The study combined analysis of public cancer datasets with clinical tissue samples, laboratory assays and mouse xenografts. Clear cell renal cell carcinoma is the most common histological form of kidney cancer, accounting for approximately 80% of renal cell carcinomas, and the paper reports that both METTL14 and FDX1 are expressed at lower levels in tumors than in matched normal tissue. In The Cancer Genome Atlas cohort, low expression of either gene was associated with shorter overall and disease-free survival. These associations were evaluated in database data rather than through a prospective clinical trial, so they establish a prognostic association but do not show that either protein can be used to predict outcomes reliably in routine practice.

FDX1 encodes a mitochondrial iron-sulfur protein involved in several biochemical processes, including electron transfer, redox catalysis, mitochondrial respiration and protein acylation. It also has a central role in cuproptosis, a copper-dependent form of regulated cell death. In the mechanism described by the investigators, FDX1 reduces divalent copper to monovalent copper, which promotes lipoacylation of proteins such as DLAT and DLST. The study’s authors describe this copper-driven protein modification as a process distinct from apoptosis and ferroptosis, the latter two of which are not inhibited by the cuproptosis pathway in the cited background research. ccRCC cells contained more intracellular divalent copper than the normal renal tubular epithelial cell line used for comparison, suggesting that reduced FDX1 expression was accompanied by impaired handling of copper in the tumor model.

To investigate why FDX1 was diminished in ccRCC, the team examined m6A regulators. m6A is a widespread post-transcriptional modification installed by “writer” proteins and removed by “eraser” proteins. METTL14 is a writer, whereas ZC3H13 is another m6A-associated factor; FTO and ALKBH5 are erasers. Tumor tissue showed reduced expression of METTL14 and ZC3H13 and increased expression of FTO and ALKBH5 in the TCGA analysis. METTL14 had the strongest positive correlation with FDX1 among the four regulators examined, with a reported correlation coefficient of 0.46. Tissue assays, immunostaining and cultured cells likewise showed lower METTL14 in ccRCC samples and cell lines than in their normal counterparts, while low METTL14 expression in the survival dataset was linked to poorer outcomes.

The molecular experiments provided evidence that METTL14 acts directly on the FDX1 transcript. A prediction tool identified potential m6A sites on FDX1 RNA, and RNA immunoprecipitation followed by quantitative PCR showed that m6A enrichment on FDX1 transcripts was lower in the 786-0 and OS-RC-2 ccRCC cell lines than in HK-2 renal tubular epithelial cells. METTL14 binding to FDX1 RNA was similarly reduced in the cancer cell lines. When METTL14 was overexpressed in 786-0 and OS-RC-2 cells, m6A modification of FDX1 mRNA increased, as did FDX1 messenger RNA and protein abundance. Actinomycin D treatment, which was used to block new RNA synthesis, showed that FDX1 RNA degraded more slowly after METTL14 overexpression, indicating that the increase in FDX1 expression was associated with greater transcript stability.

Wild-type METTL14 and a catalytically inactive D314A mutant were then compared in the same cell models. Both constructs were expressed, but only wild-type METTL14 significantly increased FDX1 messenger RNA and protein and slowed FDX1 RNA degradation. The mutant did not produce a comparable change, supporting a requirement for METTL14’s methyltransferase activity rather than a nonspecific effect of METTL14 abundance. This distinction is important because it links the phenotype to the catalytic function of the enzyme. The study did not, however, identify the specific m6A reader protein that binds the modified FDX1 transcript, leaving that part of the pathway unresolved.

Functional assays connected the METTL14-FDX1 relationship to cuproptosis and cellular metabolism. In 786-0 cells, METTL14 overexpression increased the consumption of divalent copper, while simultaneous FDX1 knockdown reduced that effect. In a 72-hour cell-viability experiment using a 300 nM elesclomol-copper complex, METTL14 overexpression was associated with the lowest survival rate, whereas FDX1 knockdown partially reversed the reduction in survival. Oxygen-consumption measurements showed that METTL14 overexpression increased basal and maximal mitochondrial respiration, with the enhancement attenuated by FDX1 depletion. METTL14 also increased lipoacylated DLAT and DLST and intracellular alpha-ketoglutarate; these changes were reversed when FDX1 was knocked down. Together, the assays support a pathway in which METTL14 raises FDX1, FDX1 promotes copper-dependent protein lipoacylation and cuproptosis, and tumor-cell survival falls.

The researchers then tested whether the cellular mechanism translated into an animal model. Groups of five six-week-old male BALB/c nude mice received subcutaneous implants of 786-0 cells carrying an empty vector, stable METTL14 overexpression, or combined METTL14 overexpression and FDX1 knockdown. Tumor volume was measured every four days for 28 days. Tumors derived from METTL14-overexpressing cells grew less and had lower mass than control tumors, while FDX1 knockdown nullified the suppression of growth. Western blotting and immunohistochemical analysis of xenograft tissue showed that METTL14 overexpression increased lipoacylated DLAT and DLST, while FDX1 knockdown abolished that increase. These rescue experiments are important because they show that FDX1 is not merely correlated with tumor behavior in the cell assays but is necessary for the observed effect of METTL14 in vivo.

Overall, the findings support a model in which loss of METTL14 contributes to reduced FDX1 expression in ccRCC by limiting m6A modification and accelerating FDX1 messenger RNA degradation. Reduced FDX1 then corresponds to weaker copper-dependent cell death and greater tumor-cell proliferation, while METTL14 overexpression produces the opposite phenotype in cell cultures and mouse xenografts. The work offers a mechanistic explanation for the previously observed association between low METTL14 or FDX1 expression and poor survival in kidney clear cell carcinoma. It also identifies FDX1-dependent cuproptosis as a measurable functional link between RNA methylation and malignant behavior. The evidence remains preclinical: the clinical sample set included 12 patients with surgically treated ccRCC, the experiments focused on two cancer cell lines and one xenograft model, and the retrospective database associations were not tested as clinical biomarkers. No therapeutic efficacy or safety was demonstrated in patients. The authors note that future work should identify the m6A reader or readers that recognize modified FDX1 RNA, which would complete the molecular description of the pathway.

Subject of Research: METTL14-dependent m6A regulation of FDX1 and cuproptosis in clear cell renal cell carcinoma

Article Title: METTL14-mediated FDX1 m6A methylation inhibited the proliferation of clear cell renal cell carcinoma

Article References: Bai, Z., Wang, C., Shen, J., Yang, Y., Liu, Q., & Shang, Z. (2026). METTL14-mediated FDX1 m6A methylation inhibited the proliferation of clear cell renal cell carcinoma. Medical Oncology, 43(11), Article 341. https://doi.org/10.1007/s12032-026-03438-9

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03438-9

Keywords: clear cell renal cell carcinoma, METTL14, FDX1, m6A methylation, cuproptosis, RNA stability, mitochondrial metabolism, cancer metabolism, xenograft model, METTL14-mediated, methylation, inhibited

Writing in the journal Genes & Diseases, the research team reports the identification of a circular RNA molecule, circLPAR3, as a previously unrecognized driver of docetaxel resistance in prostate cancer. Circular RNAs are an unusual class of non-coding RNA molecules. Unlike conventional linear RNAs, their ends are covalently joined in a closed loop through a process called back-splicing, which renders them remarkably resistant to degradation by cellular exonucleases. This structural stability has made circular RNAs objects of intense interest in cancer biology, where they can act as molecular sponges, scaffolds, or interaction hubs that rewire gene regulation from within the cell.

The investigators began their search by comparing the circular RNA profiles of docetaxel-sensitive prostate cancer cell lines with variants engineered to resist the drug. Among the differentially expressed candidates, one molecule stood out: circLPAR3, also catalogued as hsa_circ_0004390, produced from the back-splicing of exons 2 and 3 of the LPAR3 gene. Intriguingly, the abundance of the parental LPAR3 gene’s linear transcripts did not differ meaningfully between sensitive and resistant cells, indicating that the resistance phenotype was tied specifically to the circularized form rather than to a general upregulation of the gene itself. Quantitative reverse transcription PCR confirmed that circLPAR3 was substantially elevated in the resistant derivatives of three distinct prostate cancer cell lines, 22Rv1, DU145, and PC3.

Having established the correlation, the team moved to characterize the molecule in detail. Divergent primers spanning the circular junction verified the back-spliced structure, and treatment with RNase R, an enzyme that digests linear RNA but spares circular transcripts, confirmed the looped architecture. Actinomycin D chase experiments demonstrated that circLPAR3 is far more stable than its linear counterpart, consistent with the closed-loop design. Nuclear-cytoplasmic fractionation and fluorescence in situ hybridization then localized the molecule predominantly to the cytoplasm, a positioning that would prove central to its mechanism of action.

