The m6A mark is the most abundant internal modification found in the messenger RNAs of higher organisms. It is installed by a consortium of enzymes that researchers colloquially call writers, a group that includes the catalytic methyltransferase-like proteins METTL3, METTL14 and METTL16, alongside METTL5, METTL4 and accessory components such as WTAP, VIRMA, RBM15, RBM15B, ZC3H13 and PRMT1. Once deposited, the mark does not simply sit idle. Reader proteins, including members of the YTH domain family such as YTHDF1, YTHDF2, YTHDF3, YTHDC1 and YTHDC2, as well as IGF2BP1, IGF2BP2, IGF2BP3, HNRNPC, HNRNPG, HNRNPA2B1, PRRC2A and FMRP, interpret the tag and route the tagged RNA toward translation, decay, splicing or export. A third class of enzymes, the erasers FTO and the AlkB homologues ALKBH5 and ALKBH3, can strip the methyl group away again, making the entire system dynamic and reversible. That reversibility is precisely what makes m6A such a potent lever in cancer, where the balance between writing, erasing and reading can tip a cell toward uncontrolled growth.

On the protein side of the equation sits the ubiquitin system. Ubiquitin is a small polypeptide that, once attached to a lysine residue on a target protein, acts as a molecular verdict: chains of a particular architecture command the proteasome to destroy the tagged protein, while other linkages reshape signalling, localization or interactions instead. The counterweight to this system is a family of roughly one hundred enzymes known as deubiquitinases, or DUBs, many of them belonging to the ubiquitin-specific peptidase, or USP, family. DUBs cleave ubiquitin tags back off their substrates, rescuing proteins from degradation and prolonging their functional lifespan. Because tumour cells depend on the stabilized activity of oncogenic proteins, DUBs have attracted intense interest as drug targets, and several inhibitors are already being evaluated in clinical development.

The central insight highlighted in the new review, published as an open-access article in Molecular Cancer, is that these two regulatory universes constantly feed back on one another. The first direction of crosstalk runs from proteins to RNA modifications. Specific DUBs can remove ubiquitin marks from the core components of the m6A machinery, including the writers that install the tag, the erasers that remove it and the readers that interpret it. By deubiquitinating and thereby stabilizing these enzymes, a DUB can effectively raise the activity of the entire m6A pathway without the cell needing to make a single new molecule of the machinery. The consequence is a shift in the methylation landscape of thousands of RNA transcripts at once, with downstream changes in gene expression that can favour proliferation, invasion or survival under stress.

The reverse direction of the conversation is equally consequential. m6A modification can itself regulate the expression of certain deubiquitinases, either by influencing the stability of the messenger RNAs that encode them or by controlling the translation of those RNAs into protein, as well as by managing associated regulatory factors upstream. In other words, the RNA modification layer can dial the abundance of DUBs up or down, and the DUB layer can in turn remodel the stability of the very enzymes that write and erase the RNA marks. The result is a reciprocal regulatory loop, a handshake in which each system continuously calibrates the other. Such coupled feedback loops are a classic motif in biology, and in cancer they can become locked into pathological configurations that entrench malignant behaviour.

The review, whose authors also include Haolong Li, Chuyan Nie, Yongzhe Li and senior author Xiaohong Han, systematically maps how this DUB–m6A axis impinges on the hallmark processes of tumour biology. Cell proliferation is an obvious beneficiary, since stabilized m6A enzymes and stabilized DUBs together can amplify the expression of growth-promoting transcripts while suppressing signals of cell-cycle arrest. Metastasis is another, with the epithelial–mesenchymal transition, the plasticity program by which epithelial tumour cells acquire migratory and invasive properties, standing out as a process particularly sensitive to epitranscriptomic tuning. Metabolic reprogramming, the Warburg-like shift in nutrient use that sustains rapidly dividing cells, and therapy resistance, the grinding ability of tumours to shrug off chemotherapy, targeted agents and radiation, both emerge from the analysis as downstream consequences of this crosstalk.

What lends the analysis particular technical weight is its level of resolution. Rather than treating the m6A machinery as a monolith, the authors distinguish among its individual components, and the abbreviations catalogued in the paper span the full breadth of the field: the writer complex built around METTL3 and METTL14, the demethylases FTO, ALKBH5 and ALKBH3, and the reader families YTHDF, YTHDC and IGF2BP, along with nuclear RNA-binding proteins such as HNRNPC and HNRNPA2B1 that respond to m6A indirectly by changing how RNA folds. This granularity matters because different cancers appear to co-opt different nodes. A deubiquitinase that stabilizes METTL3 may push one tumour type toward aggressive methylation of pro-oncogenic transcripts, while one that stabilizes FTO or ALKBH5 may have the opposite effect in another context, erasing marks that would otherwise recruit decay machinery to tumour-suppressive RNAs. The sign of the effect depends on which substrates dominate in a given tissue, which is why the review frames the axis as a network to be mapped rather than a switch to be flipped.

