To understand why the finding matters, it helps to start with the chemistry. N6-methyladenosine, abbreviated m6A, is the most abundant internal modification found in eukaryotic messenger RNA. Rather than changing the genetic code itself, m6A acts like a sticky note attached to individual transcripts, influencing how long they survive, how efficiently they are translated into protein, and where they travel within the cell. The system relies on a cast of molecular actors: writers that deposit the methyl group, erasers that remove it, and readers such as YTHDF2 that interpret the mark and decide the fate of the tagged RNA. When YTHDF2 recognizes an m6A-modified transcript, it typically shepherds that mRNA toward degradation, effectively turning down the volume of the corresponding gene.

The research team, led by Da Gu, Huanmin Lou, Xiaojing Li, and colleagues at institutions including the First Affiliated Hospital of Anhui Medical University and Shandong First Medical University, began by mining public cancer databases. Their pan-cancer survey revealed that YTHDF2 is elevated across a range of tumor types, and in cutaneous melanoma specifically, its expression levels correlated positively with PD-L1, the molecular beacon that tumors use to suppress immune attack. Intriguingly, higher YTHDF2 also tracked with lower immune and stromal scores, suggesting that tumors rich in this RNA reader may build microenvironments that are less hospitable to infiltrating immune cells. That combination of immune evasion and aggressive growth made YTHDF2 a compelling suspect in the search for drivers of melanoma malignancy.

The next step was to ask what happens when YTHDF2 is removed. Using melanoma cell lines in the laboratory, the researchers knocked down the protein and observed a striking cascade of effects. Cell proliferation slowed markedly, and the population of Annexin V and propidium iodide positive cells, standard markers of dying cells, climbed. Crucially, when the team added a ferroptosis inhibitor to the cultures, the damage was largely rescued. That rescue experiment was the pivotal clue: it indicated that the cell death triggered by YTHDF2 loss was not ordinary apoptosis, but ferroptosis, an iron-dependent form of regulated cell death defined by the catastrophic oxidation of lipid membranes.

Ferroptosis has become one of the hottest topics in cancer biology precisely because tumor cells seem to fear it. The biochemical signature is unmistakable. In the YTHDF2-depleted melanoma cells, the researchers measured rising levels of intracellular ferrous iron, malondialdehyde, reactive oxygen species, and lipid peroxidation products, all hallmarks of membranes under oxidative assault. At the same time, glutathione, the cell’s principal antioxidant shield, dwindled. Every one of these changes was reversed when ferroptosis was pharmacologically blocked, confirming that the iron-fueled lipid destruction pathway was the mechanism at work. Experiments in animal models corroborated the same regulatory relationship in living tumors, lending physiological weight to the cell culture findings.

But how does an RNA-binding protein control a cell death pathway built from iron and lipids? The answer emerged from an integrated analysis combining RNA sequencing with RIP sequencing, a technique that maps which transcripts a protein physically binds. The data showed that YTHDF2 latches onto m6A marks on the messenger RNA of HMOX1, the gene encoding heme oxygenase 1, an enzyme with well-documented antioxidant and cytoprotective functions. By binding the methylated HMOX1 transcript, YTHDF2 destabilizes it, hastening its degradation and thereby suppressing the production of heme oxygenase 1. With less of this protective enzyme available, melanoma cells become more vulnerable to oxidative damage, yet the study’s overall picture shows that YTHDF2’s net effect in tumors is to promote malignant progression, positioning HMOX1 regulation as a key node in the network the protein controls.

The HMOX1 connection resonates with a growing body of literature. Heme oxygenase 1 has been implicated in ferroptosis regulation across diverse contexts, from liver cancer, where upregulating the enzyme synergizes with drug-induced ferroptotic stress, to retinal neovascularization and pulmonary hypertension, where YTHDF2 has separately been shown to suppress Hmox1-dependent antioxidant function in macrophages. The melanoma study now extends this theme into skin cancer, suggesting that the YTHDF2–HMOX1 axis is a recurring module that cells, whether diseased or malignant, use to tune their antioxidant capacity. In melanoma, the balance appears to tip in favor of tumor survival, consistent with YTHDF2’s established reputation as an oncogenic reader in cancers ranging from bladder carcinoma to diffuse large B-cell lymphoma.

Perhaps the most headline-grabbing element of the study is the repurposing angle. Metformin, a cheap, decades-old biguanide taken by millions of people with type 2 diabetes, has accumulated a long list of putative anticancer properties in the scientific literature. The researchers demonstrated that metformin inhibits YTHDF2 expression in melanoma cells, and in doing so promotes ferroptosis. The finding builds on the group’s earlier work, published in Cancer Genet, showing that metformin regulates ferroptosis in skin cutaneous melanoma through the ATF3/NRF2 axis. Together, the two studies sketch a coherent model in which the widely used drug pushes melanoma cells toward iron-mediated self-destruction by converging on the epitranscriptomic machinery that guards their antioxidant defenses. It also aligns with reports in breast cancer, where metformin induces ferroptosis by inhibiting the UFMylation of the cystine transporter SLC7A11, hinting that ferroptosis induction may be a unifying theme in the drug’s anticancer profile.

The therapeutic implications are tantalizing but must be tempered with appropriate caution. YTHDF2 has emerged as a target of growing interest in the field, with recent commentary in Trends in Cell Biology arguing that attacking the protein can reshape the epitranscriptome and overcome therapy resistance in tumors. A study in Science Immunology in 2024 detailed YTHDF2’s role in regulating immune evasion from within tumor cells, and the new melanoma data add a ferroptosis dimension to that immune story, given the observed correlation between YTHDF2 and PD-L1 expression. If blocking YTHDF2 simultaneously sensitizes tumor cells to ferroptosis and strips away immune camouflage, combination strategies that pair YTHDF2-directed approaches with checkpoint inhibitors become an obvious line of future investigation. Metformin, already proven safe in humans, could in principle be folded into such regimens more rapidly than a purpose-built YTHDF2 inhibitor, though clinical trials would be needed to establish any benefit in melanoma patients.

There are also broader lessons here about the m6A–ferroptosis interface, a frontier that a 2024 review in Molecular Cancer flagged as a promising avenue for advancing tumor immunotherapy. Other readers have been caught manipulating the same cell death pathway: in hepatocellular carcinoma, hypoxia was shown to block ferroptosis by suppressing the writer METTL14, which in turn unleashed YTHDF2-dependent silencing of SLC7A11. The melanoma study inverts the logic, with YTHDF2 acting on HMOX1 rather than SLC7A11, but the underlying principle is the same. Cancer cells exploit RNA modifications to fine-tune the expression of antioxidant genes, and each new target identified, whether a transporter, an enzyme like heme oxygenase 1, or a stress-response factor, adds a potential pressure point at which therapy could tip the balance toward tumor destruction. For a disease as stubborn as melanoma, that growing map of vulnerabilities is welcome news, and the humble RNA tag at the center of it may prove to be one of the most consequential sticky notes in modern cancer research.

Subject of Research: The role of the m6A reader YTHDF2 in regulating HMOX1-mediated ferroptosis and malignant progression in cutaneous melanoma

Article Title: YTHDF2 drives malignant progression in cutaneous melanoma through m⁶A-dependent HMOX1-mediated ferroptosis

Article References: Gu, D., Sun, Y., Sun, J., Kang, W., Lou, H., & Li, X. (2026). YTHDF2 drives malignant progression in cutaneous melanoma through m⁶A-dependent HMOX1-mediated ferroptosis. Medical Oncology, 43(11), Article 316. https://doi.org/10.1007/s12032-026-03427-y

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03427-y

Keywords: melanoma, YTHDF2, m6A modification, ferroptosis, HMOX1, metformin, RNA methylation, PD-L1, lipid peroxidation, epitranscriptomics, skin cancer, cell death

Hair follicles are among the most dynamic mini-organs in the mammalian body. Each follicle cycles repeatedly through phases of vigorous growth, destruction, and rest, and each new cycle depends on stem cells resident in a region of the follicle called the bulge exiting their quiescent state at precisely the right moment. Once activated, these cells must proliferate, migrate downward, and differentiate into the multiple lineages that construct the follicle and its associated structures. This process demands an extraordinary degree of coordination, and it has long been clear that transcription factors, proteins that switch specific genes on or off, are central to establishing the identity of each cell type. What has remained murky is how cells ensure that the right proteins are actually synthesized in the right amounts once their messenger RNAs have been made, a question of post-transcriptional control that the new study addresses directly.