One of the study’s most significant contributions lies in explaining how circLPAR3 becomes elevated in resistant cells in the first place. The researchers found that the circular RNA is subject to N6-methyladenosine, or m6A, the most abundant internal chemical modification found on eukaryotic messenger RNAs and increasingly recognized as a master regulator of RNA fate. Specifically, the methyltransferase METTL3 installs the m6A marks on circLPAR3, and these modifications promote recruitment of IGF2BP2, an m6A reader protein that binds the marked transcript and shields it from degradation. In effect, the epitranscriptomic machinery acts as a stabilizing shield, allowing circLPAR3 to accumulate to pathological levels in cells exposed to docetaxel pressure. This finding adds prostate cancer chemoresistance to the growing list of malignancies in which m6A dynamics shape disease behavior.

With the regulatory mechanism upstream clarified, the team turned to what circLPAR3 actually does inside the cell. Biochemical interaction assays revealed that the cytoplasmic circular RNA physically binds Poly(RC) Binding Protein 2, or PCBP2, an RNA-binding protein with a well-documented role in stabilizing specific target messenger RNAs. Among PCBP2’s targets is the messenger RNA of CHAC1, a gene encoding ChaC glutathione-specific gamma-glutamylcyclotransferase 1, a critical component of the cellular machinery that drives ferroptosis. When circLPAR3 sequesters PCBP2, the protein can no longer perform its stabilizing duty on CHAC1 transcripts, and the CHAC1 messenger RNA rapidly degrades.

The consequences of this molecular sabotage are profound. Ferroptosis is a form of regulated cell death defined by iron-dependent accumulation of lipid peroxides, and it has emerged in recent years as a key mechanism through which chemotherapy eliminates tumor cells. Docetaxel-induced ferroptosis depends on a functioning CHAC1 axis. By depleting CHAC1, circLPAR3 effectively disarms this lethal pathway. The researchers documented the expected biochemical signature of suppressed ferroptosis in resistant cells: reduced accumulation of divalent iron, diminished lipid peroxidation, lowered levels of malondialdehyde, a standard marker of oxidative membrane damage, and preserved intracellular glutathione, the cell’s principal antioxidant buffer. In other words, circLPAR3 rewires tumor cell metabolism to withstand the oxidative assault that docetaxel is meant to deliver.

Crucially, the team showed that the process is reversible. Silencing circLPAR3, or alternatively forcing CHAC1 overexpression, restored the cells’ sensitivity to docetaxel by re-enabling ferroptosis. This rescue experiment carries substantial therapeutic implications, because it demonstrates that the resistance phenotype is not a permanent genetic alteration but a regulable state maintained by a single RNA molecule. It also establishes CHAC1 as a potential downstream effector that could be targeted pharmacologically, even in tumors where the upstream circular RNA is difficult to inhibit directly.

The in vivo evidence strengthened the case further. In subcutaneous xenograft mouse models, tumors engineered to overexpress circLPAR3 grew more aggressively under docetaxel treatment than control tumors, and analysis of the excised tumors confirmed reduced intratumoral CHAC1 expression. The animal data thus recapitulated the cell culture findings, demonstrating that the circLPAR3-PCBP2-CHAC1 axis functions as a genuine resistance mechanism in a living biological system rather than an artifact of laboratory conditions.

Taken together, the study weaves together three of the most dynamic themes in contemporary cancer research: circular RNAs, epitranscriptomic regulation, and ferroptosis. By showing that an m6A-stabilized circular RNA can suppress a ferroptosis-executing gene through sequestration of an RNA-binding protein, the Nanjing Medical University team has illuminated a regulatory circuit that connects chemical RNA modification to chemotherapy failure. The findings position circLPAR3 as a candidate biomarker for predicting treatment response in patients with advanced prostate cancer, and they suggest that disrupting the circLPAR3-PCBP2 interaction, restoring CHAC1 activity, or targeting the METTL3-IGF2BP2 stabilization pathway could open new avenues for resensitizing resistant tumors to docetaxel. As ferroptosis-inducing strategies continue to advance toward clinical testing, understanding the molecular brakes that tumors deploy against this form of cell death will be essential, and circLPAR3 now stands as one of the clearest examples of such a brake in prostate cancer.

Subject of Research: m6A-modified circular RNA circLPAR3 promoting docetaxel resistance in prostate cancer by suppressing ferroptosis via the PCBP2/CHAC1 axis

Article Title: circLPAR3 drives chemotherapy resistance in prostate cancer

Article References: circLPAR3 drives chemotherapy resistance in prostate cancer. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: prostate cancer, circLPAR3, docetaxel resistance, ferroptosis, circular RNA, m6A methylation, METTL3, IGF2BP2, PCBP2, CHAC1, chemoresistance, non-coding RNA

The centerpiece of the new work is a chemical modification called lactylation, a relatively recent addition to the catalog of post-translational modifications that biologists use to describe how proteins are tuned after they are made. Lactylation attaches a lactate-derived group to lysine residues, the same amino acid building blocks that carry many other regulatory marks. What makes this modification special is its origin: lactate is the end product of the fermentation metabolism that cancer cells rely on heavily even when oxygen is plentiful, a phenomenon known as aerobic glycolysis or the Warburg effect. Tumors therefore bathe their surroundings in lactate, and lactylation provides a direct mechanism by which this metabolic byproduct can be converted into epigenetic and proteomic instructions that reshape cell behavior.

To map the full landscape of this modification in liver cancer, the team carried out global lactylome profiling, using liquid chromatography-tandem mass spectrometry to identify precisely which proteins in hepatocellular carcinoma tissue carry lactylation marks and at which lysine positions. This unbiased survey was complemented by RNA sequencing, lipidomics to quantify the repertoire of fats and sterols inside tumors, and single-cell RNA sequencing to place the molecular findings within the complex cellular ecosystem of the tumor. The researchers also generated customized site-specific antibodies, tools that recognize lactylation at a single defined amino acid position on a single protein, allowing them to detect and manipulate one specific mark among thousands.

Two distinct lactylation events emerged as the critical nodes of the pathway. The first occurs on histone H3, one of the spool-like proteins around which DNA is wound. When lysine 18 of histone H3 is lactylated, a mark known as H3K18la, it acts on chromatin the way an open sign acts on a shop door: it makes nearby genes accessible for transcription. In this case, the gene switched on by H3K18 lactylation encodes METTL3, methyltransferase-like 3, the catalytic engine of the cell’s N6-methyladenosine machinery. m6A is the most abundant internal chemical modification of messenger RNA in mammals, and METTL3 is the enzyme that installs it. By raising METTL3 production through histone lactylation, the tumor effectively turns up the dial on RNA methylation across the cell.

The second event is more unusual and more conceptually striking. METTL3 itself, a protein rather than a stretch of DNA, is lactylated at lysine 27. This non-histone lactylation of METTL3 enhances its enzymatic activity, so the very methyltransferase whose production was boosted by histone lactylation is simultaneously activated by lactylation of its own structure. The result is a feed-forward arrangement in which lactate amplifies the m6A-writing apparatus at two independent levels. Once supercharged, METTL3 deposits m6A marks onto the messenger RNA of a specific target: FDFT1, farnesyl-diphosphate farnesyltransferase 1, the enzyme that catalyzes the first committed step of the cholesterol biosynthesis pathway, converting farnesyl pyrophosphate into squalene.

m6A marks on RNA do not act alone. They are read by a family of recognition proteins that determine the fate of the tagged transcript. The study identified IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2, as the reader that recognizes the METTL3-installed marks on FDFT1 messenger RNA. Rather than destroying the transcript, IGF2BP2 stabilizes it and promotes its translation into protein. The net effect of the entire cascade is a surge in FDFT1 protein, a surge in de novo cholesterol synthesis, and, as the lipidomics data confirmed, enhanced cholesterol efflux from the tumor cells into the surrounding microenvironment. Cholesterol, in this scenario, is not merely a building block for membranes; it functions as a signaling metabolite that reprograms neighboring immune cells.

The destination of that cholesterol signal is the tumor-associated macrophage, one of the most influential cell types in the tumor microenvironment. Macrophages are plastic cells that adopt distinct functional states: M1-like macrophages tend to attack tumors and rally anti-tumor immunity, whereas M2-like macrophages suppress immune responses, promote tissue remodeling, and support tumor growth. Using spontaneous orthotopic hepatocellular carcinoma mouse models, in which tumors arise in the liver and grow in their natural anatomical location, together with humanized orthotopic models carrying human immune cells, the researchers demonstrated that the cholesterol-rich environment driven by the lactylation cascade pushes tumor-associated macrophages toward the immunosuppressive M2 phenotype. Flow cytometry confirmed the shift in macrophage polarization states within the tumors.

The clinical implications of this mechanism are considerable. An immunosuppressive macrophage population is one of the central reasons why checkpoint inhibitor therapies underperform in liver cancer: even when T cells are unleashed, they enter a microenvironment thick with M2-polarized macrophages and other suppressive elements. By tracing that suppression back to a defined molecular axis, the H3K18la/METTL3-K27la/FDFT1 pathway, the study converts a diffuse problem into a set of addressable targets. Inhibiting lactate production or lactylation enzymes, blocking METTL3 activity, disrupting the IGF2BP2-FDFT1 interaction, or intervening in cholesterol biosynthesis and efflux each represents a potential point of attack, and combining such interventions with existing immunotherapy could theoretically relieve the immunosuppression that currently blunts treatment responses.

