependent EMT in MCF-7 cells, and that uPAR-integrin signaling promotes breast cancer invasion through the extracellular matrix. The new findings slot neatly into this framework, positioning PLAUR/uPAR as a candidate molecular bridge between BP-1 exposure, macrophage reprogramming, and malignant phenotypes in estrogen receptor-positive breast cancer.

The authors are careful to note the limitations of their work. The experiments relied on THP-1-derived macrophages and predominantly MCF-7 cells, and validation in primary macrophages and additional breast cancer models would strengthen generalizability. Estrogen receptor signaling was not examined with an antagonist or receptor knockdown, so its contribution to the observed responses remains undetermined. And uPAR and TGF-beta 1 emerged as potential mediators, but direct perturbation experiments, such as PLAUR knockdown or TGF-beta 1 neutralization, will be needed to confirm causality. Importantly, the researchers emphasize that sunscreen use remains vital for preventing ultraviolet damage and skin cancer, and they point to newer filters such as bemotrizinol, a photostable triazine compound with low systemic exposure, as promising alternatives. Yet they caution that improved photoprotection does not guarantee biological or environmental safety, and that the effects of new filters, their metabolites, and repeated exposure deserve rigorous evaluation before widespread adoption. For now, the study adds a new dimension to how scientists think about ultraviolet filters: not merely as molecules that touch tumor cells directly, but as agents capable of reshaping the immune landscape in which those tumors live and grow.

Subject of Research: Effects of the ultraviolet filter benzophenone-1 on macrophage polarization and malignant phenotypes in estrogen receptor-positive breast cancer cells

Article Title: Macrophage reprogramming by the ultraviolet filter benzophenone-1 promotes malignant phenotypes in breast cancer cells: integrated computational and experimental evidence

Article References: He, B., Ding, L., Yang, X., Zhang, T., & Ma, L. (2026). Macrophage reprogramming by the ultraviolet filter benzophenone-1 promotes malignant phenotypes in breast cancer cells: integrated computational and experimental evidence. Frontiers in Molecular Biosciences, 13, Article 1946836. https://doi.org/10.3389/fmolb.2026.1946836

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1946836

Keywords: benzophenone-1, breast cancer, macrophage polarization, PLAUR, uPAR, ultraviolet filters, tumor microenvironment, epithelial-mesenchymal transition, endocrine disruption, TGF-beta 1, Macrophage, reprogramming

The finding matters because tryptophan is not just any nutrient in the tug-of-war between host and pathogen. When the immune system detects M. tuberculosis, interferon-gamma-activated macrophages switch on an enzyme called indoleamine 2,3-dioxygenase 1, or IDO1, whose job is to degrade tryptophan inside the cell. This is a deliberate host defense: starve the invader of an amino acid it cannot easily live without. Although M. tuberculosis is a tryptophan prototroph, meaning it carries the genes to synthesize the amino acid from scratch, it normally prefers to scavenge tryptophan from its host because building it de novo is energetically expensive. The bacterium can sense when tryptophan becomes scarce and responds by inducing its own biosynthetic pathway, but until now the mechanism linking that sensing to the compensatory response remained obscure.

The new work points to VapC37 as the missing link. VapC37 belongs to a family of toxin–antitoxin systems, genetic modules in which a toxin protein is normally kept in check by a labile antitoxin; under stress, the antitoxin degrades and the toxin acts. When the researchers expressed VapC37 in the bacterium, growth arrested. Biochemical characterization showed that the toxin is a highly selective ribonuclease, or tRNase, that exclusively depletes tRNA carrying tryptophan. In other words, out of the entire complement of transfer RNAs the bacterium needs to translate its genes, VapC37 cleaves only the one dedicated to tryptophan. That precision is what makes the system so elegant: rather than causing indiscriminate damage, the toxin produces a very specific molecular signal.

The consequence of that signal is a state of perceived tryptophan starvation. With tRNA-Trp gone, the bacterium behaves as though the amino acid were unavailable, and it upregulates the production of enzymes in the tryptophan biosynthetic pathway. The toxin therefore appears to couple intracellular tryptophan availability—a well-established regulator of M. tuberculosis growth—to a codon-dependent adaptive response that raises the intracellular concentration of the amino acid. In effect, the bacterium uses its own toxin as an internal alarm, converting a host-imposed nutrient limitation into a genetic program that restores the nutrient supply.

