METTL3 is a core component of the m⁶A methyltransferase complex and serves as the main catalytic subunit responsible for transferring a methyl group to the N6 position of adenosine residues in RNA, thereby regulating RNA stability, splicing, translation and degradation (33). Structurally, METTL3 contains a methyltransferase domain that binds the methyl donor S-adenosylmethionine and directly catalyzes m⁶A modification (30). Although it contains a methyltransferase-like domain, METTL14 primarily functions as an RNA-binding platform that enhances substrate recognition and complex stability (31). METTL14 forms a stable heterodimer with METTL3, and this complex is essential for efficient and specific m⁶A modification in eukaryotic RNAs (32). Previous studies also suggest that METTL14 may have additional roles in chromatin regulation and gene expression independent of its RNA methyltransferase activity (34,35). METTL14 expression is notably decreased in lung tissue from patients with IPF compared with normal lung tissue (16). High-throughput sequencing and experimental validation indicate that METTL14 downregulation reduces m⁶A methylation of DDIT4 mRNA, increases DDIT4 mRNA stability and protein expression and promotes alveolar epithelial cell senescence and fibrosis progression (16). This finding provides a mechanistic link between m⁶A remodeling and aging-related epithelial vulnerability in IPF; however, METTL14 should not be described as universally pro-fibrotic. In this model, reduced METTL14 expression promotes senescence by stabilizing DDIT4, whereas the role of METTL14 may differ in other cell types, disease stages or injury contexts. METTL3 is notably upregulated in fibrotic lung tissue compared with normal lung tissue (36). In mouse models and in vitro experiments, increased METTL3 expression leads to elevated m⁶A methylation of (TSC complex subunit 1) TSC1 mRNA. Through YTHDF2-mediated degradation of TSC1 mRNA, METTL3 reduces TSC1 protein levels and activates the AKT/mTOR pathway, thereby driving epithelial-mesenchymal transition (EMT) and fibrosis progression (36). Knockdown of METTL3 markedly impedes EMT, indicating its role in promoting fibrosis (36). In addition, METTL3-mediated m⁶A modification also promotes lung fibroblast-to-myofibroblast transition through KCNH6 mRNA translational regulation in a YTHDF1-dependent manner (18). Together, these data support a relatively consistent pro-fibrotic role for METTL3 in fibroblast activation and epithelial remodeling, although its therapeutic targeting still requires cell-specific safety evaluation.

FTO and ALKBH5 are the two major RNA demethylases that remove m⁶A modifications from RNA and dynamically regulate gene expression. FTO catalyzes oxidative demethylation of m⁶A, primarily producing N6-hydroxymethyladenosine as an intermediate, whereas ALKBH5 directly converts m⁶A to adenosine with rapid formaldehyde release, reflecting distinct biochemical mechanisms and cellular functions (37,38). Both enzymes influence RNA splicing, export, stability and translation and participate in biological processes such as differentiation, stress responses and tumor progression (39,40). ALKBH5 plays a tissue- and cell-type-specific regulatory role in PF. In PM2.5- and silica-induced PF models, ALKBH5 expression is downregulated in lung epithelial cells and macrophages, leading to increased m⁶A modification of target mRNAs such as autophagy related 13 and SLAM family member 7 (SLAMF7), thereby promoting autophagy dysfunction, inflammation and extracellular matrix (ECM) deposition (19,20). Proteasome-dependent degradation of ALKBH5 aggravates PF by enhancing autophagy-related dysfunction and activating YAP1 signaling in epithelial cells (21). In alveolar epithelial cells exposed to 1-nitropyrene, ALKBH5 undergoes SUMOylation, a reversible post-translational modification in which a small ubiquitin-like modifier protein is covalently attached to lysine residues on a substrate protein. In this model, ALKBH5 SUMOylation promotes its proteasomal degradation, thereby increasing m⁶A modification of FBXW7 mRNA, enhancing FBXW7 expression and promoting TRF2 degradation, telomere damage, cellular senescence and fibrosis (17). Moreover, ALKBH5 in macrophages regulates m⁶A modification of SLAMF7 and affects autophagy and inflammatory responses during silica-induced lung injury (22). These findings support a context-dependent role of ALKBH5. In toxicant-induced epithelial injury, ALKBH5 loss promotes senescence and fibrosis, suggesting a protective role of ALKBH5 in epithelial cells. However, ALKBH5-related pathways may differ in macrophages, fibroblasts and other environmental exposure models. Therefore, ALKBH5 should be described as a context-dependent regulator rather than a uniformly anti-fibrotic or pro-fibrotic factor.