Methodologically, the study is notable for the breadth of its toolkit and the rigor of its validation. The investigators moved from unbiased lactylome discovery to mechanistic confirmation using methylated RNA immunoprecipitation to verify m6A deposition on FDFT1 transcripts, RNA immunoprecipitation to confirm the IGF2BP2 interaction, and chromatin-level analyses to establish the H3K18la-driven transcriptional activation of METTL3. The animal work was conducted under institutional ethics approval and in accordance with ARRIVE guidelines 2.0, and the human tissue component, which collected hepatocellular carcinoma specimens and paired peritumoral tissue from surgical patients with written informed consent, was approved by the Ethics Committee of The First Affiliated Hospital of Zhengzhou University. The authors declared no competing interests, and the work received support from the National Natural Science Foundation of China and the Key Scientific Research Projects of Universities in Henan Province.

Beyond its immediate relevance to liver cancer, the research adds an important conceptual layer to a rapidly growing field. Lactylation was first described as a histone mark linking cellular metabolism to gene expression, but evidence has been accumulating that non-histone proteins are also extensively lactylated. This study is among the first to show, in a single connected pathway, how histone lactylation and non-histone lactylation cooperate: one mark turns a gene on, the other activates the protein that gene encodes, and the combined output rewires lipid metabolism to corrupt the immune landscape of a tumor. It is a vivid demonstration that metabolites can act as messengers across entirely different layers of biological regulation, from chromatin to RNA to lipid chemistry to immune cell behavior. For patients with hepatocellular carcinoma, whose options remain limited despite decades of effort, the identification of this lactylation-cholesterol-macrophage axis offers a genuinely new direction, one that treats the tumor’s metabolic exhaust not as waste but as the fuel of a communication network that medicine may now learn to cut.

Subject of Research: Lactylation-regulated cholesterol metabolic reprogramming and macrophage polarization in hepatocellular carcinoma

Article Title: Lactylation-regulated METTL3-mediated cholesterol metabolic reprogramming via FDFT1 facilitates macrophage polarization in hepatocellular carcinoma

Article References: Zhai, Y., Zhao, H., Wang, Z., Zhang, Y., Zhao, S., Wang, C., Liu, Y., Cao, J., Lin, C., Wu, Y., Liang, R., Zhu, R., Wang, W., Li, J., & Sun, Y. (2026). Lactylation-regulated METTL3-mediated cholesterol metabolic reprogramming via FDFT1 facilitates macrophage polarization in hepatocellular carcinoma. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08870-z

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08870-z

Keywords: hepatocellular carcinoma, lactylation, METTL3, m6A methylation, FDFT1, cholesterol metabolism, macrophage polarization, tumor microenvironment, IGF2BP2, H3K18la, immunosuppression, tumor-associated macrophages

The RBM family is defined by a shared structural module: the RNA recognition motif, a compact domain of roughly ninety amino acids folded into a four-stranded beta sheet packed against two alpha helices. This domain binds short stretches of RNA, typically through aromatic residues that stack against the bases, and most RBM proteins carry multiple copies of it, often connected by flexible linkers that allow tandem domains to recognize longer or composite RNA elements. Many members also harbor auxiliary domains, such as zinc fingers, OCRE motifs, or arginine-rich regions, that extend their binding repertoire or recruit interaction partners. Structural studies, including nuclear magnetic resonance analyses of RBM10’s OCRE-containing domain and crystallographic work on RBM5’s RNA-binding surface, have revealed how these proteins achieve specificity despite the modest selectivity of any single RRM domain. The result is a versatile toolkit: RBM proteins can clasp pre-messenger RNAs, mature transcripts, long noncoding RNAs, and even ribosomal RNA, positioning them to regulate nearly every step of the RNA lifecycle.

Among the best-characterized family members are RBM5 and RBM10, which the review describes as tumor suppressors. Both proteins function as components of the U2 small nuclear ribonucleoprotein particle, engaged with intron branch sites on chromatin, where they steer the splicing machinery toward particular exon choices. Their tumor-suppressive influence is vividly illustrated by their control of NUMB alternative splicing: RBM5, RBM6, and RBM10 differentially regulate which NUMB isoform is produced, and the resulting isoform balance determines whether cancer cells proliferate or restrain themselves. In lung adenocarcinoma, RBM10 loss promotes proliferation and metastasis through a feedback loop involving microRNA-224-5p and p53, and the protein also restrains the RAP1/AKT/CREB signaling pathway. RBM10 mutations, which are frequent in lung adenocarcinoma, have been proposed as negative prognostic and predictive markers, and a specific C761Y mutation in cholangiocarcinoma generates oncogenic ASPM isoforms that activate beta-catenin signaling. Recent work has even exploited this vulnerability therapeutically: RBM10-deficient lung adenocarcinoma cells show heightened sensitivity to agents that induce DNA replication stress, opening a synthetic-lethal strategy against tumors that have lost this suppressor.

RBM5 itself displays a strikingly context-dependent personality. In colorectal cancer, it suppresses proliferation, metastasis, and glycolysis by stabilizing the messenger RNA of the phosphatase and tensin homolog, PTEN, a master brake on growth signaling. It also recruits the factor MGC32805 in a sandwich mode to induce a novel FAS neoantigen, switching the death receptor’s properties in a way that may sensitize tumors to immune attack. Yet in acute myeloid leukemia, RBM5 plays the villain, activating the oncogenic protein HOXA9 and supporting leukemic growth. This duality, the same protein acting as friend in one tissue and foe in another, recurs throughout the family and underscores a central theme of the review: RBM proteins cannot be labeled simply as oncogenes or suppressors. Their function depends on the RNA landscape of the cell, the signaling pathways in play, and the selective pressures of the tumor microenvironment.

A second axis of RBM-mediated cancer regulation runs through m6A, the most abundant internal chemical modification of messenger RNA. RBM15 and its paralog RBM15B are core components of the m6A writer complex, the machinery that deposits methyl groups onto adenosines across the transcriptome. By recognizing the histone mark H3K79me2, RBM15B guides selective m6A modification of messenger RNAs and enhances oncoprotein translation in MLL-rearranged leukemia, a finding reported in the EMBO Journal in 2026 that links chromatin state directly to RNA modification patterns. In triple-negative breast cancer, RBM15 drives cell growth by stimulating serine and glycine metabolism, while in cervical cancer it promotes epithelial-mesenchymal transition through m6A modification of the EZH2 transcript and supports stemness by stabilizing the long noncoding RNA HEIH. RBM15 also enhances paclitaxel resistance in triple-negative breast cancer by methylating TNFSF9 and polarizing tumor-associated macrophages toward an immunosuppressive M2 state, connecting RNA modification to both drug resistance and the immune microenvironment.

Other family members exert their influence through equally inventive mechanisms. RBM3, a cold-shock-inducible protein, suppresses stemness remodeling of prostate cancer in the bone microenvironment by modulating m6A on CTNNB1 messenger RNA, halts the cell cycle of cutaneous squamous cell carcinoma through the PI3K/AKT pathway, and has repeatedly been associated with favorable prognosis and cisplatin sensitivity in epithelial ovarian cancer and muscle-invasive bladder cancer. RBM38, meanwhile, is a key lieutenant of the p53 tumor-suppressor network: it stabilizes the p53-MDM2 loop in hepatocellular carcinoma, and its genetic ablation promotes lymphomagenesis in the context of mutant p53 by downregulating PTEN. RBM47 restrains renal cell carcinoma by interacting with the long noncoding RNA HOXB-AS1 and acts as an anti-oncogene in colorectal cancer, yet in pancreatic cancer it promotes proliferation and immune evasion by upregulating PDIA6, and in nasopharyngeal carcinoma it drives tumorigenesis through multiple pathways. RBM45 reprograms lipid metabolism in hepatocellular carcinoma via Rictor and the acyl-CoA synthetases ACSL1 and ACSL4, and stabilizes the glutamine transporter ASCT2 through phosphorylation to fuel tumor progression.

The therapeutic implications of this biology are beginning to crystallize. The most advanced example involves RBM39, a related RNA-binding protein that can be degraded by molecular-glue compounds such as indisulam and E7820, which recruit the DCAF15 ubiquitin ligase. A 2024 study in npj Precision Oncology showed that an RBM39-degrader induces synthetic lethality in cancer cells deficient in homologous recombination repair, suggesting a rational combination with PARP inhibitors or platinum chemotherapy. For the RBM family proper, a first-in-class small-molecule inhibitor of the eIF4E-RBM38 complex has been developed; by disrupting this interaction, the compound enhances translation of wild-type p53 and suppresses tumor growth, validating protein-protein interfaces involving RBM proteins as druggable targets. A synthetic peptide called Pep8 achieves a similar effect by camouflaging the same interface. These proof-of-concept successes matter because the RNA recognition motif has long been considered difficult to drug, its shallow RNA-binding grooves resisting conventional small-molecule approaches.