But the toxin does far more than sound the alarm. The study shows that VapC37 broadly reprograms both the transcriptome, the full set of messenger RNAs, and the translatome, the set of mRNAs actually being made into proteins, toward molecules with low or no tryptophan codons. This makes intuitive sense: if the adaptor for tryptophan codons has been destroyed, genes rich in those codons will stall on the ribosome, while genes that avoid them can still be translated efficiently. The bacterium effectively reorients its protein production away from tryptophan-heavy messages, a genome-wide shift in metabolic priorities that mirrors the codon composition of the genes themselves.

Then comes the study’s most striking exception. Key enzymes in the biosynthetic pathway for phthiocerol dimycocerosate, or PDIM, a lipid critical to the bacterium’s virulence, were robustly synthesized despite being large proteins studded with tryptophan codons. Under the logic of codon depletion, these messages should have been among the hardest hit. Instead, the bacterium preserved their translation, and PDIM lipid production more than doubled upon VapC37 expression. This selective enrichment suggests that M. tuberculosis actively protects the machinery for making PDIM even under conditions of tRNA-Trp limitation, prioritizing a virulence factor over the general economy of codon scarcity.

PDIM is no incidental molecule. The waxy lipid is a well-known contributor to the bacterium’s early immune escape and virulence, helping it maintain its protective cell envelope and resist host defenses during the crucial early phase of infection. The finding that the bacterium selectively preserves PDIM production while everything else shifts toward tryptophan conservation implies a carefully choreographed reallocation of resources: the pathogen simultaneously defends its nutrient supply and its armor. That dual strategy could help explain how M. tuberculosis manages to keep replicating in an environment where the host is actively trying to starve and kill it.

The researchers also looked for clues about when VapC37 might actually be deployed during infection. They found that transcripts of the vapBC37 toxin–antitoxin module, along with PDIM biosynthetic transcripts, are upregulated when M. tuberculosis cells are subjected to nitrosative stress, a form of reactive nitrogen attack that macrophages use against engulfed pathogens, and upon infection of THP-1 macrophage-like cells. This pattern implicates early macrophage-associated stresses as potential activators of the toxin. If VapC37 switches on when the bacterium first encounters the hostile interior of an activated macrophage, it could serve as an early-response mechanism, reallocating metabolic priorities toward tryptophan biosynthesis while selectively maintaining PDIM production at the very moment the pathogen needs it most to evade immune clearance.

The study adds to a growing appreciation of toxin–antitoxin systems as regulatory tools rather than mere genomic parasites. In M. tuberculosis, which carries an unusually large number of these modules, individual toxins appear to have been recruited for specific stress responses. VapC37’s role as a tRNA-targeting switch that converts host-imposed tryptophan depletion into a compensatory biosynthetic program offers a concrete mechanism for how the pathogen links nutrient sensing to gene regulation. It also highlights the codon as a regulatory unit: because the toxin’s effect is codon-dependent, the amino acid composition of each gene determines how strongly it is affected, giving the bacterium a built-in hierarchy of what gets made and what gets shelved during stress.

For the field of tuberculosis research, the work opens several avenues. Understanding precisely how VapC37 is activated inside host cells, how the bacterium achieves selective translation of PDIM enzymes despite tryptophan codon depletion, and whether other toxin–antitoxin systems perform analogous roles under different stresses could reveal new vulnerabilities in a pathogen that has proved notoriously difficult to eradicate. With drug-resistant strains of M. tuberculosis continuing to spread, mechanisms that operate at the interface of host immunity and bacterial metabolism—such as the tryptophan tug-of-war mediated by IDO1 and countered by VapC37—are increasingly attractive targets for therapeutic intervention. The new study, published in PLOS Pathogens, demonstrates that even a single tRNA molecule can be the fulcrum on which a global pathogen balances survival, adaptation, and virulence.

Subject of Research: Toxin-mediated tRNA depletion and codon-dependent stress adaptation in Mycobacterium tuberculosis

Article Title: Toxin-mediated tRNA Trp depletion drives Trp-codon-dependent reprogramming in Mycobacterium tuberculosis while selectively enriching the PDIM biosynthetic machinery

Article References: Sain, S., Chauhan, U., Barth Jr, V. C., Troian, E. A., Abbadi, B. L., Malakar, B., Husson, R. N., & Woychik, N. A. (2026). Toxin-mediated tRNATrp depletion drives Trp-codon-dependent reprogramming in Mycobacterium tuberculosis while selectively enriching the PDIM biosynthetic machinery. PLOS Pathogens, 22(10), e1014679. https://doi.org/10.1371/journal.ppat.1014679