The answer lies in a chemical modification known as N7-methylguanosine, abbreviated m7G, in which a methyl group is attached to the nitrogen at position seven of a guanosine base. This modification has attracted growing attention in recent years as one of several RNA marks, alongside the better-known m6A modification, that influence the fate and function of RNA molecules inside cells. METTL1, working together with its partner protein WDR4, is the key methyltransferase responsible for installing m7G marks. The modification is best characterized on transfer RNAs, the adaptor molecules of protein synthesis, where it stabilizes the tRNA structure and supports efficient translation. But m7G can also be deposited internally within messenger RNAs, and it is this internal messenger RNA methylation that turned out to be central to the hair follicle story.

To probe the role of METTL1 in hair biology, the researchers created mice in which the Mettl1 gene could be deleted specifically in keratinocytes. The consequences were dramatic. Animals lacking the enzyme in these cells displayed severe dysplasia of hair follicle development, meaning the follicles formed abnormally and failed to achieve their normal architecture. Regeneration was also impaired, with the follicles unable to cycle properly through subsequent rounds of growth. In addition, the team observed disruptions in keratinocyte adhesion, the process by which these cells stick to one another to maintain the structural integrity of the epidermis and follicle. These defects point to METTL1 as a gene whose loss undermines both the construction of the follicle and its ongoing maintenance across cycles.

The complementary experiment strengthened the conclusion. When the researchers introduced a keratinocyte-specific knock-in that increased Mettl1 activity, hair regeneration accelerated. This gain-of-function result demonstrates that the enzyme is not merely permissive for hair growth but is genuinely rate-limiting: more METTL1 means faster regrowth, at least under the conditions of the experiment. Together, the loss-of-function and gain-of-function data establish a bidirectional relationship between METTL1 levels and the tempo of the hair follicle cycle, a relationship that suggests the enzyme could in principle be targeted to modulate hair growth in pathological settings, although the authors are careful to frame the work as mechanistic biology rather than as a therapeutic demonstration.

Mechanistically, the study traced the effects of METTL1 loss to a specific transcription factor with a well-established role in hair biology: HOXC13. This homeobox protein is known to govern the expression of genes required for hair shaft formation and follicle differentiation. The researchers found that when METTL1 is absent, HOXC13 messenger RNA becomes destabilized and its levels fall. The destabilization is attributed to the loss of internal m7G modification on the HOXC13 transcript itself, implying that the methyl mark normally protects or otherwise supports the messenger RNA, allowing it to persist long enough to be translated into protein. Without the mark, the transcript decays, HOXC13 protein levels drop, and the genetic program that depends on HOXC13 falters.

Downstream of HOXC13, the study mapped a signaling axis that connects the RNA modification to the observable defects in the follicle. HOXC13 normally promotes the expression of FOXN1, a transcription factor famous for its role in hair and immune development, and FOXN1 in turn supports the expression of DSG4, a desmoglein, which is a calcium-dependent adhesion molecule of the cadherin family concentrated in the hair shaft and inner root sheath. DSG4 provides the intercellular adhesion that keeps differentiating keratinocytes properly glued together as they build the hair shaft. When METTL1 is lost, HOXC13 messenger RNA decays, FOXN1 declines, and DSG4 falls with it, explaining both the differentiation defects and the adhesion disruptions seen in the knockout animals. The chain from RNA mark to mRNA stability to transcription factor to adhesion molecule constitutes a complete mechanistic pathway linking a chemical modification to tissue architecture.

The conceptual significance of the work extends beyond hair. Biologists have long distinguished between transcriptional regulation, which determines which genes are read into RNA, and post-transcriptional regulation, which determines what happens to those RNA molecules afterward. The new findings show that an RNA modification enzyme can sit upstream of a transcription factor, effectively using post-transcriptional control to tune a transcriptional circuit. In this arrangement, METTL1 does not directly change which genes are transcribed; instead, it safeguards the messenger RNA of a master regulator, ensuring that the transcriptional program for hair differentiation is executed at the right intensity. The authors describe this as an essential regulatory layer of RNA modification in hair follicle morphogenesis and cycling, one that operates through precise post-transcriptional control of a key transcriptional circuit to ensure structural integrity and timely regeneration.

For the broader field of RNA modification biology, the study adds hair follicle cycling to the growing list of developmental and physiological processes controlled by m7G methylation. It also highlights the specificity of the mechanism: although METTL1 modifies many transfer RNAs, the authors found that its effects on hair follicle biology run, at least in part, through internal modification of a single messenger RNA target. This kind of transcript-selective action suggests that m7G marks may function as individualized tuning knobs on particular messages rather than as a blanket adjustment of global protein synthesis, a distinction that will likely shape future experiments in other tissues.

Practical implications remain speculative but tantalizing. Hair loss disorders affect a large fraction of the human population, and most current treatments act indirectly on the follicle cycle. A pathway that demonstrably accelerates regeneration when its enzyme is boosted, and that acts through defined molecular intermediaries, offers a fresh set of potential targets. At the same time, the severe developmental defects caused by METTL1 loss in keratinocytes caution that the pathway is deeply embedded in normal epithelial biology, and any intervention would need to respect its broader roles. For now, the study stands as a vivid demonstration that the fate of a hair, and perhaps of many other tissues, can hinge on a methyl group attached to a single guanosine deep inside a messenger RNA molecule.

Subject of Research: METTL1-mediated m7G RNA modification and its regulation of the hair follicle cycle through the HOXC13/FOXN1/DSG4 axis

Article Title: METTL1-mediated m 7 G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis

Article References: Gan, X., Li, Q., Xiong, Q., Huang, D., Liu, Z., Yin, Q., Jiang, S., Matsubara, T., Kokabu, S., Yan, W., & Yuan, Q. (2026). METTL1-mediated m7G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis. PLOS Genetics, 22(9), e1012307. https://doi.org/10.1371/journal.pgen.1012307

Image Credits: AI Generated

DOI: 10.1371/journal.pgen.1012307

Keywords: METTL1, m7G modification, RNA methylation, hair follicle cycle, keratinocytes, HOXC13, FOXN1, DSG4, post-transcriptional regulation, hair regeneration, PLOS Genetics, epigenetics

The research, led by Penghui Song, Lijuan Ma, and Dong Yan and published in PLOS Genetics, set out to answer a deceptively simple question: what does Mettl16 actually do in Drosophila melanogaster? In mammals, METTL16 is essential for embryonic development, and its loss is lethal, largely because it modifies a specific structural RNA involved in splicing and helps regulate the synthesis of S-adenosylmethionine, the universal methyl donor of the cell. Because flies lack some of the mammalian regulatory features, the expectation was that Mettl16 might behave similarly, or perhaps be dispensable altogether. The team generated flies carrying loss-of-function mutations in the Mettl16 gene and watched what happened across the entire life cycle. The result was unexpected: unlike in mammals, Mettl16 mutant flies survived to adulthood. They were alive, but far from well, displaying a constellation of developmental and behavioral abnormalities that hinted at a deep, if selective, importance of this enzyme.