The review also highlights how RBM proteins intersect with clinical decision-making beyond drug targets. RBM3 expression levels correlate with chemosensitivity in ovarian and bladder cancers, potentially guiding platinum-based treatment choices. RBM10 mutation status may stratify patients with non-small-cell lung cancer, flagging tumors with distinct vulnerabilities and therapy responses. RBM11 serves as a prognostic biomarker in ovarian cancer, RBM19 promotes prostate cancer progression under docetaxel treatment through the SNHG21/PIM1 axis, and RBMX contributes to sorafenib resistance in hepatocellular carcinoma by stabilizing the long noncoding RNA BLACAT1. RBM38, conversely, reverses sorafenib resistance by promoting the tumor-suppressive lncRNA GAS5. As liquid biopsy platforms for circulating tumor cells mature, RNA-binding protein signatures detected in blood may eventually complement tissue-based diagnostics, though the review stops short of claiming clinical readiness for such applications.

What emerges from this synthesis is a portrait of a protein family whose complexity mirrors that of cancer itself. The same RBM protein can suppress one tumor while feeding another, can be drugged in one context and mimicked in another, and can act through splicing, m6A methylation, messenger RNA stability, translation, or long noncoding RNA scaffolding depending on circumstance. The Qingdao University team argues that disentangling these context-dependent roles, through systematic mapping of RNA targets, structural dissection of binding domains, and careful correlation with patient outcomes, is the essential next step. If that effort succeeds, the RBM family could yield a generation of biomarkers that predict treatment response and therapeutic strategies that exploit the very RNA-processing dependencies cancers have built into themselves. For now, the review stands as both a map of what is known and a catalog of what remains to be tested, from the branch sites of chromatin-bound introns to the methylated transcripts that decide a tumor’s fate.

Subject of Research: The roles of the RBM RNA-binding protein family in cancer occurrence, progression, and therapy

Article Title: RBM protein family: Focusing on the occurrence, progression and treatment of cancer

Article References: Zhang, H., Zheng, W., Li, L., Geng, C., Wang, Y., Zhang, J., Sun, Y., Zhang, X., & Li, B. (2026). RBM protein family: Focusing on the occurrence, progression and treatment of cancer. Medical Oncology, 43(11), Article 322. https://doi.org/10.1007/s12032-026-03439-8

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03439-8

Keywords: RBM proteins, RNA-binding proteins, alternative splicing, m6A methylation, tumor suppressor, oncogene, RBM10, RBM15, RBM38, therapeutic target, biomarker, cancer

Breast cancer overtook lung cancer as the most commonly diagnosed cancer in women worldwide in 2020, and roughly seventy percent of cases are hormone receptor-positive, meaning their growth is driven by estrogen signaling. While patients with localized tumors enjoy five-year survival rates above ninety percent, those with metastatic disease fall below thirty percent, largely because of chemotherapy tolerance and spread to distant organs. Understanding the epigenetic and post-transcriptional programs that fuel progression has therefore become one of the most urgent quests in cancer biology, and RNA methylation has emerged as a key frontier in that search.

The m6A mark is the most prevalent chemical modification found on both coding and non-coding RNAs. It is installed by writer proteins such as METTL3, METTL14 and WTAP, removed by erasers like FTO and ALKBH5, and interpreted by reader proteins that determine the fate of the tagged molecule. Readers are widely considered the decisive regulators of the system because they dictate whether a modified RNA is stabilized, degraded, or translated. In breast cancer, previous work has shown that the demethylase FTO strips m6A from the tumor suppressor BNIP3 and hastens its decay, while the writer METTL3 promotes expression of the proliferation-driving HBXIP. Yet the roles of many readers, and their relationship to the estrogen receptor, remained unmapped.

To find the most relevant readers, the team mined the TCGA-BRCA database and found that several, including CPSF6, HNRNPA2B1, HNRNPC, PRRC2A and TRMT112, were abnormally elevated in tumors. HNRNPC stood out. Its levels were higher in tumor tissue than in adjacent normal tissue in paired patient samples, it was upregulated in most breast cancer cell lines tested, including the estrogen receptor-positive lines MCF7 and T47D, and analysis of two independent clinical datasets, GSE4922 and GSE7378, showed that patients with high HNRNPC expression had significantly worse disease-free survival.

Functionally, the protein behaved like a classic oncogene. When the researchers silenced HNRNPC with small interfering RNAs, proliferation of MCF7 and T47D cells dropped sharply across CCK-8 growth assays, colony formation tests and EdU incorporation assays that measure DNA replication. Flow cytometry revealed a G1-to-S phase arrest in the depleted cells, while wound healing and Transwell experiments showed reduced migration and invasion. Conversely, restoring HNRNPC reversed these effects. The picture was consistent: HNRNPC is not a passive passenger but an active driver of malignant behavior in estrogen receptor-positive cells.

The next question was what HNRNPC actually binds. Using RNA immunoprecipitation followed by sequencing, the team mapped its binding sites across the transcriptome of both cell lines. The majority of peaks clustered in three-prime untranslated regions, and the dominant sequence motif was a run of continuous uracil bases, exactly what earlier structural studies had predicted for this protein. Pathway analysis of the bound RNAs pointed to cancer-relevant programs including PI3K-Akt, mTOR and cell cycle regulation. Within the resulting network, one hub gene emerged: DDX6, an ATP-dependent DEAD-box RNA helicase already known to act oncogenically in gastric and colorectal cancers, where it regulates transcripts such as HER2, FGFR2 and c-Myc.

The mechanism connecting HNRNPC to DDX6 is the study’s most technically striking finding. HNRNPC does not bind the m6A mark itself. Instead, methylating an adenosine weakens its pairing with an opposite uracil, loosening the local RNA structure so that HNRNPC can latch onto the exposed continuous uracil tract, a phenomenon known as an m6A switch. In the DDX6 three-prime UTR, the team identified such a poly-U region around nucleotide 5500, flanked by predicted m6A sites. RNA pull-down assays with wild-type and mutated DDX6 probes confirmed the direct interaction, and immunofluorescence combined with fluorescent in situ hybridization placed both the protein and the transcript in the nucleus, where the binding occurs. Crucially, when the researchers lowered global m6A levels by knocking down METTL3 or using the inhibitor SAH, the HNRNPC-DDX6 interaction weakened, while knocking down the erasers FTO or ALKBH5 strengthened DDX6 expression. The binding is therefore genuinely m6A-dependent.

What does that binding accomplish? RNA decay assays using actinomycin D showed that loss of HNRNPC destabilized DDX6 mRNA, whereas overexpression of HNRNPC preserved it. DDX6, in turn, proved to be a bona fide tumor promoter in breast cancer: silencing it reduced proliferation and caused G1-S arrest, and it lowered levels of the cell cycle proteins cyclin D1 and CDK6. Most persuasively, overexpressing DDX6 rescued the proliferation, cell cycle progression, migration and invasion defects caused by HNRNPC depletion, establishing DDX6 as a functional downstream target. When the team mutated the poly-U sequence in the DDX6 transcript, converting it to poly-C, the mutant RNA could no longer rescue the tumor-suppressive phenotype, sealing the argument that the oncogenic effect flows through the m6A-switch-mediated interaction.

Upstream, the team traced the origin of HNRNPC overexpression to the estrogen receptor alpha itself. Database mining with JASPAR and Cistrome predicted ERα binding sites in the HNRNPC promoter, correlation analysis of TCGA data showed a significant positive relationship between ESR1 and HNRNPC expression, and chromatin immunoprecipitation with an ERα antibody confirmed that the receptor physically occupies the HNRNPC promoter. The result sketches a complete axis: estrogen receptor alpha transcriptionally upregulates HNRNPC, which stabilizes DDX6 mRNA in an m6A-dependent manner, and DDX6 drives cell cycle progression, proliferation and metastasis.

Animal experiments lent in vivo weight to the model. In nude mice implanted subcutaneously with luciferase-labeled MCF7 cells, stable knockdown of HNRNPC markedly slowed tumor growth, reduced final tumor weight and lowered Ki-67 staining, a standard marker of proliferation. In a tail-vein metastasis model using T47D cells, HNRNPC depletion reduced metastatic colonization of the lungs and liver. The authors are candid about limitations: the m6A switch model rests partly on bioinformatic prediction and lacks direct molecular structural validation, and HNRNPC is also elevated in some estrogen receptor-negative cancers, implying that other mechanisms must exist to upregulate it there. Even so, the ERα/HNRNPC/DDX6 axis offers a fresh mechanistic explanation for how hormone signaling and RNA epigenetics conspire in breast cancer, and it points to HNRNPC, or the m6A-switch interaction it mediates, as an actionable vulnerability in a disease that still needs better options for patients with advanced, treatment-resistant tumors.