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014679

Keywords: Mycobacterium tuberculosis, VapC37, toxin-antitoxin system, tRNA-Trp, tryptophan biosynthesis, PDIM, IDO1, macrophage, nitrosative stress, translatome, virulence, PLOS Pathogens

The research, led by Wanqiu Huang and Jinjing Ni together with colleagues at Shanghai Jiao Tong University School of Medicine and collaborating institutions, focuses on a histone modification known as H2BK16ac. This tag refers to the acetylation of lysine 16 on histone H2B, one of the proteins around which DNA is wound. Acetylation of histone tails generally loosens the chromatin structure, making genes more accessible to the transcription machinery. When the researchers examined macrophages infected with Salmonella, they found that this acetylation mark on H2BK16 was actively removed. The deacetylation was carried out by two enzymes, HDAC1 and HDAC3, which strip acetyl groups from histones and thereby tighten chromatin at specific genomic locations.

The consequence of this chromatin tightening was the transcriptional silencing of a gene called Id3, which encodes Inhibitor of Differentiation 3. ID3 is a member of the helix-loop-helix protein family and is known to influence the behavior of various immune cells, but its role in macrophage-mediated antibacterial defense had not been clearly defined. The new study shows that when Salmonella drives H2BK16 deacetylation through HDAC1 and HDAC3, the Id3 gene is switched off, and macrophages lose an important layer of antimicrobial capacity. This finding places ID3 at the center of an infection-induced epigenetic pathway that directly shapes how macrophages respond to bacterial challenge.

To establish that ID3 genuinely strengthens macrophage defenses, the team performed both loss-of-function and gain-of-function experiments. When ID3 was removed or reduced, macrophages showed a weakened inflammatory response and diminished antimicrobial activity. Conversely, when ID3 was increased, macrophages displayed enhanced antibacterial function. These results demonstrate that ID3 is not a passive bystander in the infection response but an active contributor to the macrophage arsenal against invading bacteria.

The mechanistic heart of the study lies in how ID3 controls the expression of another protein, Z-DNA binding protein 1, commonly abbreviated as ZBP1. ZBP1 is a sensor that recognizes certain nucleic acid structures and participates in immune signaling. The researchers discovered that a transcription factor called E2A binds to the ZBP1 gene and represses its transcription. ID3 counteracts this repression by sequestering E2A, effectively pulling it away from the ZBP1 promoter. With E2A occupied by ID3, the ZBP1 gene is free to be transcribed, and macrophages maintain robust ZBP1 expression. This sequestration mechanism reveals a precise molecular handoff in which ID3 acts as a decoy to relieve transcriptional braking on an antimicrobial effector gene.

The in vivo relevance of this circuit was tested in mice engineered to lack Id3 specifically in myeloid cells, the lineage that includes macrophages. When these myeloid-specific Id3-deficient mice were infected with Salmonella, they carried higher bacterial burdens and suffered greater pathological damage than control animals. This outcome confirms that the ID3-ZBP1 axis is not merely a cell-culture curiosity but a functional component of antibacterial immunity in living organisms. The data suggest that the integrity of this epigenetic pathway determines how effectively the host can contain systemic bacterial spread.

Perhaps the most translational aspect of the study involves a pharmacological intervention. The researchers treated infected mice with MS-275, an inhibitor of histone deacetylases that targets HDAC1 among other class I enzymes. Administration of MS-275 restored the H2BK16ac mark, reactivated the Id3 gene, and thereby rebuilt the ID3-ZBP1 signaling axis. In practical terms, the drug reversed the epigenetic silencing that Salmonella had imposed on macrophages. Mice receiving this treatment showed amelioration of systemic Salmonella infection, demonstrating that pharmacologically reopening the chromatin at Id3 can translate into meaningful protection against bacterial disease.

These findings carry several implications for the broader field of infection biology. First, they establish that pathogens do not merely evade immune detection; they actively reshape the epigenetic landscape of host immune cells to disable specific defense genes. The Salmonella-driven deacetylation of H2BK16 represents a concrete example of how bacterial infection can hijack the host’s own chromatin-modifying enzymes to silence protective transcriptional programs. Second, the study identifies ID3 as a previously underappreciated regulator of macrophage immunity, bridging histone acetylation status to the expression of a nucleic acid sensor involved in antimicrobial signaling. Third, the demonstration that an HDAC inhibitor can restore this axis in vivo suggests a therapeutic window in which epigenetic drugs, originally developed for oncology, might be repurposed as adjunct treatments for severe bacterial infections.