The therapeutic implications are the most forward-looking part of the analysis. Inhibitors of m6A writers and erasers are already in preclinical and early clinical development, and DUB inhibitors are advancing along a parallel track. The crosstalk described in the review suggests that monotherapy against either layer may be undermined by compensatory feedback from the other: block a DUB and the m6A machinery may re-equilibrate, or suppress a methyltransferase and DUB-driven stabilization of erasers may fill the void. Conversely, the coupling creates opportunities. Combination strategies that target both sides of the axis simultaneously, or that exploit a tumour’s dependency on a specific DUB–m6A wiring pattern that normal cells do not share, could deliver selective pressure that malignant cells find much harder to escape. The review explicitly positions the DUB–m6A axis as a critical regulatory hub whose deciphering unveils promising targets for overcoming drug resistance and developing innovative anti-cancer strategies.

There are, of course, substantial obstacles between this systems-level map and the clinic. The ubiquitin code is baroque, with different chain linkages carrying different meanings, and many DUBs are promiscuous, acting on dozens of substrates whose identities remain incompletely catalogued. The m6A landscape, meanwhile, is dynamic across the cell cycle, across tissues and across stages of tumour evolution, and measuring it at single-transcript resolution in patient samples remains technically demanding. Disentangling cause from consequence in a bidirectional loop requires perturbation experiments rather than correlation, and the review’s synthesis makes clear how much systematic mapping work remains. Yet the conceptual payoff is considerable. If cancer is, at bottom, a disease of misregulated information, then the discovery that its RNA-level and protein-level information systems are in constant negotiation offers researchers a genuinely new coordinate on the map, one where the two dancers, as the paper’s title suggests, truly do take two to tango.

Subject of Research: The bidirectional crosstalk between deubiquitinases and N6-methyladenosine RNA modification in cancer biology

Article Title: It takes two to tango: the intersection of deubiquitinases and m6A modification in cancer

Article References: Zhang, X., Lou, N., Wang, Y., Li, H., Nie, C., Li, Y., & Han, X. (2026). It takes two to tango: the intersection of deubiquitinases and m6A modification in cancer. Molecular Cancer, 25(1), Article 241. https://doi.org/10.1186/s12943-026-02808-1

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02808-1

Keywords: deubiquitinases, m6A modification, epitranscriptomics, cancer, post-translational modification, RNA modification, METTL3, ubiquitin, therapy resistance, metastasis, tumorigenesis, Molecular Cancer

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 research team, led by investigators at Harbin Medical University and Northeast Agricultural University, used two complementary models of cell fate change: the reprogramming of mouse embryonic fibroblasts into induced pluripotent stem cells and the differentiation of embryonic stem cells into neuroectoderm. In both systems, disrupting SEC with KL-2, a peptidomimetic compound that selectively interferes with the interaction between the SEC scaffold protein AFF4 and the P-TEFb subunit Cyclin T1, dramatically impaired the transition. Crucially, the compound had no effect on the survival or proliferation of fibroblasts or stem cells under steady-state conditions, indicating that SEC is dispensable for maintaining a cell’s existing identity but indispensable for building a new one.

Timing proved to be everything. When the researchers inhibited SEC during the early days of reprogramming, the efficiency of induced pluripotent stem cell colony formation collapsed, and cells remained trapped in a mesenchymal state, never acquiring the epithelial morphology that marks successful reprogramming. RNA sequencing at day four revealed that more than half of the differentially expressed genes were downregulated, including core reprogramming factors such as Klf4 and Myc, along with cell cycle genes like Orc1 and pluripotency-associated genes such as Sall1. The downstream consequences were severe: cells accumulated in the G0/G1 phase, spindle structures became multipolar and abnormal, and karyotype analysis showed widespread chromosome number abnormalities in daughter cells.