The most dramatic phenotype was sterility. Both male and female mutants were completely infertile, and microscopic examination of their gonads revealed severe defects in gametogenesis, the intricate choreography by which germ cells divide, specialize, and mature into sperm and eggs. This was a crucial clue. Fertility is one of the most sensitive readouts of RNA metabolism, because germ cells undergo some of the most dramatic transcriptional and developmental transitions in any tissue. The fact that Mettl16 loss brought the entire reproductive program to a grinding halt suggested that the enzyme supports specific, non-redundant steps in the formation of gametes, rather than serving as a general housekeeping factor that cells could easily compensate for.

To pinpoint where things went wrong, the researchers traced germ cell development stage by stage. Remarkably, Mettl16 mutant germ cells were able to navigate the early milestones without obvious catastrophe: they completed the mitotic divisions that expand the germline population and progressed through meiosis, the specialized reductional division that generates haploid cells. The breakdown came later, during spermiogenesis, the transformation of round spermatids into the sleek, elongated, motile sperm that define male fertility. In the mutants, spermatid elongation faltered and individualization, the process by which each spermatid is sculpted, compacted, and encased in its own membrane sheath, failed to proceed properly. This stage-specific failure is telling, because spermatid elongation and individualization demand massive, precisely timed remodeling of the cytoskeleton, of chromatin, and of RNA populations inherited from earlier stages. Mettl16 therefore appears to be required for the late maturation program of sperm rather than for the fundamental mechanics of cell division.

Where does the enzyme live inside the cell, and what does it do when it gets there? The team tagged Mettl16 with green fluorescent protein and found that the fusion protein localized predominantly to the nucleus, consistent with a role in nuclear RNA processing rather than in the cytoplasmic control of translation. To test whether Mettl16 loss broadly crippled protein synthesis, the researchers examined wing disc epithelial cells, a classic Drosophila model tissue, and found that global protein production was not impaired in the absence of the enzyme. This observation carries real weight. If Mettl16 were a major regulator of mRNA translation, its removal should have left a visible signature on the protein output of the cell. Instead, the data pointed toward a narrower, more targeted function, in which only a specific set of RNA substrates depends on Mettl16 activity.

That selectivity was confirmed at the level of the transcriptome-wide methylome. Using MeRIP-Seq, a technique that immunoprecipitates methylated RNA fragments and maps them back to the genome, the researchers compared the m6A landscape of normal flies with that of Mettl16 mutants. The comparison produced a striking contrast. When Mettl3 is lost, the effect on m6A is broad, sweeping away the modification from a large fraction of transcripts across the transcriptome. Mettl16 loss, by comparison, altered m6A on only a small subset of RNAs. This result reframes the two enzymes as complementary writers with distinct substrate preferences: Mettl3 acts as the bulk methyltransferase decorating thousands of messages, while Mettl16 behaves as a specialist, placing marks on a curated list of targets whose identity appears central to the phenotypes observed in the mutant flies.

Among those targets, one stood out with particular clarity: U6 snRNA, the small nuclear RNA that forms the catalytic heart of the spliceosome, the molecular machine that removes intervening sequences from pre-messenger RNAs. The team demonstrated that Mettl16 physically interacts with U6 snRNA and is required for its m6A modification. This finding connects the fly enzyme to one of the most conserved functions described for METTL16 in other organisms, the methylation of U6, and it immediately suggested a mechanism by which the enzyme could exert widespread downstream effects. Splicing is the process that stitches together the coding segments of genes, and alternative splicing allows a single gene to produce multiple protein variants. If Mettl16 fails to methylate U6, the spliceosome’s precision could be subtly compromised, reshuffling the splicing patterns of many genes even though only a handful of transcripts lose their m6A marks directly.

That prediction held up. The researchers found that Mettl16 mutants display widespread alterations in alternative splicing, meaning that the way numerous pre-messenger RNAs are assembled into mature messages changes throughout the animal. This splicing dysregulation provides a plausible mechanistic bridge between the enzyme’s narrow biochemical footprint and its pleiotropic developmental consequences. Genes required for spermatid elongation, for oogenesis, and for normal behavior could each be mis-spliced in the mutant, producing protein isoforms that are truncated, unstable, or functionally altered. The picture that emerges is one of indirect amplification: a single, targeted RNA modification on a core splicing component ripples outward into broad changes in gene expression, which in turn manifest as the sterile, behaviorally abnormal flies observed in the study.

The evolutionary implications of the work are equally compelling. Comparing flies with mammals reveals a remarkable divergence in biological logic. In mammals, METTL16 is indispensable, its loss lethal during embryogenesis, whereas in flies the enzyme is dispensable for viability but essential for reproduction and normal development. This kind of comparative data helps researchers understand how the epitranscriptome has been rewired across hundreds of millions of years of evolution, with the same chemical modification and the same family of writer enzymes being deployed in different tissues and at different developmental checkpoints depending on the organism. It also cautions against assuming that findings from one model system translate directly to another, a lesson with practical consequences for biomedical research that relies on m6A biology as a therapeutic target.

For the growing community of scientists studying RNA modifications, the Drosophila study adds an important piece to the puzzle of how m6A writers divide their labor. Mettl3 emerges as the generalist, methylating a broad swath of the transcriptome, while Mettl16 operates as a specialist whose most clearly defined substrate is the U6 snRNA at the heart of the splicing machinery. The pleiotropic phenotypes of Mettl16 mutants, from failed spermatid individualization to behavioral defects, most likely stem from the combination of direct m6A deposition on specific target transcripts and the indirect consequences of U6-dependent splicing regulation. As epitranscriptomics moves from cataloging modifications toward understanding their causal roles in development and disease, this fly work demonstrates that even a small subset of methylated RNAs, when left unmodified, can be enough to derail some of the most elaborate programs an animal ever runs, including the construction of the next generation itself.

Subject of Research: The role of the m6A methyltransferase Mettl16 in Drosophila development, fertility, and RNA splicing regulation

Article Title: Role of the m 6 A methyltransferase Mettl16 in Drosophila development

Article References: Song, P., Ma, L., & Yan, D. (2026). Role of the m6A methyltransferase Mettl16 in Drosophila development. PLOS Genetics, 22(9), e1012317. https://doi.org/10.1371/journal.pgen.1012317

Image Credits: AI Generated

DOI: 10.1371/journal.pgen.1012317

Keywords: m6A, Mettl16, Drosophila, epitranscriptomics, RNA methylation, U6 snRNA, alternative splicing, gametogenesis, spermatid individualization, PLOS Genetics, methyltransferase, developmental biology

The work, led by Jianzhao Liu and Xin-Hua Feng of Zhejiang University together with colleagues at Soochow University and other Chinese institutions, began with a simple but technically demanding question: is METTL14, the scaffold subunit of the m6A methyltransferase complex, itself chemically modified? Using immunoprecipitation followed by immunoblotting in HEK293T and HeLa cells, the team found that METTL14, but not its catalytic partner METTL3 nor the regulatory subunit WTAP, is robustly ubiquitinated. Ubiquitin is best known as a destruction tag: chains linked through its lysine-48 residues deliver proteins to the proteasome. But ubiquitin can be assembled into eight distinct chain types, and several of them, including K27-linked chains, are thought to modulate protein interactions and localization rather than stability. When the researchers restricted cellular ubiquitin to single-linkage variants, METTL14’s modification turned out to be dominated by exactly this noncanonical K27 linkage.

Mass spectrometry then mapped the modification to specific lysine residues on METTL14, including lysines 148 and 278, positions that sit near the interfaces through which METTL14 grips its partners. To find the enzyme responsible, the team pulled down METTL14 and searched its associated proteins for candidate E3 ubiquitin ligases. The screen converged on RLIM, also known as RNF12, a RING-domain ligase first characterized as a corepressor of LIM homeodomain transcription factors. RLIM’s catalytic activity proved essential: a ligase-dead H569A/C572A mutant or a construct lacking the RING domain entirely failed to promote METTL14 ubiquitination, whereas wild-type RLIM drove robust K27-linked tagging in cells and in reconstituted in vitro reactions with defined E1 and E2 enzymes.