FTO is notably downregulated in lung tissues during PF, specifically in a mouse model of silicosis (23). This suppression leads to increased global m⁶A RNA methylation in fibrotic lungs. Single-cell sequencing further revealed that FTO expression is reduced in epithelial cells, endothelial cells, fibroblasts and monocytes, all of which are involved in fibrosis (23). By contrast, ALKBH5 and other m⁶A regulators such as METTL3 and METTL14 did not show notable changes between normal and fibrotic lung tissues in that specific dataset (23). These findings suggest that FTO may act as a cell-type-sensitive regulator in silica-induced pulmonary inflammation and fibrosis. Nevertheless, whether FTO downregulation is an initiating event, a secondary response to injury or an amplifier of fibrotic inflammation remains to be clarified by cell-specific gain- and loss-of-function studies. YTHDF1, YTHDF2, YTHDF3 and insulin-like growth factor 2 mRNA-binding protein (IGF2BP)1-3 are key m⁶A reader proteins that recognize m⁶A modifications and regulate mRNA fate. YTHDF1 primarily promotes the translation of selected m⁶A-modified transcripts, whereas YTHDF2 generally facilitates their degradation. YTHDF3 has been reported to act as a co-reader that enhances YTHDF1-associated translation of certain m⁶A-marked transcripts and facilitates YTHDF2-associated decay of others. Therefore, the function of YTHDF3 depends on the bound transcript and cellular context rather than representing a uniform translational or degradative effect (41-43). By contrast, IGF2BP1-3 recognize m⁶A-containing transcripts through their K homology domains and recruit RNA-stabilizing proteins, thereby protecting the bound RNAs from degradation, prolonging their half-lives and, in some contexts, increasing protein translation (44,45). These proteins participate in cell proliferation, differentiation, stress responses and disease progression. During PF progression, the expression of m⁶A readers such as YTHDF1, YTHDF3 and IGF2BP2 undergoes dynamic changes. In arsenite-related IPF, YTHDF1 recognizes m⁶A-modified neuronal regeneration-related protein (NREP) mRNA and enhances NREP translation, increasing TGF-β1 secretion from alveolar epithelial cells and promoting fibroblast-to-myofibroblast transition. The resulting myofibroblasts release extracellular lactate; therefore, lactate is a metabolic product of activated myofibroblasts rather than a direct product of NREP. After uptake into alveolar epithelial cells through monocarboxylate transporter 1, lactate increases H3K18 lactylation, which promotes YTHDF1 transcription and reinforces the YTHDF1/m⁶A/NREP/TGF-β1 fibrotic circuit (25). This mechanism illustrates crosstalk between metabolic remodeling, histone lactylation and m⁶A-mediated translational control. However, the term ‘positive feedback loop’ should be used only for this experimentally supported axis and should not be generalized to all oxidative stress-m⁶A interactions. In hypoxia/reoxygenation injury models, YTHDF3 and IGF2BP2 knockdown protects bronchial epithelial cells by reducing apoptosis and inflammation and inhibiting p38 MAPK, AKT, ERK1/2 and NF-κB pathways (46). Direct evidence for dynamic changes in YTHDF2 and IGF2BP1/3 in PF remains limited, and these readers should be presented as potential rather than fully validated PF regulators. m⁶A modification regulates the degradation of fibrosis-related mRNAs through writers, erasers and readers. Deadenylation is the progressive shortening of the 3' poly(A) tail of an mRNA, which reduces transcript stability and commonly precedes decapping and exonucleolytic degradation. YTHDF2 binds m⁶A-modified transcripts and recruits the CCR4/NOT deadenylase complex to initiate poly(A)-tail shortening and RNA decay. Alternatively, YTHDF2 can engage the HRSP12-RNase P/MRP endoribonuclease complex to promote endonucleolytic cleavage (47,48). Although these are general m⁶A-dependent RNA-decay mechanisms, they are directly relevant to PF, as METTL3-dependent methylation enables YTHDF2-mediated degradation of TSC1 mRNA. The resulting reduction in TSC1 protein activates AKT/mTOR signaling and promotes alveolar epithelial remodeling and fibrotic progression (36).