To understand how SEC controls these genes, the team turned to the biophysics of transcription. After RNA polymerase II initiates transcription, it typically pauses 20 to 100 nucleotides downstream of the transcription start site, awaiting a release signal before productive elongation begins. Using published RNA polymerase II ChIP-seq datasets, the researchers quantified pause dynamics with two complementary metrics: the Traveling Ratio, which compares promoter-proximal to gene-body polymerase occupancy, and a two-dimensional Traveling Matrix method that simultaneously maps changes at both regions. Their analysis showed that early-activated genes like Klf4 and Myc carry pre-established paused polymerase even before reprogramming begins, and that reprogramming triggers their rapid release. In contrast, Oct4 and Sox2 lack pre-paused polymerase and instead acquire pause and release in a coupled, sequential manner during the mid-late stage.

CUT&Tag experiments confirmed that early SEC inhibition caused polymerase to pile up at the promoters of Klf4 and Myc while depleting from their gene bodies, a signature of failed pause release. ChIP-qPCR further showed reduced Ser2 phosphorylation of the polymerase C-terminal domain, the hallmark of productive elongation, and elevated pause indices at both loci. Ethynyl uridine incorporation assays demonstrated a global collapse in nascent RNA synthesis after SEC disruption, while overexpression of the SEC component ELL boosted it. The picture that emerged is one in which SEC acts as the trigger for the first transcriptional wave of reprogramming by liberating polymerase that was already parked at the most critical genes.

The most striking discovery, however, lay beyond the canonical mechanism. SEC is classically understood to promote pause release through P-TEFb-mediated phosphorylation of the polymerase C-terminal domain and the pause factors DSIF and NELF. But the researchers noticed that more than 40 percent of SEC target transcripts carry N6-methyladenosine, or m6A, the most abundant internal modification on eukaryotic messenger RNA. In Drosophila, m6A had already been shown to promote pause release, but whether the same held true in mammals was unknown. When the team inhibited SEC early in reprogramming, global m6A levels dropped sharply, as measured by RNA dot blot, ELISA, and the antibody-independent GLORI-seq method, which converts unmodified adenosines to inosines for single-nucleotide quantification. More than 23,000 m6A sites showed decreased modification, and the classic DRACH motif was enriched among the affected peaks, confirming their identity as bona fide m6A marks.

Using metabolic labeling with 4-thiouridine to isolate newly transcribed RNA, the researchers showed that SEC regulates m6A deposition co-transcriptionally. The single-base SELECT assay revealed that SEC inhibition significantly reduced m6A at specific sites in nascent Klf4 and Myc transcripts, including the promoter-proximal A701 site and gene-body A855 site of Klf4, while leaving non-m6A control sites untouched. Molecular docking predicted a close interaction between the SEC component ELL and the m6A methyltransferase METTL3, and this was validated by co-immunoprecipitation and immunofluorescence co-localization. ChIP-qPCR demonstrated that METTL3 and ELL co-occupy the promoters of Klf4 and Myc, and that SEC inhibition evicts both from these loci without changing total METTL3 protein levels. More than half of the transcripts losing m6A after SEC inhibition overlapped with those affected by METTL3 knockout, pointing to a shared regulatory pathway.

Functional experiments sealed the argument. Inhibiting METTL3 with the selective inhibitor STM2457 during the early stage of reprogramming reproduced the effects of SEC disruption: Klf4 and Myc expression fell, polymerase accumulated at their promoters, Ser2 phosphorylation declined, and reprogramming efficiency collapsed. Intriguingly, the study also uncovered a stage-specific duality: while early METTL3 inhibition was catastrophic for reprogramming, inhibition during the mid-late stage actually enhanced colony formation, suggesting that m6A plays opposing roles at different phases of the process. This may explain why previous studies have reported conflicting results about METTL3’s role in pluripotency. Most decisively, combined inhibition of SEC and METTL3 produced no additional increase in polymerase pausing beyond either treatment alone, and METTL3 overexpression could not rescue pause release when SEC was disrupted — evidence that the two operate in a single pathway, with SEC providing the scaffold that recruits METTL3 to specific loci.

The team then asked whether the same logic governs normal development. During retinoic acid-induced differentiation of embryonic stem cells, SEC inhibition selectively impaired the neuroectoderm lineage while leaving mesoderm and endoderm differentiation largely intact. Neural genes such as Nes and Tubb3 showed increased promoter-proximal pausing and reduced Ser2 phosphorylation upon SEC disruption, and global m6A levels again declined. STM2457 treatment similarly blocked neural marker acquisition, and reanalysis of published NET-seq data from METTL3 knockout cells revealed stalled nascent transcripts at the promoters of Nes and Tubb3. The authors propose that the functional divergence between SEC and the related elongation factor BRD4, which is known to drive mesendoderm specification, may act as a molecular determinant of lineage choice.