Subject of Research: An ERα/HNRNPC/DDX6 regulatory axis in m6A-mediated mRNA stabilization and estrogen receptor-positive breast cancer progression

Article Title: ERa-induced m6A reader HNRNPC maintains DDX6 mRNA stability to promote tumor progression in ER+BC

Article References: Huang, Z., Xu, W., Xiao, Y., Li, W., Xu, M., Zhao, Q., & Yi, P. (2026). ERa-induced m6A reader HNRNPC maintains DDX6 mRNA stability to promote tumor progression in ER+BC. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03506-x

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03506-x

Keywords: breast cancer, m6A methylation, HNRNPC, DDX6, estrogen receptor alpha, RNA-binding proteins, mRNA stability, epigenetics, oncology, tumor progression, RNA biology, British Journal of Cancer

Liver abscess is a severe suppurative infection in which pockets of pus and necrotic debris accumulate within hepatic tissue. The core pathological problem, the authors note, is not simply the presence of bacteria but the failure to promptly clear the large amounts of dead cells and pathogen fragments left behind at the infection site. That debris sustains an excessive and persistent inflammatory response, worsening local tissue damage and eroding clinical prognosis. Left unchecked, the process can progress to peritonitis and sepsis, causing irreversible and potentially fatal injury. Current standard treatments, antibiotics and percutaneous drainage, are effective at eliminating pathogens and managing the abscess cavity, but they do little to strengthen the body’s intrinsic capacity to calm inflammation, and some patients respond poorly, particularly when initial treatment is delayed.

At the center of the new work is efferocytosis, the process by which macrophages recognize, engulf, and digest apoptotic and necrotic cells. Efferocytosis is far more than housekeeping: as macrophages consume cellular corpses, they are pushed toward an anti-inflammatory and reparative phenotype, releasing mediators that actively resolve inflammation and initiate tissue reconstruction. Under the high-burden infectious stress of a liver abscess, however, this scavenging function is often suppressed or impaired, creating a vicious cycle in which necrotic debris accumulates, inflammation persists, and tissue damage compounds. Enhancing efferocytosis, the researchers argue, is therefore a key scientific challenge for promoting genuine healing of abscessed liver lesions rather than merely containing them.

To find a lever for that enhancement, the team looked to Nrf2, a central transcription factor in cellular anti-inflammatory defense that is known to maintain macrophage functional homeostasis and regulate phagocytosis-related genes. The upstream mechanisms controlling Nrf2 expression in liver abscess had not been elucidated. The investigators focused on m6A, the most abundant internal chemical modification of eukaryotic mRNA, which is catalyzed by methyltransferases such as METTL3 and dynamically regulates target genes by influencing mRNA stability, splicing, nuclear export, and translation efficiency. Whether METTL3-mediated m6A methylation of Nrf2 mRNA could serve as a regulatory node for macrophage efferocytosis under infectious stress was the central question of the study.

The experimental design combined a mouse model with cell culture rescue experiments. Forty male SPF-grade C57BL/6J mice were randomly assigned to control, bacterial liver abscess model, abscess plus control vector, and abscess plus METTL3 overexpression groups. After receiving adeno-associated virus vectors via tail vein injection four weeks before modeling, the animals underwent intrahepatic injection of Klebsiella pneumoniae, the leading clinical cause of liver abscess, accounting for more than half of isolates. All live-pathogen procedures were conducted under Biosafety Level 2 conditions. The model was validated by significant weight loss, pathological liver damage, and elevated serum inflammatory cytokines, while fluorescence imaging confirmed successful hepatic delivery of the vectors.

The gross and microscopic results were striking. Livers from untreated abscess mice appeared dark red with multiple firm, whitish round protrusions of one to two millimeters along the lobular margins, occasionally coalescing into larger lesions, together with regional yellowish abscesses and histological evidence of hepatocyte necrosis, inflammatory infiltration, and fibroblast proliferation. In mice overexpressing METTL3, the focal protrusions were noticeably fewer and hepatic tissue damage was significantly attenuated. Serum analysis reinforced the picture: overexpression lowered the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α while raising the anti-inflammatory, pro-resolution mediators IL-10 and TGF-β. The authors interpret this bidirectional shift as evidence that METTL3 redirected the inflammatory milieu toward resolution and repair rather than inducing nonspecific immunosuppression.

Molecular profiling revealed the mechanism underneath. METTL3 overexpression increased m6A enrichment on Nrf2 mRNA, as measured by methylated RNA immunoprecipitation followed by quantitative PCR, and further activated the Nrf2/HO-1 signaling axis, elevating Nrf2 and HO-1 protein levels while suppressing the negative regulator Keap-1. Downstream, the expression of the TAM receptor family, MerTK, Tyro3, and AXL, rose significantly in the livers of abscess mice and climbed higher still with METTL3 overexpression. These receptors form the molecular machinery of efferocytosis: MerTK directly drives clearance of apoptotic and necrotic cells and promotes reparative macrophage polarization, while AXL and Tyro3 fine-tune immune homeostasis. Immunofluorescence co-localization showed that F4/80-positive hepatic macrophages co-expressing MerTK and Nrf2 increased in the abscess model and increased further with METTL3, linking Nrf2 activation spatially to enhanced efferocytic capacity.

Causality was established in LPS-stimulated RAW264.7 macrophages using a four-group design crossing METTL3 overexpression with Nrf2-targeting siRNA. METTL3 overexpression markedly increased mRNA and protein levels of all three TAM receptors and shifted the macrophage phenotype, reducing the proportion of CD86-positive pro-inflammatory cells and increasing CD206-positive anti-inflammatory, pro-repair cells. Nrf2 knockdown reversed every one of these effects, and two-way ANOVA confirmed significant interactions between the two manipulations for MerTK, Tyro3, and AXL expression as well as for polarization markers. The rescue experiments establish Nrf2 as the key downstream mediator through which METTL3 promotes an anti-inflammatory, pro-efferocytic macrophage state, consistent with prior evidence that Nrf2/HO-1 signaling regulates MerTK expression and that Nrf2 deficiency impairs apoptotic-cell clearance.

The study situates itself within a growing literature showing that METTL3’s role is context-dependent. It promotes post-infarction inflammation after myocardial infarction, exacerbates renal tubular inflammation and inflammatory bowel disease, yet its knockdown worsens neuroinflammation in hyperuricemic mice. In the abscess model, endogenous METTL3 rose alongside inflammatory cytokines, suggesting it may act as a compensatory protector early in disease, and its deliberate overexpression exerted therapeutic anti-inflammatory effects. The authors are candid about limitations: the TBG-driven AAV induced hepatic rather than macrophage-specific overexpression, rescue experiments used a macrophage cell line rather than primary Kupffer cells, direct apoptotic-cell engulfment assays and Nrf2 promoter-binding experiments were not performed, and the work covered a single bacterial strain and one terminal time point. Future studies with macrophage-specific genetic models, ChIP-qPCR, and m6A site mapping are planned. Even so, the METTL3/Nrf2 axis now stands as a compelling candidate target for therapies that would help patients resolve liver abscess inflammation from within, complementing antibiotics and drainage rather than replacing them.

Subject of Research: METTL3-mediated m6A methylation of Nrf2 mRNA regulating macrophage efferocytosis in bacterial liver abscess

Article Title: METTL3 Alleviates Liver Abscess by Enhancing Macrophage Efferocytosis via m6A Methylation of Nrf2 mRNA

Article References: Wang, G., Luo, D., Pang, Y., Gao, C., Jin, D., & Wang, Q. (2026). METTL3 Alleviates Liver Abscess by Enhancing Macrophage Efferocytosis via m 6 A Methylation of Nrf2 mRNA. Immunity, Inflammation and Disease, 14(10), Article e70534. https://doi.org/10.1002/iid3.70534

Image Credits: AI Generated

DOI: 10.1002/iid3.70534

Keywords: METTL3, m6A methylation, Nrf2, efferocytosis, macrophages, liver abscess, Klebsiella pneumoniae, TAM receptors, MerTK, inflammation resolution, epitranscriptomics, HO-1

The clinical starting point was a group of patients whose stomachs suffer as a consequence of their livers. The team enrolled 111 patients with hepatitis B-related liver cirrhosis or hepatic failure at the Third Affiliated Hospital of Sun Yat-sen University between January 2022 and August 2024, alongside 118 control subjects. Using the gastrointestinal symptom rating scale, a validated 15-item questionnaire, the researchers found that patients with liver disease scored significantly higher overall than controls, 51.49 versus 42.40, with heartburn, acid reflux, nausea, bloating and diarrhea all markedly more frequent. Endoscopy told a matching story: the diseased mucosa showed more erosion and bleeding, and statistical analysis confirmed that mucosal lesions correlated with higher symptom scores, while normal mucosa tracked with lower scores.