Beyond mRNAs, m⁶A also regulates non-coding RNAs, including miRNAs, long non-coding RNAs and circRNAs, which modulate fibrosis-related genes and signaling pathways (26). Dynamic changes in m⁶A modification affect the stability of fibrotic mRNAs involved in TGF-β signaling, collagen production, fibroblast activation, apoptosis and inflammation (27,49). However, because much of the evidence for m⁶A-mediated ECM regulation comes from multiple-organ fibrosis rather than PF-specific systems, PF-specific transcript targets should be distinguished from extrapolated mechanisms (28). The reported expression or functional alterations of major m⁶A writers, erasers and readers in PF-related mechanisms are summarized in Table II.

Fibroblast-to-myofibroblast transition is a central event in the development and progression of PF. Myofibroblasts arise from activated fibroblasts and are major effector cells responsible for excessive ECM production, tissue contraction and structural remodeling in the fibrotic lung (50). This transition is driven by TGF-β/Smad signaling, mechanical cues from stiffened ECM and mechanosensitive ion channels such as TRPV4 and BK channels (51). The process is marked by increased α-SMA expression, cytoskeletal reorganization and enhanced collagen synthesis (52). Inhibiting fibroblast-to-myofibroblast transition reduces collagen deposition and improves lung function in animal models, supporting its potential as a therapeutic target (53). m⁶A RNA modification plays a notable role in the translational regulation underlying fibroblast activation. Elevated m⁶A levels mediated by methyltransferases such as METTL3 enhance translation of specific mRNAs required for fibroblast-to-myofibroblast transition. For example, m⁶A modification promotes KCNH6 mRNA translation in a YTHDF1-dependent manner, facilitating fibroblast activation and fibrotic progression (18). Silencing METTL3 reduces m⁶A levels and inhibits this transition in vitro and in vivo (18). This pathway represents one of the stronger causal examples linking m⁶A modification to PF because it is supported by patient tissue, animal models and cellular experiments. In addition, m⁶A reader proteins such as IGF2BP1 and YTHDF1 can bind to m⁶A-modified mRNAs and enhance stability or translation in related biological contexts (54,55). In a non-PF myogenic model, IGF2BP1 bound m⁶A-modified FGFR1 mRNA, increased its stability and translation, and activated downstream ERK signaling, thereby promoting myogenic differentiation (55). This finding illustrates how an m⁶A reader can stabilize a receptor transcript; however, it is included only as supportive mechanistic background and should not be interpreted as direct evidence for fibroblast activation in PF.