The implications extend well beyond the culture dish. Because SEC is dispensable for cell survival under steady-state conditions but essential whenever a cell must adopt a new identity, the findings suggest it may be a common driver of cell fate transitions throughout life, including embryonic development, tissue regeneration, and the initiation and progression of diseases such as cancer. The discovery that a transcription elongation complex doubles as a scaffold for RNA methylation adds a new layer to the growing intersection between the epitranscriptome and the transcriptional machinery, and hints that m6A deposited through the SEC-METTL3 pathway may act on R-loops to resolve paused polymerase. If confirmed, targeting this pathway could open new therapeutic avenues for conditions in which cell identity goes awry, from tumorigenesis to infertility.

Subject of Research: Role of the Super Elongation Complex and METTL3-mediated m6A modification in regulating RNA polymerase II pause release during cell identity transitions

Article Title: SEC Mediates m6A Deposition and Transcription Pause Release to Drive Cell Identity Transition

Article References: Zhang, Z., Xu, J., Wu, Y., Qu, Y., Hu, X., Sun, Y., Wu, Y., Liu, Z., Wang, J., & Lei, L. (2026). SEC Mediates m 6 A Deposition and Transcription Pause Release to Drive Cell Identity Transition. Advanced Science, Article e78131. https://doi.org/10.1002/advs.78131

Image Credits: AI Generated

DOI: 10.1002/advs.78131

Keywords: Super Elongation Complex, m6A, METTL3, RNA polymerase II, transcription pause release, iPSC reprogramming, embryonic stem cells, neuroectoderm differentiation, Klf4, Myc, cell fate transition, epitranscriptomics

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

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

USP16 belongs to a large family of deubiquitinating enzymes, proteases that snip ubiquitin tags off target proteins. Ubiquitination is one of the cell’s principal mechanisms for marking proteins for destruction: when chains of ubiquitin molecules, particularly those linked through their lysine 48 residues, are attached to a protein, the proteasome recognizes the tag and degrades the cargo. Deubiquitinases reverse this process, rescuing proteins from degradation and thereby fine-tuning their abundance. In the new study, the researchers found that USP16 is markedly upregulated in gemcitabine-resistant pancreatic cancer specimens, and that elevated levels of the enzyme correlate with metastatic disease and poor patient prognosis, positioning USP16 as a potential biomarker of aggressive disease.

The functional experiments carried out by the team went beyond correlation. When the researchers silenced USP16 genetically or inhibited it pharmacologically, pancreatic cancer cells lost key malignant behaviors: proliferation slowed, invasive capacity diminished, and, critically, sensitivity to gemcitabine was restored. The same effects were reproduced in animal models, where USP16 suppression curbed tumor progression and re-sensitized tumors to chemotherapy. These results, the authors report, held both in vitro and in vivo, suggesting that USP16 is not merely a passenger mutation or a passive marker of aggressive disease but an active participant in maintaining the resistant phenotype.

The mechanistic heart of the paper lies in metabolism. Cancer cells famously favor glycolysis, the fermentation of glucose into lactate, even in the presence of abundant oxygen, a phenomenon known as the Warburg effect. This metabolic reprogramming supplies rapidly dividing tumors with biosynthetic building blocks and helps them survive environmental stress. The researchers demonstrated that USP16 promotes this glycolytic switch by stabilizing a transcription factor called Far Upstream Element Binding Protein 1, or FUBP1. Biochemical analysis showed that USP16 preferentially removes K48-linked polyubiquitin chains from FUBP1, shielding the protein from proteasomal destruction. With FUBP1 stabilized, pancreatic cancer cells accumulate higher levels of this transcription factor in the nucleus.

FUBP1, in turn, drives transcription of lactate dehydrogenase A, or LDHA, the enzyme that catalyzes the conversion of pyruvate to lactate, the final and defining step of anaerobic glycolysis. By enhancing FUBP1-dependent LDHA expression, USP16 effectively turns up the dial on lactate production, fueling the metabolic state that supports rapid proliferation and chemoresistance. The connection is biologically plausible: high glycolytic flux has been repeatedly linked to drug resistance in solid tumors, partly because glycolytic tumors maintain acidic, hypoxic microenvironments that blunt the efficacy of chemotherapeutic agents and promote survival signaling. The USP16-FUBP1-LDHA axis therefore offers a coherent explanation for how a single deubiquitinase can simultaneously promote metastatic behavior and undermine gemcitabine therapy.