What makes this finding conceptually striking is what the ubiquitin mark does not do. RLIM knockout did not alter METTL14 protein abundance, and immunofluorescence showed that METTL14 still entered the nucleus normally in cells lacking RLIM. Instead, the modification acted on function. In vitro methylation assays demonstrated that K27-ubiquitinated METTL3–METTL14 complexes were markedly impaired in their ability to methylate RNA substrates. Two mechanisms accounted for the deficit. First, structural modeling and biochemical assays indicated that ubiquitin conjugated at lysine 278 distorts the loop regions at the METTL3–METTL14 interface, weakening the heterodimer that constitutes the active writer. Second, electrophoretic mobility shift assays and microscale thermophoresis showed that ubiquitinated or ubiquitination-mimicking complexes bound RNA less tightly, reducing substrate engagement. A split Nano-Luciferase reporter confirmed in living cells that RLIM expression disrupts METTL3–METTL14 association. In other words, RLIM acts as a rheostat on the writer’s activity rather than a trigger for its disposal.

The physiological consequence was visible across the transcriptome. MeRIP-seq and RNA-seq comparisons of control and RLIM-knockout cells revealed widespread hypermethylation of mRNA m6A peaks when RLIM was absent, with the affected transcripts enriched for genes governing the G2/M transition of the cell cycle. Consistent with known links between m6A and mRNA stability, hypermethylated transcripts in RLIM-knockout cells showed shortened half-lives, and many overlapped with binding targets of the m6A reader YTHDF2, which routes methylated transcripts toward degradation. Representative loci such as E4F1 and RHOB, both implicated in cell-cycle control, gained m6A and lost stability when RLIM was removed, and MeRIP-qPCR validated these changes independently.

The cell-cycle connection then became explicit. When the researchers synchronized cells by double thymidine block and released them, they observed coordinated periodic oscillations in three quantities: transcriptome-wide m6A levels, the intensity of K27-linked ubiquitin on METTL14, and RLIM protein abundance. RLIM knockout arrested cells at the G2/M boundary, an effect that could be rescued by knocking down METTL14, placing RLIM upstream of the writer in a pathway that governs mitotic entry. Measurements of global m6A-to-A ratios by LC-MS/MS across G1/S, S, G2, M and G1 phases confirmed that the methylation landscape rises and falls with the cycle, and immunofluorescence for phospho-histone H3 showed RLIM levels dropping precisely in mitotic cells.

The mechanism behind RLIM’s own oscillation turned out to be a classic mitotic kinase. The CDK1–cyclin B1 complex, the master switch for mitotic entry, physically associated with RLIM and phosphorylated it. Phosphatase treatments and Ser/Thr-to-Ala mutant analysis identified the phosphorylation sites responsible, and these modifications triggered RLIM to ubiquitinate itself with K48-linked chains, condemning it to proteasomal degradation. Blocking CDK1 or cyclin B1 by RNA interference stabilized RLIM, while proteasome inhibition with MG132, but not lysosomal inhibition with chloroquine, rescued the protein. This arrangement creates an elegant feedback loop: as CDK1–cyclin B1 surges at G2/M, it destroys RLIM, which releases METTL14 from inhibitory ubiquitination, allowing the writer complex to reassemble and retune the m6A landscape for the next phase of the cycle.

To test whether this axis matters beyond cultured cells, the team turned to animal and clinical models. In mice with Rlim deleted specifically in the myeloid lineage, bone marrow cells showed elevated m6A methylation on cell-cycle and differentiation genes, and flow cytometry revealed perturbed hematopoietic populations, effects that intensified after vesicular stomatitis virus infection. Endogenous METTL14 in these marrow cells lost its K27-linked ubiquitination, confirming the pathway operates in primary tissue. The researchers also examined MOLM-13, an acute myeloid leukemia cell line, where RLIM knockdown altered cell-cycle distribution and myeloid differentiation markers and reduced colony formation. Most compellingly, samples from patients with acute monocytic leukemia, collected through collaborating hospitals in Suzhou, displayed dysregulation of the RLIM–METTL14 axis, linking the molecular circuit to human disease.

The study’s broader significance lies in expanding the vocabulary of epitranscriptomic regulation. For a decade, the m6A writer has been viewed largely as a stable assembly whose output is tuned by accessory proteins, substrate availability and chromatin state. This work adds a temporal dimension: a cell-cycle-programmed, noncanonical ubiquitin code that switches the writer’s activity on and off without touching its concentration. Because K27-linked chains are increasingly recognized as scaffolds for protein–protein interactions in cell-cycle and quality-control pathways, the finding suggests that other RNA-processing enzymes may carry similar non-degradative marks awaiting discovery. It also reframes ubiquitin ligases, traditionally studied in the context of protein turnover, as direct modulators of the epitranscriptome.

Therapeutically, the implications are tantalizing but preliminary. Acute myeloid leukemia has already emerged as a disease exquisitely sensitive to m6A dosage, with the writer METTL3, the erasers FTO and ALKBH5, and the reader YTHDF2 each implicated in leukemic self-renewal. The new axis adds RLIM, and the CDK1–cyclin B1 switch that controls it, to the list of potential intervention points. CDK1 inhibitors are already in clinical use for other indications, raising the possibility that modulating RLIM stability could tune m6A levels in leukemia cells. For now, the study stands as a demonstration that the cell’s division clock reaches deep into its RNA chemistry, and that a ubiquitin tag once dismissed as obscure may be one of the hands on that clock.

Subject of Research: Cell-cycle-regulated noncanonical K27-linked ubiquitination of METTL14 controlling mRNA m6A methylation

Article Title: Cell-cycle-driven noncanonical ubiquitination of METTL14 orchestrates RNA methylation

Article References: Cao, J., Ying, X., Zhou, L., Zhang, Q., Huang, C., Dai, T., Shu, X., Gao, M., Mi, Y., Wu, X., Wang, F., Zhang, L., Zhou, F., Feng, X.-H., & Liu, J. (2026). Cell-cycle-driven noncanonical ubiquitination of METTL14 orchestrates RNA methylation. Nature Chemical Biology. https://doi.org/10.1038/s41589-026-02328-5

Image Credits: AI Generated

DOI: 10.1038/s41589-026-02328-5

Keywords: m6A, METTL14, RLIM, ubiquitination, K27-linked ubiquitin, cell cycle, CDK1, cyclin B1, epitranscriptomics, RNA methylation, acute myeloid leukemia, post-translational modification

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

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

The new study, published as an open-access original article in Cellular and Molecular Life Sciences, focuses on a chemical tag known as N6-methyladenosine, or m6A, the most abundant internal modification found in messenger RNA molecules across eukaryotic cells. Far from being decorative, m6A marks act as a dynamic layer of gene regulation: they influence how efficiently a transcript is translated into protein, how long it survives before being degraded, and even where it localizes within the cell. Writers install the mark, readers interpret it, and erasers remove it. The enzyme at the heart of the new findings, alkylation repair homolog protein 5, better known as ALKBH5, belongs to this last category. It is a demethylase, an enzyme that chemically strips m6A marks from RNA, and previous work had implicated it in everything from spermatogenesis to cancer progression. Whether it played any role in the diseased placenta, however, was unknown.

To find out, the researchers began where the disease begins: in placental tissue. Analyzing clinical samples from patients with preeclampsia, they discovered that ALKBH5 was consistently upregulated in the placentas of affected mothers compared with healthy pregnancies. Crucially, this overabundance of the demethylase coincided with a global decrease in m6A levels across placental transcripts, exactly what one would expect if an RNA eraser were working overtime. The same pattern appeared in a mouse model of preeclampsia-like disease, strengthening the case that the observation was not a human-tissue artifact but a reproducible feature of the disorder. The correlation, while compelling, left open the central question of causation: was ALKBH5 merely a bystander in the stressed placenta, or was it actively driving the pathology?