EMT is a process in which epithelial cells lose polarity and cell-cell adhesion and acquire mesenchymal characteristics, thereby contributing to epithelial dysfunction, migratory capacity and ECM-associated signaling (56,57), and EMT has been implicated in PF. In IPF, EMT-like changes and abnormal epithelial-fibroblast crosstalk can activate local fibroblasts, increase collagen deposition and impair lung function (58,59). However, whether complete EMT directly contributes substantially to the myofibroblast pool in vivo remains debated. Therefore, the present review uses ‘epithelial plasticity’ and ‘EMT-like remodeling’ where appropriate, rather than overstating full EMT as a dominant source of myofibroblasts. During EMT, m⁶A RNA methylation undergoes dynamic changes. METTL3 expression and global m⁶A levels are often upregulated during TGF-β-induced EMT in lung and other epithelial cells (60,61). Increased m⁶A promotes translation or stability of EMT-related transcription factors such as Snail, JUN, JUNB and zinc finger MYM-type containing 1 (ZMYM1), thereby enhancing mesenchymal marker expression and repressing epithelial markers such as E-cadherin (62,63). Mechanistically, m⁶A modifications on specific mRNAs facilitate recognition by readers such as YTHDF1 and human antigen R, which promote translation or stability of EMT drivers (64). In a breast cancer model, METTL3-dependent m⁶A modification increased MALAT1 stability. MALAT1 subsequently acted as a competing endogenous RNA for miR-26b, thereby relieving miR-26b-mediated repression of HMGA2. The resulting increase in HMGA2 was accompanied by decreased CDH1/E-cadherin expression and increased CDH2/N-cadherin and VIM/vimentin expression, thereby promoting EMT, migration and invasion (65). As this evidence was obtained outside PF, it is presented as a mechanistic example rather than PF-specific proof.

Macrophage activation states contribute to the temporal evolution of PF, although they are more appropriately viewed as a continuum than as a strict M1/M2 dichotomy (66,67). Pro-inflammatory macrophage programs may aggravate epithelial injury during the early stages of disease, whereas persistent M2-like or pro-fibrotic macrophages release TGF-β1 and other pro-fibrotic mediators, thereby promoting epithelial plasticity, fibroblast activation, myofibroblast differentiation and ECM deposition. m⁶A modification may regulate these macrophage states by altering the stability, translation and decay of transcripts involved in inflammatory and metabolic programs. METTL3 is upregulated during M1-like polarization and modifies transcripts such as STAT1 and HDGF, thereby promoting inflammatory responses (68,69). Conversely, ALKBH5-mediated demethylation of CPT1A mRNA enhances fatty-acid metabolism and supports M2-like polarization in a colorectal cancer model (70). As most of these mechanisms were identified outside PF, they should be interpreted as mechanistic background requiring direct validation in lung macrophage-specific PF models. Multi-omics studies reveal dynamic m⁶A and 5-hydroxymethylcytosine changes during macrophage differentiation and polarization (71,72). For example, in rheumatoid arthritis macrophages, circ_0066715 acts as a competing endogenous RNA for miR-486-5p, thereby relieving miR-486-5p-mediated repression of ETS1 and altering macrophage-polarization programs (73). This axis is cited as an inflammatory-disease example and has not yet been validated in PF. However, most macrophage-polarization mechanisms cited here are not PF-specific. Therefore, these mechanisms are interpreted as mechanistic background, and PF-specific macrophage m⁶A regulation still requires direct validation using lung macrophage-specific models, single-cell analysis and lineage-resolved functional studies. Collectively, these findings indicate that m⁶A-dependent regulation may influence pulmonary cell fate through fibroblast activation, epithelial plasticity and macrophage-associated responses, although the strength and PF specificity of the evidence differ among these cellular processes, as summarized in Fig. 2.

Oxidative stress is a major contributor to PF pathogenesis because it promotes epithelial injury, mitochondrial dysfunction, DNA damage, inflammatory signaling, cellular senescence and fibrotic remodeling (12,17,23). Oxidative stress and m⁶A modification may interact through specific regulatory axes, but current evidence does not justify a universal ROS-m⁶A feedback model across all PF contexts. Exposure to 1-nitropyrene leads to excessive mitochondrial ROS production in alveolar epithelial cells, which triggers SUMOylation and proteasomal degradation of ALKBH5(17). Consequently, loss of ALKBH5 increases m⁶A modification of FBXW7 mRNA, enhances FBXW7 expression and promotes telomeric repeat binding factor 2 (TRF2) degradation, telomere damage and cellular senescence, thereby accelerating PF (17). Antioxidant treatment can reverse some of these effects, highlighting the notable effect of oxidative stress-induced m⁶A dysregulation in this specific model (17). Similarly, in silica-induced PF, oxidative stress suppresses FTO and increases global m⁶A abundance across epithelial cells, endothelial cells, fibroblasts and monocytes (23). However, the cited study did not identify or functionally validate individual FTO-dependent methylated transcripts. Therefore, this finding should be interpreted as a cell-type-resolved global methylation change rather than evidence for specific methylated genes.