Perhaps the most intricate portion of the study concerns how USP16 itself becomes overexpressed in pancreatic cancer in the first place. The researchers traced the excess USP16 to two upstream layers of regulation. The first involves N6-methyladenosine, or m6A, the most abundant internal chemical modification in messenger RNA. The methyltransferase-like 3 enzyme, METTL3, installs m6A marks on the USP16 transcript, and these modifications enhance the message’s translation or processing. The second layer involves Insulin-like Growth Factor 2 mRNA-Binding Protein 1, or IGF2BP1, a reader protein that recognizes m6A-modified transcripts and stabilizes them, preventing degradation. Together, METTL3-mediated methylation and IGF2BP1-dependent stabilization elevate USP16 protein levels in pancreatic cancer cells, setting the entire pathological cascade in motion.

This architecture, which the authors describe as a METTL3/IGF2BP1-USP16-FUBP1-LDHA regulatory axis, is notable because it links three major themes in contemporary cancer biology: epitranscriptomic regulation through RNA modifications, post-translational control through ubiquitination, and metabolic reprogramming through glycolysis. Each layer of the axis represents a potential point of therapeutic intervention, and the study’s demonstration that both genetic and pharmacological USP16 inhibition suppress tumor progression suggests that deubiquitinase inhibitors could form the basis of new combination strategies designed to be administered alongside gemcitabine.

The clinical implications are considerable. Gemcitabine resistance is one of the chief reasons pancreatic cancer has a five-year survival rate that remains among the lowest of any major cancer. If USP16 levels can be measured reliably in tumor biopsies, the enzyme could serve as a biomarker identifying patients likely to derive limited benefit from gemcitabine-based regimens, guiding clinicians toward alternative or intensified approaches. More ambitiously, if USP16 inhibitors can be developed with acceptable safety profiles, they might resensitize resistant tumors to existing chemotherapy, extending the usefulness of a drug that has been a workhorse in pancreatic oncology for decades. The study’s finding that pharmacological USP16 inhibition restored gemcitabine sensitivity in vivo provides an early proof of concept for that strategy.

Caveats remain, as they do with any preclinical study. The work was conducted in cell lines and animal models, and the translation of deubiquitinase inhibition into human therapy will require medicinal chemistry advances, since deubiquitinases share catalytic mechanisms that can make selective inhibition challenging. The authors also note that the published version is an early-release, peer-reviewed accepted manuscript subject to further editorial refinement. Nonetheless, the identification of a complete signaling axis, from RNA modification through protein stabilization to metabolic enzyme expression, gives researchers a detailed map of a resistance pathway that had remained poorly understood, and it adds USP16 to the growing list of deubiquitinating enzymes implicated in cancer metabolism.

For a disease that has seen painfully slow therapeutic progress, studies that illuminate the machinery of chemoresistance carry real weight. By showing how an m6A-modified, IGF2BP1-stabilized transcript elevates a deubiquitinase that in turn protects a transcription factor governing lactate metabolism, the research team has connected molecular layers that are usually studied in isolation. Whether targeting USP16 will ultimately improve outcomes for patients with pancreatic ductal adenocarcinoma will depend on the development of clinically viable inhibitors and appropriately designed trials, but the study establishes a clear, testable framework for attacking gemcitabine resistance at its metabolic roots, and it underscores how deeply the survival of this formidable cancer depends on the reprogramming of its energy economy.

Subject of Research: USP16-mediated glycolytic reprogramming and gemcitabine resistance in pancreatic ductal adenocarcinoma

Article Title: USP16 promotes pancreatic ductal adenocarcinoma progression and gemcitabine resistance through FUBP1/LDHA axis-mediated glycolysis

Article References: Dong, Y., Lin, C., Fang, H., Tan, Z., Lu, J., Liu, Z., Lai, S., & Wang, Y. (2026). USP16 promotes pancreatic ductal adenocarcinoma progression and gemcitabine resistance through FUBP1/LDHA axis-mediated glycolysis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06466-w

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06466-w

Keywords: pancreatic ductal adenocarcinoma, USP16, deubiquitinase, FUBP1, LDHA, glycolysis, gemcitabine resistance, m6A modification, METTL3, IGF2BP1, cancer metabolism, chemoresistance

The research, led by Gaizhen Li and Dong Liu of Xiamen University together with colleagues including corresponding authors Haibin Wang, Haili Bao and Shuangbo Kong, focuses on METTL3, the core writer enzyme of N6-methyladenosine, or m6A, the most abundant internal modification in eukaryotic messenger RNA. By depositing methyl groups on adenosine bases, METTL3 influences how transcripts are processed, translated and degraded, effectively acting as a post-transcriptional tuning dial for gene expression. While m6A is known to govern stem cell fate and organogenesis in several systems, its role in the postnatal uterus had remained unexplored.