Why would a congested stomach become a hypoxic one? The explanation is vascular. In portal hypertension and hepatic failure, restricted blood flow through the portal vein causes gastric venous congestion, and the oxygen supply to the epithelium falls behind demand. Using Hypoxyprobe-1 staining, the team demonstrated that hypoxia was indeed present in the gastric epithelium of these patients. In parallel, they established a mouse model of portal hypertension by partially ligating the portal vein, and again the hypoxia signal rose in step with a quantified gastric injury index. Crucially, the transcription factor HIF-1α, the master regulator of the cellular response to low oxygen, accumulated in the nuclei of epithelial cells in both human and mouse tissue, poised to reprogram gene expression.

That reprogramming showed up first as a metabolic shift. RNA sequencing of clinical gastric samples revealed enrichment of glycolysis and anaerobic metabolism pathways, and untargeted metabolomics of epithelial cells from the mouse model confirmed the biochemical signature: lactic acid rose while isocitric acid and citric acid, intermediates of the mitochondrial citric acid cycle, fell. This is the classic Warburg-like pattern in which cells, deprived of the oxygen needed for oxidative phosphorylation, burn glucose to lactate instead. In the short term this is a survival strategy, but the study suggests that under sustained hypoxia it becomes pathological, feeding a vicious cycle of metabolic disorder, reactive oxygen species generation and cell death.

The central molecular discovery concerns FUNDC1, an outer mitochondrial membrane protein previously known to help build mitochondria-associated ER membranes, or MAMs. These contact sites are far more than structural curiosities: they regulate calcium transfer from the ER to mitochondria, lipid exchange and mitochondrial dynamics. The researchers found that HIF-1α binds directly to a hypoxia-responsive element in the FUNDC1 promoter, driving its transcription, and that a second, post-transcriptional layer reinforces this. The m6A methyltransferase METTL3 chemically modified FUNDC1 messenger RNA, and the RNA-binding protein IGF2BP3, the most upregulated m6A reader in cirrhotic gastric tissue, recognized and stabilized that modified transcript. In mice carrying a mutant METTL3, FUNDC1 upregulation was blunted, confirming the epitranscriptomic mechanism.

With FUNDC1 elevated, the ER and mitochondria embraced more tightly. Transmission electron microscopy showed expanded contact zones in epithelial cells from portal hypertensive mice and from cirrhotic patients, and a proximity ligation assay for the IP3R2–VDAC1 tethering pair quantified the same increase. Coimmunoprecipitation confirmed that FUNDC1, IP3R2, VDAC1 and GRP75 formed complexes under hypoxic conditions. Truncation experiments pinpointed amino acids 7 to 48 of FUNDC1 as the domain essential for MAMs formation, a detail the authors highlight as a blueprint for designing inhibitors that could block the tethering interface specifically.

The consequences of this hyper-tethering were metabolic and oxidative. Seahorse extracellular flux analysis showed that epithelial cells under hypoxia had reduced maximal respiration, increased proton leak, elevated non-mitochondrial oxygen consumption and heightened basal and compensatory glycolysis, all of which were reversed when FUNDC1 was knocked down. Levels of electron transport chain subunits NDUFA9, SDHA, cytochrome b and ATP5A fell, along with ATP production. Meanwhile, mitochondrial superoxide, lipid peroxidation products such as 4-HNE and malondialdehyde, and oxidized mitochondrial DNA all climbed, while antioxidant defenses, superoxide dismutase activity and the glutathione redox ratio, collapsed. Calcium handling was also disturbed, with both cytosolic and mitochondrial calcium rising and membrane potential falling.

The final executioner in the cascade was NINJ1, a transmembrane protein that has recently emerged as the mediator of plasma membrane rupture during lytic cell death. In its inactive state NINJ1 is scattered across the membrane; when activated it oligomerizes into polymers that lyse the membrane and spill cellular contents. The team found NINJ1 oligomerization increased in gastric tissue from cirrhotic and hepatic failure patients, alongside elevated cleaved caspase-3 and cleaved caspase-1, markers of apoptosis and pyroptosis. Silencing NINJ1 in mice with portal hypertension reduced lactate dehydrogenase release, a readout of membrane permeabilization, restored epithelial viability and lessened mucosal injury. Notably, NINJ1 blockade did not change caspase activation, indicating it acts at the terminal step of membrane rupture rather than upstream of cell death signaling.

Two intervention experiments tied the whole axis together and pointed toward the clinic. Mito-TEMPO, a mitochondria-targeted antioxidant, suppressed NINJ1 oligomerization, reduced LDH release and protected the gastric mucosa in the mouse model, placing mitochondrial reactive oxygen species upstream of NINJ1 activation. The HIF-1α inhibitor PX-478 suppressed FUNDC1 expression and attenuated injury. Confocal imaging also showed that fragmented mitochondrial DNA released under oxidative stress colocalized with NINJ1, hinting at a direct or indirect role for escaping mtDNA in activating the rupture machinery, though the authors acknowledge the precise mechanism remains unresolved.

The authors are candid about limitations. The partial portal vein ligation model mechanically constricts the portal vein without reproducing hepatic parenchymal injury, systemic inflammation or the other comorbidities of clinical cirrhosis, and only knockdown rather than tissue-specific knockout approaches were used. Yet the reversibility of the pathway is encouraging: because MAMs remodeling is dynamic rather than covalent, targeted disruption of excessive ER-mitochondria tethering, inhibition of METTL3 or IGF2BP3 with emerging small molecules, or blockade of NINJ1 oligomerization with monoclonal antibodies could, in principle, interrupt the cycle before irreversible tissue damage sets in. If those strategies survive preclinical and clinical testing, the humble contact points between two organelles may become the address at which doctors finally treat the stomach’s silent suffocation.

Subject of Research: The FUNDC1–MAMs–NINJ1 signaling axis in hypoxia-induced gastric mucosal injury

Article Title: Mitochondria-associated endoplasmic reticulum membranes facilitate gastric epithelial injury in hypoxia-induced gastric mucosal lesions

Article References: Tan, S., Luo, J., Ou, X., Guo, X., Ke, B., & Tan, S. (2026). Mitochondria-associated endoplasmic reticulum membranes facilitate gastric epithelial injury in hypoxia-induced gastric mucosal lesions. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.007

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.007

Keywords: hypoxia, gastric mucosal injury, mitochondria-associated ER membranes, FUNDC1, HIF-1α, m6A methylation, METTL3, IGF2BP3, NINJ1, portal hypertension, mitochondrial oxidative stress, plasma membrane rupture

The study, published in BMC Genomics, focused on N6-methyladenosine, commonly abbreviated as m6A. This modification is the most abundant internal chemical tag found on messenger RNA in eukaryotic cells. Rather than altering the genetic code itself, m6A acts like a set of sticky notes on the transcript, influencing how efficiently each message is read, how stable it remains, and how it is processed. Scientists have known for over a decade that m6A shapes development in organisms ranging from plants to mammals, but its role in the skin biology of livestock has remained largely uncharted territory.

To probe this frontier, the research team, led by Binpeng Xi and Jianbin Liu of the Xinjiang Academy of Agricultural and Reclamation Science, employed two complementary sequencing technologies. The first, MeRIP-seq, uses antibodies that specifically recognize the m6A mark, allowing researchers to immunoprecipitate methylated RNA fragments and map exactly where on the transcriptome these tags reside. The second, RNA-seq, measures the abundance of every transcript, revealing which genes are switched up or down. By running both methods on skin samples from three newborn black-fleeced lambs and three 179-day-old white-fleeced lambs, the team could compare not only gene expression but also the epitranscriptomic landscape that governs it.

The mapping results revealed a strikingly consistent architecture of methylation across both age groups. Most m6A peaks clustered within coding sequences and near stop codons, the regions where the cellular machinery translates RNA into protein. The team also detected the canonical GGACU motif, the sequence signature most commonly recognized by m6A-binding proteins, in both the newborn and older animals. This consistency suggests that the fundamental machinery of RNA methylation operates similarly at both stages of coat development, while the differences lie in which specific genes carry the marks.

Those differences proved substantial. Across three paired comparisons between individual lambs of the two age groups, the researchers identified between 1,273 and 1,716 differential m6A peaks, alongside 400 to 1,657 differentially expressed genes. Functional enrichment analysis of these changing genes and peaks highlighted biological processes intimately tied to the coat transition: hair follicle development, epidermal morphogenesis, extracellular matrix remodeling, and focal adhesion. Signaling pathways long implicated in pigmentation and skin renewal also featured prominently, including Wnt, TGF-beta, PI3K-Akt, Notch, and melanogenesis-related cascades. The convergence of methylation changes and expression shifts on these pathways provides compelling circumstantial evidence that RNA modification participates in reprogramming the skin as fleece color flips.