The work also raises questions that will likely drive future research. It remains to be seen whether other pathogens employ similar strategies to silence Id3 or related immune regulators through histone deacetylation. The precise kinetics of HDAC1 and HDAC3 recruitment to the Id3 locus during infection, and whether additional chromatin marks cooperate with H2BK16ac in this process, are areas that warrant deeper investigation. Furthermore, because ZBP1 has been implicated in antiviral as well as antibacterial pathways, the ID3-E2A-ZBP1 circuit could have relevance beyond Salmonella, potentially influencing how macrophages respond to a wider spectrum of infectious threats. The study by Huang, Ni, and colleagues thus opens a new line of inquiry into how epigenetic therapies might bolster innate immunity at a time when antibiotic resistance continues to limit conventional treatment options.

Subject of Research: Infection-driven epigenetic regulation of macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

Article Title: Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

Article References: Huang, W., Ni, J., Tang, H., Chen, Y., Zhou, T., Yu, J., Wang, Z., Wen, B., Yan, H., Wang, C., Tao, J., Lu, J., Zhao, G.-P., Wang, D., & Yao, Y.-F. (2026). Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06432-6

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06432-6

Keywords: macrophage, innate immunity, epigenetics, histone acetylation, H2BK16ac, ID3, ZBP1, Salmonella, HDAC1, HDAC3, E2A, MS-275

Glioma is the most common malignant primary brain tumor in adults, and its most aggressive form, glioblastoma, carries a median survival measured in months rather than years. The therapeutic arsenal remains painfully thin: surgical resection, radiation, and the chemotherapy drug temozolomide extend life only modestly, and the blood-brain barrier blocks many otherwise promising compounds from ever reaching the tumor. Against this backdrop, scientists have increasingly turned to cell death programs as therapeutic levers. Apoptosis, the quiet and orderly form of cell suicide, has long been the target of conventional cancer drugs, but tumors routinely evolve resistance to it. Pyroptosis, by contrast, is loud, inflammatory, and lytic: cells swell, rupture, and release their contents, simultaneously destroying the tumor cell and sounding an immune alarm.

The molecular machinery of pyroptosis centers on the gasdermin family of proteins. When enzymes such as caspases cleave a gasdermin protein, the released fragment migrates to the cell membrane and punches oligomeric pores into it. The cell loses its ionic balance, swells with water, and ultimately bursts, spilling damage-associated molecular patterns and inflammatory cytokines such as interleukin-1 beta into the tumor microenvironment. One family member in particular, gasdermin E, or GSDME, has attracted intense interest because it can be cleaved by caspase-3, the very executioner enzyme of apoptosis. In principle, this creates a molecular switch: a stimulus that begins as apoptotic can be diverted into pyroptosis when GSDME is present, converting a silent death into an immunostimulatory event capable of reshaping the tumor’s immune landscape.

Recognizing this potential, Hanwen Lu and Zhanxiang Wang of the First Affiliated Hospital of Xiamen University and their collaborators set out to do something that had not been done systematically before: build a dedicated library of pyroptosis-inducing compounds and filter it through the unforgiving realities of brain tumor pharmacology. The team assembled their library by combining commercially available pyroptosis inducers with candidates harvested from an exhaustive mining of the PubMed and Web of Science literature. But identifying a molecule that triggers pyroptosis in a dish is only the first hurdle. For a brain cancer drug, the compound must also survive the gauntlet of drug-likeness filters and, crucially, cross the blood-brain barrier, the tightly sealed endothelial lining that excludes the vast majority of small molecules from the central nervous system.

To solve this, the researchers applied a sequential computational and pharmacological funnel. First came Lipinski’s rule of five, the classic checklist of molecular weight, hydrogen-bond donors and acceptors, and lipophilicity that predicts oral absorbability. Next, they used predictive models of blood-brain barrier permeability, followed by central nervous system multiparameter optimization scoring, a more sophisticated metric that balances multiple physicochemical properties to estimate the likelihood that a molecule will achieve adequate brain exposure without unacceptable side effects. Stringent descriptor-based criteria narrowed the field further, and a final round of pharmacological curation and literature vetting elevated a short list of priority candidates. Rising to the top of that list was diacerein, a drug oncologists had never seriously considered but rheumatologists have prescribed for years.