To map the normal course of epithelial specification, the team charted the transcriptional and chromatin landscape of uterine epithelial cells during early postnatal life. Their analysis showed that luminal epithelial specification is not a simple switch but a dynamic transition: cells first pass through a proliferative phase and then shift into a state of metabolic activation. This shift is orchestrated by coordinated networks of transcription factors acting on chromatin regions that become progressively more accessible, allowing the cell to lock in its luminal identity. From these data, the researchers defined a set of genes specifically associated with luminal epithelial specification, providing a molecular reference point for what a properly specified luminal cell should look like.

The decisive experiment came from genetics. Using a uterine-specific Mettl3 knockout mouse model, the researchers deleted METTL3 from the developing uterus and watched what happened to epithelial specification. The result was striking: without METTL3, luminal epithelial specification broke down. Instead of committing cleanly to the luminal lineage, epithelial cells emerged in a hybrid state, co-expressing markers of both luminal and glandular epithelium. The developing tissue, in other words, could no longer tell its two epithelial lineages apart, producing cells that belonged fully to neither.

The consequences of this failed specification extended well beyond the developmental window itself. Adult mice whose uteri had lacked METTL3 during early postnatal life showed a predisposition to hormone-driven glandular hyperplasia, an abnormal proliferation of glandular tissue in response to ovarian hormones. This finding carries a provocative implication: errors made in a brief postnatal period of lineage specification can lay the groundwork for uterine pathology in adulthood, suggesting that the developmental window during which luminal epithelium matures is a critical period whose disruption may echo for a lifetime.

Mechanistically, the study disentangled two ways in which METTL3 safeguards proper specification. First, the enzyme helps regulate the expression levels of the genes that define luminal epithelial identity, ensuring that the specification program is executed at the right intensity. Second, and more specifically, METTL3 stabilizes the transcripts of key transcription factors, including Etv5, a member of the ETS family known for its roles in epithelial growth and differentiation. By methylating these transcripts, METTL3 protects them from premature decay, keeping the transcription factor circuitry supplied with the raw material it needs to drive the luminal program forward. When METTL3 is absent, these regulatory transcripts dwindle, the circuitry falters, and the hybrid luminal-glandular phenotype emerges.

The work places RNA modification squarely within the framework of developmental lineage decisions. Classical models of cell fate specification emphasize transcription factors and chromatin remodeling as the primary arbiters of identity, and the new data support that view, showing coordinated transcription factor networks and changing chromatin accessibility during specification. But the findings add a crucial post-transcriptional layer: the same genetic program can be derailed if the RNA messages encoding its regulators are not chemically stabilized. In this sense, m6A modification functions less as an independent decision-maker and more as an essential quality-control system that keeps the specification machinery running at full capacity.

For reproductive biology, the study fills a significant gap. The formation of glandular epithelium from undifferentiated luminal epithelium, followed by the precise maturation of both lineages, is essential for establishing uterine architecture and, ultimately, female fertility. Glands of the endometrium are central to implantation and early pregnancy, and defects in uterine epithelial development are implicated in infertility and endometrial disease. By identifying METTL3-dependent m6A modification as indispensable for luminal epithelial specification, the researchers have pinpointed a molecular node whose dysfunction could plausibly contribute to disorders of uterine development and hormone responsiveness.

The mouse model used in the study also offers a platform for future investigation. Because the knockout was restricted to the uterus, the phenotype can be attributed directly to the uterine epithelium rather than to systemic effects of METTL3 loss, an important consideration given the enzyme’s broad roles throughout the body. The authors acknowledge contributions of Pgr-Cre and Mettl3-flox mouse lines from Francesco DeMayo of the National Institute of Environmental Health Sciences and Minghan Tong of the Center for Excellence in Molecular Cell Science, CAS, tools that made the tissue-specific deletion possible. The work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China and the Natural Science Foundation of Fujian Province.

Looking ahead, the study raises questions that extend beyond the uterus. If m6A modification is required for lineage specification in this organ, similar requirements may operate in other epithelial systems that mature postnatally, from the gut to the mammary gland. The identification of a defined set of luminal specification-associated genes, together with the demonstration that transcript stabilization of factors such as Etv5 underpins the process, gives researchers concrete molecular handles for probing those questions. For now, the message from Xiamen is clear: the chemical editing of RNA is not a footnote to development but a load-bearing pillar, and the architecture of the adult uterus rests on it.