The team turned to a laboratory workhorse to answer that question. HTR8/SVneo cells, an immortalized human trophoblast line widely used to model placental cell behavior, were exposed to hydrogen peroxide to induce oxidative stress, mimicking the hostile environment that trophoblasts face in a preeclamptic placenta. As anticipated, the stressed cells lost their ability to invade and migrate, the very functions that healthy trophoblasts must perform to anchor the placenta and remodel maternal spiral arteries. But when the researchers knocked down ALKBH5 using small interfering RNA, the damage was partially reversed. The treated cells recovered a significant portion of their invasive and migratory capacity, suggesting that ALKBH5 was not simply responding to stress but actively contributing to the functional collapse of trophoblasts under oxidative assault.

With a functional link established, the next challenge was to identify the molecular target through which ALKBH5 exerted its effects. The researchers performed an integrated bioinformatics analysis, cross-referencing the RM2Target database with Gene Expression Omnibus datasets to search for genes that were both regulated by ALKBH5 and relevant to trophoblast biology. The search converged on a single compelling candidate: formyl peptide receptor 2, or FPR2, a G-protein-coupled receptor known to participate in inflammatory signaling. Subsequent validation experiments, including RNA immunoprecipitation and dual-luciferase reporter assays, confirmed that ALKBH5 physically and functionally interacts with FPR2 messenger RNA, establishing FPR2 as a bona fide downstream target of the demethylase.

The mechanistic details that emerged are elegant and, in the context of pregnancy disease, genuinely novel. ALKBH5 binds to the 3′ untranslated region of the FPR2 transcript, the stretch of RNA that follows the protein-coding sequence and typically governs transcript stability. By erasing m6A marks at this location, ALKBH5 stabilizes the FPR2 mRNA, allowing it to persist longer in the cell and driving up the production of the FPR2 receptor protein. In other words, the demethylase does not change the genetic message itself; it changes how long the message survives, and in doing so it amplifies a receptor that ultimately undermines trophoblast behavior. This m6A-dependent stabilization mechanism illustrates how epitranscriptomic regulation, a field barely two decades old, can produce consequences as dramatic as a pregnancy disorder.

The functional experiments sealed the argument. When the researchers overexpressed FPR2 in trophoblasts that had been protected by ALKBH5 knockdown, the protective effect vanished: the cells once again lost their invasive and migratory prowess under oxidative stress. FPR2, it appeared, was the executioner carrying out the damage that ALKBH5 had set in motion. Conversely, when the team administered WRW4, a pharmacological antagonist of FPR2, to mice with preeclampsia-like features, the disease phenotype improved. The antagonist ameliorated the key characteristics of the disorder in the animal model, providing proof of principle that blocking the receptor downstream of ALKBH5 can counteract the pathological process in a living system.

Taken together, the findings define what the authors describe as an ALKBH5–FPR2 axis in preeclampsia pathogenesis: an RNA-erasing enzyme upregulated in the diseased placenta strips methylation marks from FPR2 transcripts, prolongs their half-life, boosts receptor expression, and thereby disrupts the trophoblast functions on which a healthy pregnancy depends. The chain of evidence runs from human placental tissue through cell culture under oxidative stress to a mouse model and back again, with pharmacological rescue at the endpoint. Few studies of preeclampsia have traced a causal pathway with this degree of molecular resolution, and the identification of an epitranscriptomic mechanism in the disorder opens a fresh dimension in a field long dominated by angiogenic factors and immune hypotheses.

The therapeutic implications are tantalizing, though tempered by the usual caveats of early-stage research. Both nodes of the axis offer potential points of intervention: inhibiting ALKBH5 activity or blocking FPR2 signaling with agents such as WRW4 could, in theory, restore trophoblast function before the maternal syndrome takes hold. Because FPR2 already has known pharmacological modulators, the receptor represents a particularly attractive druggable target, and repurposing efforts could accelerate translation. Yet significant hurdles remain. The mouse model recapitulates preeclampsia-like features but not the full human disease, the precise timing and cell types in which the axis operates during human placentation require further mapping, and any intervention in pregnancy demands an exceptionally high safety bar. Still, the study adds a powerful new concept to the preeclampsia literature: that the fate of a pregnancy may hinge not on which genes are present, but on how long their RNA messages endure. As m6A biology continues to reshape our understanding of human disease, the placenta has now joined the list of organs where the epitranscriptome writes, and erases, the story of health.

Subject of Research: The role of the m6A demethylase ALKBH5 and its downstream target FPR2 in the pathogenesis of preeclampsia

Article Title: ALKBH5 contributes to preeclampsia through m6A-dependent upregulation of FPR2

Article References: Fan, C., Zhang, C., Liu, L., & Zhang, M. (2026). ALKBH5 contributes to preeclampsia through m6A-dependent upregulation of FPR2. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06471-z

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06471-z

Keywords: preeclampsia, ALKBH5, FPR2, m6A, RNA methylation, epitranscriptomics, trophoblast, placenta, oxidative stress, RNA stability, pregnancy, molecular biology

The m6A mark is deposited on RNA by a conserved writer complex. In plants, this complex comprises the methyltransferases MTA and MTB together with FIP37, VIRILIZER-like proteins, and HAKAI, counterparts of the METTL3-METTL14-WTAP machinery familiar from animal cells. The modification preferentially lands on adenosines within the DRACH sequence motif, clustering near stop codons and in 3-prime untranslated regions. Demethylase enzymes known as erasers, including ALKBH9B and ALKBH10B in plants, can strip the mark away, while YTH-domain reader proteins bind methylated transcripts and determine their fate, whether stabilization, degradation, translation, or sequestration. Because the mark is reversible and acts post-transcriptionally, it provides a rapid regulatory layer that operates without altering the underlying genetic sequence. Disrupting core writers such as MTA or FIP37 is lethal to plant embryos, underscoring how deeply this system is woven into normal development, from meristem maintenance to flowering time and cold-stress adaptation.

Whether plant viral RNAs actually carry m6A was unresolved for decades, but since 2017 a series of studies has delivered converging proof. The first biochemical evidence came from Alfalfa mosaic virus, whose RNAs were enriched by immunoprecipitation with anti-m6A antibodies. Subsequent work mapped high-confidence methylation peaks on Wheat yellow mosaic virus, Plum pox virus, Potato virus Y, and Pepino mosaic virus, the latter detected even inside purified viral particles. More recently, antibody-independent nanopore direct RNA sequencing has confirmed m6A on Cucumber mosaic virus genomes, with sites overlapping those found by antibody-based methods, and liquid chromatography coupled to tandem mass spectrometry has verified the modification chemically. In Sugarcane mosaic virus, a potyvirus of maize, researchers pinpointed a single modified adenosine at position 6556, deposited by the maize writer ZmMTA, and showed that a synonymous mutation at that site significantly enhanced infection. Bamboo mosaic virus yielded 122 candidate sites by direct RNA sequencing. Together these techniques leave little doubt that m6A is an authentic feature of diverse plant viral RNAs.