One of the study’s most technically interesting contributions is its integrative analysis of how methylation status and transcript abundance couple. The researchers observed distinct coupling patterns depending on the comparison. In one pairing, hypermethylation coincided with downregulated expression, a pattern consistent with m6A accelerating transcript decay. In the other two comparisons, the predominant pattern was the opposite: hypomethylation paired with increased expression, suggesting that removal of the mark stabilizes certain messages during the white-fleece phase. This comparison-dependent coupling underscores a key principle of epitranscriptomics: the functional consequence of an m6A mark depends on its position within the transcript and the cellular context in which it appears.

From this integrated dataset, the team prioritized a shortlist of candidate m6A-associated genes that may drive the color transition. The list includes FZD7, a receptor in the Wnt signaling pathway with established roles in hair follicle cycling; GAS1, a growth arrest factor involved in developmental signaling; COL4A1, a structural collagen of the basement membrane; PXDN, an enzyme involved in collagen cross-linking; LAMC3, a laminin chain component of the extracellular matrix; ARID1A, a chromatin remodeling factor; FA2H, an enzyme in fatty acid metabolism; and RAPGEFL1, a signaling scaffold. The presence of extracellular matrix and Wnt pathway genes on this list fits the biology of the transition, since shifting from black to white fleece requires not only changes in pigment production by melanocytes but also structural remodeling of the follicle environment in which those pigment cells operate.

To validate their sequencing results, the researchers performed quantitative real-time PCR on selected genes, confirming that the expression trends observed by RNA-seq held up under an independent measurement method. This verification step strengthens confidence in the dataset, though the authors are careful to note that the m6A sites themselves have not yet been individually validated by orthogonal techniques, and functional studies of the candidate genes remain to be done. The work is explicitly framed as a candidate-generation study, laying the groundwork for targeted follow-up experiments rather than closing the case.

The authors also flag an important caveat: in their design, age and coat-color stage are confounded, since every older lamb was both white-fleeced and 179 days old. The molecular differences they detected therefore reflect the developmental transition as a whole, and disentangling which changes are specifically responsible for pigment switching will require additional experiments, potentially including time-course sampling at intermediate ages or comparisons with sheep breeds that do not undergo a color change. This honest framing is a model of scientific caution in a field where epitranscriptomic datasets can invite overinterpretation.

Nevertheless, the implications extend well beyond a single sheep breed. Coat color is an economically significant trait in wool and meat production, and understanding its developmental regulation could inform breeding strategies. More broadly, the study adds livestock skin biology to the growing map of tissues where m6A shapes developmental programs, joining work on embryogenesis, neurodevelopment, and immune differentiation. As the tools for precise m6A site validation and genome editing mature, the candidate genes identified here offer a concrete starting point for functional dissection. The humble Junken lamb, transforming from black to white in its first six months of life, has now given scientists a molecular thread to pull, and the fabric it unravels may reshape how we think about the epigenetic control of visible traits in farm animals.

Subject of Research: m6A RNA modification and gene expression during developmental coat color transition in Junken meat sheep

Article Title: Integrated MeRIP-seq and RNA-seq analyses identify candidate m6A-associated genes during developmental coat color transition in Junken meat sheep

Article References: Xi, B., Zhao, S., Yu, Q., Zhou, H., Zhang, W., Chen, Y., Cheng, R., Wang, Z., Yang, H., & Liu, J. (2026). Integrated MeRIP-seq and RNA-seq analyses identify candidate m6A-associated genes during developmental coat color transition in Junken meat sheep. BMC Genomics. https://doi.org/10.1186/s12864-026-13311-8

Image Credits: AI Generated

DOI: 10.1186/s12864-026-13311-8

Keywords: m6A methylation, MeRIP-seq, RNA-seq, coat color transition, Junken meat sheep, hair follicle development, melanogenesis, Wnt signaling, epitranscriptomics, skin biology, livestock genetics, BMC Genomics

The first family, post-translational modifications, or PTMs, are chemical tags appended to proteins after they are synthesized. Ubiquitin and ubiquitin-like modifiers such as SUMO can be attached to a protein to change its stability, localization, or interaction partners, while phosphorylation, O-GlcNAc glycosylation, and palmitoylation tune enzymatic activity and trafficking with remarkable speed. In the gut, these tags act as precision regulators. They fine-tune the activity of key inflammatory signaling molecules, including the transcription factor NF-κB, the innate immune receptors NOD2 and NLRP3, and components of the TNF-α and interleukin-17 pathways. The review catalogs an extensive cast of E3 ubiquitin ligases, such as TRIM8, TRIM25, RNF186, and PELI3, alongside deubiquitinases like CYLD, USP7, and USP25, that add or remove ubiquitin marks on these targets and thereby amplify or dampen inflammatory signals.

The second family operates one step upstream, on the RNA itself. RNA modifications, including N6-methyladenosine, the most abundant internal mark on messenger RNA, N4-acetylcytidine, and adenosine-to-inosine RNA editing, are installed, read, and erased by dedicated enzymes. The methyltransferase complex of METTL3 and METTL14 writes m6A marks, proteins such as YTHDF2 and IGF2BP2 read them, and the demethylase ALKBH5 erases them. The deaminase ADAR1 converts adenosine to inosine in double-stranded RNA, altering both coding potential and immune recognition of RNA transcripts. These modifications act as rapid response regulators: they change how efficiently specific messenger RNAs are translated into proteins, how long those transcripts persist, and how the innate immune system interprets them, all without altering the underlying genome.

The central claim of the review is that these two layers talk to each other extensively, and that this crosstalk is what allows the intestinal epithelium to respond quickly and precisely to injury. The authors describe a synthesis-precision regulation cascade: RNA modifications rapidly adjust the production of effector proteins, while PTMs then fine-tune the activity, stability, and localization of the proteins that have just been made. This two-step logic ensures that barrier repair and inflammation resolution happen efficiently, because the cell can both control how much of a protein is produced and modulate what that protein does once it exists. Neither layer alone achieves this level of control.

Concrete molecular examples illustrate the principle. In innate immune signaling, ubiquitination of RIP2, the kinase downstream of the Crohn’s disease risk gene NOD2, controls NF-κB activation, while RNA editing and m6A modification shape the expression of inflammatory transcripts in macrophages and epithelial cells. In the hypoxic environment of an inflamed gut, the stability of HIF-1α, a master regulator of barrier protection, is governed by PTM-dependent degradation pathways, and its downstream transcriptional output is further shaped by RNA modification machinery. Autophagy regulators such as ATG5 and AMBRA1, central to the cell’s ability to handle intracellular bacteria, are likewise controlled at both the transcript level through m6A-dependent processing and the protein level through ubiquitin-like conjugation systems.

Critically, the review emphasizes that PTMs and RNA modifications can act either synergistically or antagonistically on shared signaling pathways. When both layers push in the same direction, for example when m6A-driven translation of a pro-inflammatory cytokine coincides with ubiquitin-mediated stabilization of the transcription factors that induce it, inflammation escalates sharply. When the layers oppose each other, the outcome can be restraint or resolution. The dynamic balance between these opposing inputs, rather than the absolute level of any single modification, appears to determine the cellular outcome. This reframes IBD pathogenesis as a systems-level failure of regulatory coordination rather than a simple excess of any one inflammatory pathway.

Another key theme is specificity. The crosstalk between the two modification layers is pronouncedly cell-type dependent and disease-stage dependent. Epithelial cells, dendritic cells, macrophages, innate lymphoid cells, T helper 1 and T helper 17 subsets, and intestinal stem cells each deploy distinct combinations of writers, erasers, readers, ligases, and deubiquitinases. The same modification network that drives epithelial barrier breakdown in active disease may support stem cell-driven repair during remission. The authors argue that this cell-type and stage specificity contributes significantly to the clinical heterogeneity of IBD, helping to explain why patients with seemingly similar diagnoses follow such different courses and respond so differently to therapy.

The therapeutic implications are substantial. Existing IBD drugs, including TNF-α blockers, interleukin-12 and interleukin-23 pathway inhibitors, and 5-aminosalicylic acid, target inflammatory cytokines and their receptors. The modification network offers a deeper layer of intervention. Enzymes that write, erase, or read RNA modifications, such as METTL3, ALKBH5, and ADAR1, are increasingly druggable, as are E3 ubiquitin ligases and deubiquitinases that control signaling protein stability. Small molecules targeting the ubiquitin-proteasome system and m6A machinery are already in development in oncology, and the review suggests that repurposing and refining these approaches for intestinal inflammation is a realistic near-term goal. Modulating the crosstalk itself, rather than a single node, could in principle restore the regulatory balance that chronic disease has disrupted.

Diagnostic potential follows a parallel logic. Because modification patterns are cell-type specific and stage dependent, the authors propose that signatures of RNA modifications and PTM-associated enzymes could serve as biomarkers that distinguish active inflammation from remission, predict flares, or stratify patients for targeted therapy. Such biomarkers could be measured in intestinal biopsies or potentially in circulating immune cells and extracellular RNA, offering a more dynamic readout of disease state than static genetic risk scores. The review frames this as an emerging frontier, noting that systematic mapping of the modification landscape in defined IBD patient cohorts remains an early-stage but rapidly advancing endeavor.