Subject of Research: The role of METTL3-mediated m6A RNA modification in postnatal uterine luminal epithelial lineage specification

Article Title: METTL3-mediated RNA m6A modification orchestrates postnatal uterine epithelial specification

Article References: Li, G., Liu, D., Liu, J., Ni, Y., Deng, N., Wang, L., Huang, L., Tang, Y., Hao, J., Wang, M., Zhang, Y., Deng, W., Wang, H., Bao, H., & Kong, S. (2026). METTL3-mediated RNA m6A modification orchestrates postnatal uterine epithelial specification. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06462-0

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06462-0

Keywords: METTL3, m6A modification, uterine development, luminal epithelium, glandular epithelium, lineage specification, Etv5, transcription factors, postnatal development, epigenetics, reproductive biology, glandular hyperplasia

The mechanics of m6A are elegant. The tag is deposited on RNA by a methyltransferase complex whose catalytic core is the enzyme METTL3, working alongside METTL14, which recognizes the target sequence, and the scaffolding proteins WTAP and RBM15, which shepherd the machinery to specific sites on transcripts. The marks cluster near stop codons and within three-prime untranslated regions, precisely where they can influence how efficiently a message is translated into protein or how quickly it is degraded. Demethylases such as FTO and ALKBH5 can remove the marks, although recent evidence questioning whether FTO truly reverses m6A in vivo suggests the system may be more nuanced than a simple write-and-erase cycle. Once installed, the tags are interpreted by reader proteins, most carrying a conserved YTH domain, that determine the fate of each modified transcript, directing splicing in the nucleus, export to the cytoplasm, ribosome loading, or routing to processing bodies for destruction.

What makes m6A so compelling in oncology is its contextual duality. In lung adenocarcinoma cells, METTL3 was found to be elevated, where it stabilized the mRNA of SLC7A11, a ferroptosis-suppressing transporter, thereby blocking iron-dependent cell death and fueling proliferation. Yet when the tumor suppressor p53 is intact, the very same enzyme amplifies p53 stress responses and suppresses cellular transformation, a finding that highlights how the same molecular writer can act as villain or guardian depending on the genetic backdrop. The demethylase ALKBH5 shows similar ambivalence: it promotes proliferation in non-small cell lung cancer by destabilizing genes such as TIMP3 and CDKN1A, but a specific regulatory insertion variant that boosts ALKBH5 expression was found to suppress tumor growth through the ALKBH5-FBXL5 axis, inhibiting the PI3K/AKT and NF-kB pathways.

Environmental carcinogens appear to hijack this system. Chronic exposure to hexavalent chromium, an industrial pollutant, upregulated METTL3 and drove cell transformation, cancer stem cell-like properties, and spontaneous lung tumors in experimental models. The tobacco-specific nitrosamine NNK, meanwhile, triggered malignant transformation of bronchial epithelial cells through the reader protein IGF2BP1, which correlated with shorter overall survival and metastatic spread, while ALKBH5-mediated demethylation of COL5A1 promoted NNK-induced proliferation that could be reversed when the eraser was knocked down. These findings suggest that the epitranscriptome is not merely a passenger in carcinogenesis but a mechanistic conduit through which the environment rewrites cellular behavior.

Invasion and metastasis, the processes that make lung cancer lethal, are also under m6A control. METTL3 enhances the translation of EGFR mRNA by recruiting the initiation factor eIF3 and promotes motility through EML4, while its induction of the long noncoding RNA LCAT3 activates the MYC oncogene via the binding protein FUBP1. The writer VIRMA suppresses the kinase DAPK3 through YTHDF2- and YTHDF3-mediated inhibition, releasing the brakes on migration, and FTO drives metastasis by elevating fibroblast activation protein in a YTHDF2-dependent manner. Angiogenesis, the sprouting of blood vessels that feeds growing tumors, is accelerated when m6A marks on the VEGFA internal ribosome entry site recruit the YTHDC2/eIF4GI complex to boost translation, and IGF2BP2 shuttled from tumor cells to endothelial cells activates PI3K-Akt signaling to promote vessel formation. The reader IGF2BP3, through its MCM5/Notch and STRIP2/TMBIM6 axes, drives the epithelial-mesenchymal transition that converts stationary epithelial cells into mobile, invasive ones.