How cytoplasmic plant viruses gain access to a methyltransferase complex that normally resides in the nucleus has become one of the most intriguing mechanistic questions in the field. Unlike nuclear-replicating animal viruses such as influenza or HIV, most plant viruses replicate exclusively in the cytoplasm, seemingly far from the writer machinery. The answer, it turns out, is that viruses actively drag the machinery to themselves. In wheat, the WYMV NIb protein physically interacts with the writer TaMTB and triggers its translocation to cytoplasmic replication sites, where the enzyme methylates viral RNA at a defined position. In Arabidopsis infected with Cucumber mosaic virus, the viral coat protein binds the core writer MTB directly and promotes nuclear-to-cytoplasmic relocation of the entire complex. During Sugarcane mosaic virus infection, ZmMTA co-localizes with viral genomic RNA in cytoplasmic aggregates, though the exact relocation mechanism remains to be worked out. Notably, not every virus succeeds in this recruitment; recent antibody-independent analyses of Chikungunya and Dengue viruses found no detectable m6A, a reminder that epitranscriptomic engagement is selective rather than universal.

Once deposited, the mark can cut in either direction. In several systems m6A behaves as a classic antiviral flag. Hypermethylated Cucumber mosaic virus RNAs are recognized by the reader protein ECT8, which directs them into decay pathways, likely through processing bodies. In Pepino mosaic virus infection of Nicotiana benthamiana, overexpressing the writers MTA or HAKAI boosts viral RNA methylation and restricts infection, while the methylated transcripts are bound by the YTH-domain readers NbECT2A, 2B, and 2C, which recruit nonsense-mediated decay factors such as UPF3 and SMG7 to destroy them. Silencing NbECT2B or the NMD components increases viral RNA stability and susceptibility. In maize, the reader ZmECT23 recognizes methylated Sugarcane mosaic virus RNA and recruits the CCR4-NOT deadenylation complex to destabilize it, and in Nicotiana benthamiana the writer NbMTA targets Potato virus Y genomes for degradation.

Yet some viruses have turned the same mark to their advantage. When the WYMV NIb protein lures TaMTB to replication complexes, the resulting site-specific methylation stabilizes the viral RNA and prevents its degradation, and mutating the methylation site reduces viral stability and pathogenicity. A parallel strategy appears in the plant rhabdovirus Barley yellow striate mosaic virus, whose P6 messenger RNA is hypermethylated; loss of the mark reduces P6 stability and infectivity. Intriguingly, barley fights back with its own eraser, HvALKBH1B, which binds P6 mRNA into cytoplasmic condensates through liquid-liquid phase separation, a process requiring the protein’s intrinsically disordered region, thereby stripping the viral advantage. The lesson is that m6A is not inherently antiviral or proviral; it is a regulatory currency that whichever side controls it can spend.

The mark also shapes viral systemic movement, not merely local accumulation. Alfalfa mosaic virus depends on the host demethylase ALKBH9B removing m6A from its RNAs for efficient long-distance spread, an interaction mediated by the viral coat protein. Excessive methylation reduces phloem transport and restricts movement through the plant, so a balanced level of the mark is essential for the virus to travel. Consistent with this, infection by Plum pox virus and Potato virus Y lowers global m6A levels in Nicotiana benthamiana, and knocking down ALKBH9 homologs diminishes accumulation of both viruses. On the defensive side, the YTHDF-family readers ECT2, ECT3, and ECT5 bind Alfalfa mosaic virus RNAs in an m6A-dependent manner and act as restriction factors suppressing viral accumulation. Strikingly, this regulation is specific to ALKBH9B, since disrupting the related homologs ALKBH9A or ALKBH9C leaves infection untouched, revealing a fine-grained specificity in how plants deploy their epitranscriptomic arsenal.

Viruses, unsurprisingly, have evolved countermeasures. The 2b protein of Cucumber mosaic virus, already infamous as a suppressor of RNA silencing, competitively binds the writer components HAKAI and MTB, impairing the integrity of the writer complex in both nucleus and cytoplasm. This suppresses methylation not only on viral RNAs but across the host transcriptome; plants lacking m6A are more susceptible to a 2b-deficient mutant but not to wild-type virus, and simply expressing 2b in transgenic plants lowers global m6A levels. Pepino mosaic virus takes a different route: its RNA-dependent RNA polymerase interacts with the tomato writer SlHAKAI and the autophagy protein SlBeclin1, forming cytoplasmic granules that route SlHAKAI to autophagic destruction, thereby stripping methylation from viral RNA. In maize, the Sugarcane mosaic virus protease NIa-Pro hijacks the initiation factor ZmeIF4A3 into viral replication complexes, sterically blocking ZmMTA-mediated methylation and sparing viral RNA from ZmECT23-directed decay. Each case illustrates a mutually antagonistic arms race fought at the level of RNA chemistry.

Viral infection also rewrites the host’s own methylation landscape in ways that reshape immunity. Tobacco mosaic virus lowers m6A levels in tobacco, coinciding with upregulation of the eraser NbALKBH5, while Rice stripe virus and Rice black-streaked dwarf virus raise methylation levels in rice, enriching marks on transcripts involved in RNA silencing and hormone defense, including the antiviral genes OsAGO18 and OsSLRL1. In watermelon facing Cucumber green mottle mosaic virus, susceptible plants show early hypermethylation of stress-related transcripts, whereas resistant cultivars exhibit later hypomethylation that preserves defense gene expression. In Arabidopsis, CMV-induced hypomethylation upregulates the salicylic acid regulators NPR3 and CBP60a, and Potato virus Y triggers a transient rise in methylation at five to ten days post-inoculation that falls by day fourteen, accompanied by activation of a transcription factor that boosts NbMTA expression and accelerates viral RNA degradation. These virus-specific, time-dependent shifts integrate m6A into the broader networks of hormone signaling and stress adaptation.

The review’s authors argue that these findings position m6A as a promising lever for crop protection, whether through overexpressing writer components, modulating reader activity, or breeding viral methylation sites out of susceptible hosts. Significant questions remain, however. Recent work warns that false-positive signals can arise in both antibody-based and some antibody-independent mapping methods, making rigorous negative controls essential, and emerging single-molecule technologies are expected to sharpen the resolution of modification detection. Researchers still do not fully understand what sequence or structural features direct methylation to particular viral transcripts, how the temporal choreography of methylation unfolds during infection, or how reliably these mechanisms can be engineered into durable field resistance. What is already clear is that the epitranscriptome has moved from the margins of plant virology to its center, and that the contest over a single methyl group on adenosine may help decide the outcome of infections that devastate staple crops worldwide.

Subject of Research: The role of m6A RNA modification in plant-virus interactions

Article Title: The expanding role of m6A RNA modification in plant-virus dynamics: friend, foe, or both?

Article References: Liu, J.-H., Yu, H., & Duan, C.-G. (2026). The expanding role of m6A RNA modification in plant-virus dynamics: friend, foe, or both?. Advanced Biotechnology, 4(1), Article 7. https://doi.org/10.1007/s44307-026-00100-3

Image Credits: AI Generated

DOI: 10.1007/s44307-026-00100-3

Keywords: m6A, RNA modification, epitranscriptome, plant viruses, plant immunity, methyltransferase, YTH-domain proteins, RNA decay, viral countermeasures, crop resistance, Cucumber mosaic virus, RNA methylation

Inherited retinal dystrophies are a leading cause of irreversible blindness worldwide, and retinitis pigmentosa, the most common form, affects an estimated 2.5 million people. More than 100 causative genes have been identified, yet between 30 and 50 percent of cases still lack a genetic diagnosis, and the observation of incomplete penetrance hints that factors beyond DNA sequence are at work. Epigenetic mechanisms, which modulate gene expression without altering the genome, have increasingly come into focus in ocular disease. Among these, m6A stands out as the most abundant internal modification in eukaryotic messenger RNA, deposited by writer enzymes, removed by erasers such as FTO and ALKBH5, and interpreted by reader proteins that influence splicing, export, stability, and translation.