The work, funded by the National Natural Science Foundation of China and regional research programs in Jiangsu and Wuxi, arrives as single-cell transcriptomics and modification-mapping technologies make it feasible to profile these chemical tags at unprecedented resolution. Its broader message is one of convergence: epigenetics, post-transcriptional regulation, and protein homeostasis, long studied in separate silos, are best understood as one layered control system. For a disease as heterogeneous and stubborn as inflammatory bowel disease, that integrated view may be exactly what is needed to turn molecular detail into clinical benefit, from new drug targets to biomarkers that tell clinicians which patients need which intervention, and when.

Subject of Research: Crosstalk between post-translational protein modifications and RNA modifications in the pathogenesis of inflammatory bowel disease

Article Title: Crosstalk between post-translational and RNA modifications in inflammatory bowel disease: a comprehensive review

Article References: Zhou, J., Fang, B., Zhang, Y., Liu, Y., & Wang, F. (2026). Crosstalk between post-translational and RNA modifications in inflammatory bowel disease: a comprehensive review. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09006-z

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09006-z

Keywords: inflammatory bowel disease, post-translational modifications, RNA modifications, m6A methylation, ubiquitination, RNA editing, NF-κB, intestinal barrier, Crohn's disease, ulcerative colitis, therapeutic targets, biomarkers

To understand why the connection matters, it helps to grasp both halves of the equation. m6A is added to RNA molecules by a suite of proteins called writers, spearheaded by the methyltransferase METTL3, which partners with METTL14 and auxiliary factors such as WTAP and VIRMA to deposit methyl groups onto thousands of transcripts. Two demethylases, FTO and ALKBH5, serve as erasers that strip the mark away, while a family of reader proteins, including YTHDF1, YTHDF2, YTHDC1 and the IGF2BP family, interprets the tag and decides the fate of the modified RNA, whether that means enhanced translation, accelerated degradation or altered splicing. The result is a dynamic, reversible layer of gene regulation that operates after DNA has been transcribed.

Ferroptosis, by contrast, is a violent and distinctive way to die. When iron accumulates inside a cell, it catalyses the Fenton reaction, converting hydrogen peroxide into hydroxyl radicals that shred the polyunsaturated fatty acids of cellular membranes. A self-amplifying lipid peroxidation cascade follows, rupturing the plasma membrane and shrivelling the mitochondria without ever activating the caspase enzymes that define apoptosis. Cells normally defend themselves through the cystine-glutathione-glutathione peroxidase 4 axis, in which the SLC7A11 transporter imports cystine to build the antioxidant glutathione, and through parallel systems involving FSP1, DHODH and the GCH1/BH4 pathway. Enzymes such as ACSL4 and LPCAT3, meanwhile, load vulnerable fatty acids into membranes and set the threshold at which the cascade ignites.

The new synthesis shows that m6A machinery grips this death circuitry at nearly every point. METTL3 marks the ACSL4 transcript in a YTHDC1-dependent manner, boosting production of the very enzyme that feeds lipid peroxidation. METTL16, working with the reader IGF2BP2, stabilises the SENP3 mRNA and thereby protects lactotransferrin from proteasomal destruction. On the eraser side, FTO lifts the antiferroptotic proteins GPX4, FTH1 and SLC7A11 while suppressing the iron importer TFR1, and ALKBH5 appears to stabilise ACSL4 mRNA. Among readers, IGF2BP3 binds specific motifs on GPX4 mRNA to tune antioxidant capacity, and hypoxia-driven long noncoding RNAs recruit YTHDF2 to degrade ACSL4 transcripts, forming feedback loops that respond to the tumour microenvironment.

What emerges from the disease-by-disease survey is a striking paradox. In aortic dissection, Parkinson’s disease and hepatic ischaemia-reperfusion injury, m6A-driven ferroptosis destroys healthy tissue and worsens disease; METTL3 suppresses SLC7A11 and FSP1 in the aorta, while YTHDF1 ramps up ACSL4 in dopaminergic neurons. Yet in gastric, lung and colorectal cancers, the very same mechanism becomes a weapon against the tumour, because forcing malignant cells into ferroptosis halts their growth. Even within a single tumour, the effect splits: ferroptosis in immune cells of the tumour microenvironment promotes cancer progression, while ferroptosis inside the cancer cells themselves suppresses it. Any therapy must therefore navigate this double-edged biology with precision.

The catalogue of specific axes is now long enough to guide drug design. In lung cancer, YTHDC1 stabilises FSP1 mRNA and restrains ferroptosis, and the JMJD6-METTL14-SLC3A2 axis drives carcinogenesis. In colorectal cancer, blocking AKT triggers ferroptosis through the FTO/YTHDF2/GPX4 pathway, and histone deacetylase inhibitors activate FTO and ALKBH5 to sensitise tumours. In bladder cancer, WTAP and YTHDF1 stabilise NRF2 mRNA and shield cells from lipid damage, while METTL7B marks ACSL3. In glioblastoma, the C5aR1-ERK pathway elevates METTL3 to protect GPX4, and in cervical cancer METTL14 destabilises FTH1 to enhance sorafenib-induced death. Cardiovascular studies implicate YTHDF2-mediated marking of NCOA4 in myocardial infarction and METTL14-driven ACSL4 modification in thoracic aneurysm, while in the kidney METTL3 modifies Hmox1 mRNA to trigger iron overload in acute injury.

Translational efforts are already following the map. The first-in-class METTL3 catalytic inhibitor STM2457 has shown prolonged survival in acute myeloid leukaemia models and, when paired with anti-PD-1 immunotherapy, can drive tumour regression in NAFLD-associated liver cancer. FTO inhibitors FB23 and FB23-2 suppress leukaemic proliferation, and the antibiotic mupirocin has been repurposed as an FTO inhibitor that pushes colorectal tumours into ferroptosis by cutting SLC7A11 and GPX4. Nanotechnology adds another layer: PLGA nanoparticles coated with gastric cancer cell membranes deliver STM2457 directly to tumours, and glutathione-bioimprinted nanocomposites simultaneously block FTO and deplete glutathione, inducing ferroptosis selectively in leukaemic blasts. Even a blood-brain-barrier-penetrating nanosystem carrying METTL3 inhibitors has shown benefit in mouse models of stroke and traumatic brain injury.

Nature’s own chemistry is joining the arsenal. Arbutin, an antioxidant from bearberry, eases fatty liver disease through the FTO/SLC7A11 pathway. Curdione from turmeric relatives promotes METTL14 and YTHDF2 while stripping away SLC7A11, SLC3A2 and GPX4 in colorectal cancer cells. Lobeline reverses lenvatinib resistance in liver cancer, chrysin covalently binds the enzyme ENO1 to recruit YTHDF2 against beta-catenin mRNA, and traditional formulations such as Yanghe Pingchuan granules relieve asthma by activating the METTL3/P53/SLC7A11 axis. Metformin, edaravone and interferon-alpha have all been drawn into the framework, each acting on m6A writers or readers to shift ferroptotic sensitivity in liver, brain and metabolic disease models.

The authors are candid that the field remains young. Most evidence comes from mouse models that may not translate cleanly to humans, the effect of m6A varies dramatically with cell type, tissue and disease stage, and current inhibitors of writers and erasers still suffer from off-target effects and incomplete selectivity. The conflicting roles of reader proteins remain unresolved, and the spatiotemporal dynamics of the m6A-ferroptosis network, particularly inside tumours and inflamed neural tissue, are only beginning to be charted. Future progress, the review argues, will depend on single-cell and spatial transcriptomics to map cellular heterogeneity, tissue-selective drug delivery, bifunctional molecules that hit both m6A effectors and ferroptosis nodes, and biomarkers such as YTHDF1/NRF2 and FTO/GPX4 for patient stratification. If those hurdles fall, the humble methyl tag on RNA may become one of the most powerful levers in medicine, a switch that doctors could flip to kill tumours, protect the heart and rescue dying neurons.

Subject of Research: Regulation of ferroptosis by N6-methyladenosine RNA methylation and its therapeutic implications

Article Title: m6A methylation in ferroptosis regulation: mechanisms, targets, and therapeutic interventions

Article References: Wen, C., Jiao, Y., Wang, Z., Shi, T., Wang, Y., Xu, J., Deng, T., Zhang, G., & Xiao, C. (2026). m6A methylation in ferroptosis regulation: mechanisms, targets, and therapeutic interventions. Journal of Advanced Research, 88, 825-840. https://doi.org/10.1016/j.jare.2026.01.021

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.01.021

Keywords: m6A methylation, ferroptosis, RNA modification, METTL3, FTO, GPX4, SLC7A11, cancer therapy, lipid peroxidation, nanoparticle drug delivery, programmed cell death, epitranscriptomics