Diacerein is an anthraquinone derivative that works as a slow-acting anti-osteoarthritic agent, traditionally understood to inhibit interleukin-1 beta signaling in cartilage. Its established safety profile, oral availability, and favorable predicted brain penetration made it an attractive repurposing candidate. In laboratory experiments, the team found that diacerein significantly inhibited the proliferation of glioma cells and suppressed tumor growth in animal models. But the mechanism they uncovered was far more interesting than simple growth arrest. Treatment with diacerein activated caspase-3, the canonical apoptotic executioner, and simultaneously triggered the cleavage of GSDME, the gasdermin protein that converts caspase-3 activity into pyroptotic membrane rupture. In other words, the drug appeared to push glioma cells down a hybrid death pathway that begins with apoptosis and culminates in pyroptosis-like lysis.

To confirm that GSDME was not merely a bystander in this process, the researchers performed loss-of-function experiments. When they knocked down GSDME in glioma cells, the cytotoxic punch of diacerein was substantially blunted: cell viability recovered, and the drug’s killing efficiency dropped. This partial rescue demonstrates that GSDME is functionally required for a significant share of diacerein-induced glioma cell death, anchoring the drug’s effect in the pyroptotic pathway the screen was designed to find. The team also traced changes in inflammation-related signaling, observing reduced activity along the interleukin-1 beta, NF-kappa B, and phosphorylated STAT3 axes. Because these pathways sit at the heart of macrophage-mediated inflammation, the authors suggest the drug may also alter macrophage-related immune dynamics within the tumor microenvironment in living animals, a possibility with major implications given the prominent role of tumor-associated macrophages in glioma immunosuppression.

The implications extend beyond a single molecule. The study validates a repurposing strategy that begins with a cell death mechanism rather than a molecular target, then filters candidate drugs through the pharmacological constraints of the diseased tissue. This pyroptosis-oriented pipeline could in principle be rerun for other cancers of the central nervous system, or adapted to other lytic death programs such as necroptosis and ferroptosis. It also illustrates the growing power of literature mining as a discovery tool: by systematically extracting pyroptosis-inducing activity from thousands of published pharmacological studies, the team assembled a candidate pool that no single laboratory’s compound collection would have contained. The approach effectively converts the accumulated knowledge of pharmacology into a searchable, filterable database of mechanism-directed therapeutics.

Considerable work remains before diacerein could reach glioma patients. The doses used in laboratory and animal studies may not map directly onto the exposures achievable and tolerable in humans, and the authors evaluated brain exposure using liquid chromatography-tandem mass spectrometry methods developed specifically for this study, but clinical pharmacokinetics in glioma patients, where the blood-brain barrier is often locally disrupted yet heterogeneously intact, will need dedicated investigation. The precise molecular target through which diacerein initiates caspase-3 activation in glioma cells also remains to be fully defined, and the immunological consequences of triggering pyroptosis inside the brain, an organ exquisitely sensitive to inflammation, must be carefully characterized. Nevertheless, the fact that diacerein is already an approved, well-characterized medicine with a known safety record could substantially shorten the path from bench to bedside, potentially through investigator-initiated clinical trials in recurrent glioma, where new options are desperately needed and the regulatory bar for repurposed drugs is lower than for entirely novel agents.

For a disease that has defeated nearly every therapeutic innovation thrown at it, the idea that an arthritis pill sitting in pharmacy shelves worldwide might recruit the immune system against glioma through gasdermin pores is the kind of unexpected twist that drug repurposing was made for. The Xiamen team’s work provides both a concrete candidate and a reusable discovery framework, suggesting that the next breakthrough in brain cancer may not come from a molecule designed from scratch, but from an old drug viewed through an entirely new biological lens.

Subject of Research: Pyroptosis-oriented drug repurposing identifies diacerein as a therapeutic candidate for glioma

Article Title: Pyroptosis-oriented drug discovery identifies diacerein as a promising therapeutic candidate for glioma

Article References: Lu, H., & Wang, Z. (2026). Pyroptosis-oriented drug discovery identifies diacerein as a promising therapeutic candidate for glioma. BMC Medicine. https://doi.org/10.1186/s12916-026-05187-y

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05187-y

Keywords: glioma, diacerein, pyroptosis, GSDME, caspase-3, drug repurposing, blood-brain barrier, immune microenvironment, macrophage, NF-kappa B, IL-1 beta, BMC Medicine