METTL16 is a relative newcomer to the m6A field. Unlike the well-known METTL3/METTL14 complex, it recognizes a specific motif, UACAGARAA, within structured RNA contexts, and its validated substrates include MAT2A mRNA, which it regulates to maintain cellular levels of the universal methyl donor S-adenosylmethionine, and U6 snRNA, a small nuclear RNA at the heart of the splicing machinery. METTL16 methylates U6 at position A43 within the ACAGAGA sequence that base-pairs with the 5′ splice site of introns during pre-mRNA splicing. Work in fission yeast, roundworms, plants, and human cells has shown that losing this modification impairs 5′ splice site recognition. Intriguingly, dominant mutations in U6 snRNA have recently been linked to autosomal dominant retinitis pigmentosa, and those variants cluster in regions that contact spliceosome components such as PRPF3, PRPF8, and PRPF31, proteins that are themselves mutated in RP.

To probe METTL16’s role in the retina, the team, led by Jiangbo Ren, Wenjing Liu, and colleagues, generated rod-specific Mettl16 knockout mice by crossing Mettl16-floxed animals with RHO-Cre mice, in which the recombinase is active only in rods. The resulting RKO mice showed efficient excision of the targeted exon and a marked reduction of METTL16 protein in the retina. Single-cell RNA sequencing data from the Human Protein Atlas had already indicated that METTL16 is broadly expressed across retinal cell types, with notable enrichment in rods, making the knockout strategy well suited to testing its function in the cells most vulnerable to retinitis pigmentosa.

The physiological consequences were swift and measurable. Electroretinograms recorded at one month of age revealed that scotopic responses, which reflect rod function, were severely blunted: a-wave and b-wave amplitudes were reduced by roughly 54 and 55 percent, respectively, compared with littermate controls. Cone-mediated photopic responses, by contrast, were largely preserved at this stage, pointing to a rod-first pattern of degeneration. Behavioral assays corroborated the electrophysiology. In a light-dark box test, RKO mice spent only about 39 percent of their time and traveled about 42 percent of their distance in the dark chamber, unlike control mice, which normally prefer darkness. Their optomotor response, a reflexive head movement that tracks rotating visual gratings, dropped to 1.56, well below the values of 2.0 or higher seen in controls.

Under the microscope, the story continued. At postnatal day 20, retinal architecture looked normal, but by day 30 the outer nuclear layer and outer segments of RKO retinas were visibly thinning, and by day 40 the outer nuclear layer had lost roughly 40 percent of its thickness relative to controls. Immunofluorescence showed that key outer segment proteins, including rhodopsin, PRPH2, GRK1, PDE6B, and CNGA1, were markedly reduced in abundance even though their localization within the photoreceptor was not disrupted. Signs of degenerative stress were everywhere: Müller glia became reactive, microglia adopted an amoeboid morphology and invaded the outer nuclear layer, and TUNEL staining detected apoptotic nuclei among the photoreceptors. Cones, meanwhile, showed only delayed involvement, with reduced M-opsin-positive cells appearing by day 40.

To trace the molecular roots of this collapse, the researchers integrated RNA sequencing with quantitative proteomics on one-month-old retinas. Among the genes concordantly downregulated at both the transcript and protein levels, Gene Ontology and KEGG analyses pointed squarely at photoreceptor development, photoreceptor cilia, inner and outer segments, visual perception, and the phototransduction cascade. Five established retinitis pigmentosa genes emerged from this analysis: Tulp1, Cnga1, Pde6g, Crb1, and Prcd. Four of them showed significant differential expression at both levels after correction for multiple testing, and the reductions were confirmed by RT-qPCR and Western blotting. The metabolic arm of the analysis revealed perturbations in the S-adenosylmethionine pathway as well, with Mat2a mRNA, a direct METTL16 substrate, reduced in knockout retinas, and Csad, a key enzyme of taurine biosynthesis, markedly decreased.

The mechanistic core of the paper lies in splicing. Using a single-base elongation and ligation-based qPCR assay called SELECT on purified U6 snRNA, the team confirmed that m6A at position A43 was reduced in knockout retinas. Transcriptome-wide analysis with rMATS then revealed extensive alternative splicing changes, with skipped exons as the predominant event class. Sequence analysis of affected 5′ splice sites showed a telling pattern: sites whose usage decreased in knockout retinas were enriched for adenosine at the +4 position, the very nucleotide engaged by methylated U6, and carried an RAG motif across the U6-interacting positions, whereas sites with increased usage favored stronger U5 snRNA base pairing and non-adenine nucleotides at +4. Crucially, aberrant splicing was already detectable at postnatal day 20, before any overt cell loss. Both Tulp1 and Pde6g, two established retinal dystrophy genes, showed increased exon skipping, and the affected donor sites shared the conserved //GURAG motif previously implicated in METTL16 loss in plants and worms. MeRIP-seq showed no change in m6A enrichment on the Tulp1 and Pde6g transcripts themselves, consistent with a U6-dependent mechanism rather than direct methylation of the mRNAs. The Tulp1 exon 4-skipped transcript is predicted to encode an in-frame deletion of 51 amino acids, and immunostaining revealed disrupted ribbon synapse architecture in knockout retinas, echoing the synaptic defects known from Tulp1 knockout mice.

The study also documented METTL16’s influence beyond the nucleus. MeRIP-seq identified Tor1b and Nlgn2 as candidate direct m6A targets, with reduced methylation in their 3′ untranslated regions and reduced expression in knockout retinas; luciferase reporter assays showed that wild-type METTL16 enhanced reporters bearing the wild-type 3′ UTRs but not motif-mutated versions, and a catalytic-domain-deficient METTL16 mutant failed to do so. In photoreceptor-derived 661W cells, loss of METTL16 accelerated the decay of both transcripts, indicating effects on mRNA stability. Meanwhile, immunoprecipitation coupled with mass spectrometry revealed that retinal METTL16 associates with translation factors including PURA, PABPC1, and EIF3B, and with the splicing factors SF3B1 and SF3B3. SUnSET assays and polysome profiling showed that Mettl16 knockdown reduced global translation efficiency in 661W cells, and polysome analysis confirmed diminished translational efficiency of phototransduction genes such as Cep164, Rpgr, Prph2, and Cnga1, whose mRNA levels were unchanged even as their proteins declined.

The authors are careful to note the limitations: most molecular analyses used bulk retinal tissue, which can blur cell-type-specific effects and mix primary METTL16-dependent events with secondary degenerative changes, and the mechanistic work relied on the 661W cell line because mature rods are difficult to manipulate in vitro. Catalytically dead rescue experiments and ribosome profiling will be needed to determine whether the translational role depends on methyltransferase activity. Even so, the picture that emerges is striking. METTL16, working in both the nucleus and the cytoplasm, appears to safeguard photoreceptors on at least three fronts: by methylating U6 snRNA to preserve splicing fidelity in dystrophy genes, by stabilizing specific m6A-marked transcripts, and by supporting the translation of the proteins that build the light-sensing machinery. Given that mutations in U6 snRNA and multiple spliceosome components cause retinitis pigmentosa in humans, the study suggests that RNA processing defects may be a broader and previously underappreciated theme in photoreceptor disease, one that could eventually inform diagnostic and therapeutic strategies for the many patients whose blindness still has no genetic explanation.

Subject of Research: The role of the m6A methyltransferase METTL16 in photoreceptor survival and retinal degeneration

Article Title: METTL16 maintains photoreceptor integrity via splicing fidelity, mRNA stability, and translational regulation

Article References: Ren, J., Liu, W., Zou, R., Sun, K., Yang, M., Zhu, X., & Yang, Z. (2026). METTL16 maintains photoreceptor integrity via splicing fidelity, mRNA stability, and translational regulation. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.09.012

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.09.012

Keywords: METTL16, m6A, photoreceptors, retinitis pigmentosa, U6 snRNA, alternative splicing, RNA methylation, retinal degeneration, translation regulation, Tulp1, Pde6g, epitranscriptomics

The chemical modification at the heart of the study is N6-methyladenosine, abbreviated m6A, the most abundant internal modification found in messenger RNA. In this process, a methyl group is attached to the nitrogen at position six of adenosine bases, a change that can alter how efficiently a transcript is translated, where it localizes, and, crucially, how long it survives before being degraded by the cell’s RNA-decay machinery. METTL3 is the catalytic core of the methyltransferase complex that writes these marks. Because m6A methylation has already been implicated in cancer, cardiovascular disease, and a range of fibrotic disorders, and because previous work showed that silencing METTL3 blocks the conversion of fibroblasts into scar-forming myofibroblasts, the team reasoned that the enzyme might also govern the lipid disturbances that increasingly appear central to pulmonary fibrosis.