Perhaps the most clinically electrifying chapter concerns therapy. In immunotherapy, METTL3 promotes the circularization of circIGF2BP3, which reduces CD8-positive T cell infiltration and undermines anti-PD-1 efficacy, while its suppression lifts hsa-LINC02418, a transcript that enhances PD-L1 ubiquitination via Trim21. Two METTL3 inhibitors are already in human testing: STC-15 showed well-tolerated responses in a phase 1 trial of advanced cancers, and a multicenter phase 1b/2 trial is now combining it with the anti-PD-1 antibody toripalimab. The second inhibitor, STM2457, reprogrammed the tumor microenvironment into a more inflamed state, rendering anti-PD-1 therapy more effective in preclinical models. Conversely, ALKBH5 increased susceptibility to immunotherapy by recruiting PD-L1-positive tumor cells and macrophages through CCL2 and CXCL10 secretion, and a five-regulator m6A score predicted anti-PD-1 benefit with an area under the curve of 0.8.

Drug resistance, the Achilles heel of targeted therapy, is likewise epitranscriptomically scripted. The writer KIAA1429, overexpressed in gefitinib-resistant tumors, stabilizes HOXA1 mRNA and activates JNK/MAPK signaling, while FTO delivered in serum exosomes boosts the drug efflux pump ABCC10 through YTHDF2, pumping gefitinib out of cells. An IGF2BP3-COX6B2 axis rewires nicotinamide metabolism toward oxidative phosphorylation to confer acquired resistance, and YTHDF2 with METTL3 degrade TUSC7 and cLMNB1 to drive erlotinib and osimertinib resistance respectively. In chemotherapy, KRAS-mutant tumors inhibit ALKBH5, hypermethylating the DNA repair genes DDB2 and XPC to survive platinum agents, while IGF2BP-stabilized SNRPA builds the ERCC1-XPF repair complex. In small cell lung cancer, METTL3 accelerates DCP2 degradation and mitophagy to produce chemoresistance, a phenotype that STM2457 could reverse. Even radiotherapy is affected: IGF2BP2 and METTL3 both promote radioresistance through a methionine-transport feedback loop and RMRP-stabilized stemness, respectively.

Beyond treatment, m6A regulators are emerging as prognostic instruments. Individual markers tell mixed stories: high ALKBH5 and IGF2BP1 worsen survival, while deletions of FTO and YTHDC2 predict better disease-free survival, and higher YTHDF1 and YTHDF2 levels associate with improved overall and recurrence-free survival. Combination models perform better still. A three-gene risk score built from METTL3, KIAA1429, and IGF2BP1 stratified non-small cell lung cancer patients by survival and correlated with smoking history and stage, and a PD-L1-linked prognostic model achieved an area under the curve of 0.746. In small cell lung cancer, a seven-regulator LASSO Cox model predicted chemotherapy benefit with a striking area under the curve of 0.935, while three distinct m6A modification patterns, corresponding to immune activation, immune escape, and immune desert, mapped the tumor microenvironment and identified patients likely to respond to immunotherapy.

The review’s authors are candid about the obstacles ahead. The same regulator can show opposite effects in different studies, as the METTL3 paradox illustrates, underscoring the heterogeneity of m6A biology across pathological subtypes and p53 statuses. Diagnostic applications remain scarce, most single-molecule prognostic markers have not been quantified rigorously, and combination models still show only moderate performance. Druggability poses its own challenge: ideal targets require spatial conformations amenable to small-molecule binding, and conserved or closed structures risk off-target effects and poor pharmacokinetics. Yet the trajectory is unmistakable. With clinical trials of METTL3 inhibitors underway, liquid biopsy offering a non-invasive route to detect m6A signatures, and multi-dimensional models integrating epitranscriptomic data with radiological and clinicopathological features, the humble methyl tag on adenosine is rapidly moving from bench curiosity to a potential linchpin of precision oncology, one RNA molecule at a time.

Subject of Research: The role of N6-methyladenosine RNA modification in lung cancer progression, treatment regulation, and prognosis prediction

Article Title: Role of N6-methyladenosine in the progression, treatment regulation, and prognosis prediction of lung cancer

Article References: Liang, S., Shao, J., Li, J., Liu, X., Yang, L., Li, W., & Wang, C. (2026). Role of N6-methyladenosine in the progression, treatment regulation, and prognosis prediction of lung cancer. Holistic Integrative Oncology, 5(1), Article 47. https://doi.org/10.1007/s44178-026-00259-8

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00259-8

Keywords: N6-methyladenosine, m6A, lung cancer, RNA modification, epitranscriptomics, METTL3, immunotherapy, drug resistance, prognosis, biomarkers, non-small cell lung cancer, targeted therapy

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