That lipid connection is not incidental. Lipids serve not only as structural components of cellular membranes but also as signalling molecules that modulate fibroblast activation and extracellular matrix production, and dysregulated lipid metabolism has emerged as a critical factor in the pathogenesis of idiopathic pulmonary fibrosis. The protein PLIN2, a member of the perilipin family, coats the surface of intracellular lipid droplets and acts as a gatekeeper, controlling the entry of lipases and their cofactors into the stored lipids and thereby regulating lipolysis. PLIN2 has been linked to myocardial infarction, obesity, fatty liver disease, and lipogenic differentiation in lung fibrosis, but its relationship with METTL3 had never been explored.

To establish the disease context, the researchers used the well-characterized bleomycin model, in which the chemotherapy drug bleomycin is delivered directly into the airways of mice to provoke fibrotic injury that resembles the human condition. Histological examination with haematoxylin and eosin and Masson’s trichrome staining confirmed that bleomycin destroyed normal lung architecture and drove collagen deposition. Molecular assays showed elevated levels of the fibrosis markers collagen I and alpha-smooth muscle actin, while Nile Red fluorescence staining of lung sections revealed a marked increase in lipid deposition. Critically, METTL3 expression was significantly upregulated in the fibrotic lungs. The same pattern appeared in vitro: WI-38 human embryonic lung fibroblasts treated with transforming growth factor beta 1, a standard mimic of the fibrotic environment, also raised their METTL3 levels.

The team then asked what happens when METTL3 is removed. Using short hairpin RNA to knock down the enzyme in TGF-beta1-treated WI-38 cells, they observed a broad calming of the fibrotic program. Expression of lipogenesis markers including fatty acid synthase, acetyl-CoA carboxylase 1, SREBP1, and PPARalpha, all of which had been elevated by TGF-beta1, fell back toward baseline. Collagen I and alpha-smooth muscle actin declined at both the messenger RNA and protein levels, a result confirmed by immunofluorescence imaging of alpha-smooth muscle actin. Oil Red O staining showed that the abundance of lipid droplets induced by TGF-beta1 was partly abolished when METTL3 was silenced, demonstrating that the enzyme’s influence extends from scar formation to fat handling within the same cells.

The mechanistic core of the paper lies in what METTL3 does to PLIN2. When the researchers silenced METTL3, PLIN2 expression rose. Methylated RNA immunoprecipitation showed that the m6A levels on PLIN2 transcripts dropped in parallel, and RNA immunoprecipitation confirmed a direct physical interaction between METTL3 and the PLIN2 RNA. Using the SRAMP prediction database, the team identified five candidate methylation sites, selected the three with the highest confidence, and tested them individually with a dual-luciferase reporter assay in which the wild-type or site-mutated PLIN2 sequence was inserted downstream of a luciferase gene. Silencing METTL3 increased reporter activity only for the construct containing site 2, pinpointing that single adenosine as the functionally relevant methylation site. Actinomycin D chase experiments, which block new RNA synthesis and allow existing transcripts to decay, showed that METTL3 knockdown significantly prolonged PLIN2 messenger RNA half-life, confirming that the enzyme normally destabilizes the transcript through m6A-dependent decay.

To prove that PLIN2 is not merely a bystander but the functional downstream effector, the researchers performed an epistasis experiment. When they knocked down PLIN2 in cells in which METTL3 had already been silenced, the protective effects of METTL3 loss were reversed. The suppression of lipogenesis markers was abrogated, collagen I and alpha-smooth muscle actin climbed back up, and the reduction in lipid droplets was counteracted. In other words, removing PLIN2 restored the fibrotic and lipid-accumulating phenotype even in the absence of METTL3, placing PLIN2 squarely downstream of the methyltransferase in the pathway that connects RNA methylation to scar formation.

The in vivo experiments reinforced the story. Twenty mice per group were randomly assigned to control, bleomycin, bleomycin plus a control short hairpin RNA, or bleomycin plus shMETTL3 delivered intratracheally by adenovirus. Over 28 days, bleomycin reduced survival, while METTL3 knockdown improved it. Histology showed that silencing METTL3 impeded the destruction of lung structure and the deposition of collagen fibres. Nile Red staining demonstrated that the lipid accumulation driven by bleomycin was counteracted by METTL3 knockdown, and the elevated collagen I and alpha-smooth muscle actin levels in fibrotic lungs fell after METTL3 interference. Immunohistochemistry revealed that PLIN2, which was downregulated in the bleomycin model, was restored by METTL3 silencing, mirroring the cellular findings and tying improved survival and tissue architecture to the restored lipid-droplet protein.

The findings fit into a growing body of work implicating m6A machinery in fibrotic disease across organs. METTL3 knockdown has been reported to inhibit fibroblast proliferation and migration in cardiac fibrosis, to ameliorate kidney fibrosis by reducing fibrotic marker expression, and to promote macrophage pyroptosis that aggravates liver fibrosis. In the lung specifically, METTL3-mediated methylation has been shown to drive fibroblast differentiation into myofibroblasts through the miR-21/PTEN pathway, and m6A-modified circular RNAs have been linked to ferroptosis in pulmonary fibrosis. The new study extends this landscape by identifying PLIN2 as a novel methylation substrate and by connecting RNA epigenetics directly to lipid metabolism, a dimension of pulmonary fibrosis biology that involves lipofibroblast activation, lung remodelling, and pathways such as lysophosphatidic acid signalling.

The authors are careful to note the limitations of their work. WI-38 embryonic fibroblasts, while genetically stable and widely used to study the fibroblast-to-myofibroblast transition, cannot fully recapitulate the pathology of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis, and embryonic cells may differ from adult disease fibroblasts in epigenetic and lipid metabolic profiles, so validation in MRC-5 cells or primary patient fibroblasts will be needed. The team validated a single methylation site by reporter assay but did not perform transcriptome-wide m6A mapping such as MeRIP-seq or miCLIP to exclude additional sites, and the role of PLIN2 in vivo requires further preclinical testing. Even so, the central conclusion stands: METTL3 promotes lipid deposition and fibrosis by destabilizing PLIN2 messenger RNA in an m6A-dependent manner, and interventions that raise PLIN2 expression, whether directly or by silencing METTL3, offer a conceptually new route to treating a disease that urgently needs one.

Subject of Research: The role of METTL3-mediated m6A modification of PLIN2 in lipid metabolism and pulmonary fibrosis

Article Title: METTL3 Promotes Lipid Deposition and Pulmonary Fibrosis by Destabilizing PLIN2 in a m6A‐Dependent Manner

Article References: Liu, Q., Xu, R., & Du, X. (2026). METTL3 Promotes Lipid Deposition and Pulmonary Fibrosis by Destabilizing PLIN2 in a m6A‐Dependent Manner. Journal of Cellular and Molecular Medicine, 30(17), Article e71239. https://doi.org/10.1111/jcmm.71239

Image Credits: AI Generated

DOI: 10.1111/jcmm.71239

Keywords: idiopathic pulmonary fibrosis, METTL3, m6A methylation, PLIN2, lipid metabolism, RNA modification, pulmonary fibrosis, fibroblasts, myofibroblast, bleomycin model, epitranscriptomics, TGF-beta1