Aging is a marked risk factor for PF, particularly IPF, which predominantly affects older adults (74,75). Aging-related mechanisms include genomic instability, telomere shortening, epigenetic alterations, mitochondrial dysfunction, cellular senescence, impaired tissue repair and chronic inflammation (76-79). In IPF, methylated RNA immunoprecipitation-sequencing and RNA-sequencing analyses have revealed widespread remodeling of m⁶A methylation patterns, with thousands of m⁶A peaks altered compared with healthy controls (16). METTL14 is notably downregulated in IPF, leading to reduced m⁶A modification of DDIT4 mRNA, increased DDIT4 stability and higher DDIT4 protein expression, which promotes alveolar epithelial cell senescence (16). These findings were validated in animal and senescent cell models (16). These findings indicate that METTL14-DDIT4 represents a notable m⁶A-dependent aging-senescence axis in IPF, but aging-related PF remains multifactorial and cannot be attributed to m⁶A dysregulation alone.

m⁶A methylation also participates in ECM remodeling. Disruption of m⁶A regulation can alter the expression and deposition of ECM components such as collagen, elastin and fibrosis-associated genes in multiple organs (28,80). For example, METTL3-mediated m⁶A regulation contributes to cardiac fibroblast activation and ECM deposition after myocardial infarction (81). In hypertrophic-scar fibroblasts, ALKBH5 directly regulates the m⁶A status of COL1A1, COL3A1 and ELN transcripts. Loss of ALKBH5 increases their m⁶A modification and expression, leading to excessive collagen I, collagen III and elastin deposition, whereas ALKBH5 overexpression reduces pathological ECM accumulation (82). As this evidence is derived from cutaneous fibrosis, its applicability to PF remains to be established. FTO also regulates ECM-related genes such as ADAM metallopeptidase with thrombospondin type 1, collagen type XII alpha 1 chain and thrombospondin-2 in pancreatic cancer cell migration and invasion (83). Although these studies support the broader concept that m⁶A can regulate ECM homeostasis, direct PF-specific evidence for individual ECM transcripts remains limited. Collectively, current evidence links m⁶A dysregulation to toxicant-induced oxidative injury, aging-related epithelial senescence and abnormal ECM remodeling in PF; however, these mechanisms remain stimulus-, cell-type- and model-dependent, as summarized in Fig. 3.

The development of small-molecule m⁶A modulators has progressed in several disease fields. FTO inhibitors, including Compound 2 and Compound 3, have been evaluated in neurological models (84), whereas the YTH-family inhibitor N-7 broadly interferes with m⁶A recognition by YTH-domain proteins (85). In cancer models, the METTL3 inhibitor STM2457 and FTO inhibitors, including FB23, FB23-2, CS1 and CS2, have shown antitumor activity (86). Quercetin and rutin have also been reported to influence m⁶A-related pathways, although their pleiotropic effects preclude their classification as selective m⁶A modulators (87). Among these compounds, STM2457 has been evaluated directly in an experimental IPF model in C57BL/6 mice. Intraperitoneal administration of STM2457 reduced fibroblast activation, collagen deposition and pathological and functional lung abnormalities, reportedly through inhibition of the METTL3/CTGF signaling axis (88). By contrast, Compound 2, Compound 3, N-7, FB23, FB23-2, CS1 and CS2 have not been tested in PF models. Accordingly, these agents should be presented as non-PF tool compounds, whereas STM2457 represents preliminary preclinical evidence rather than an established anti-fibrotic therapy. Therefore, they are presented as tool compounds or preclinical candidates rather than established anti-fibrotic therapies. Gene editing technologies, especially CRISPR/dCas13 or dCasRx fused with m⁶A methyltransferases or demethylases, have enabled transcript-specific regulation of m⁶A modification (89-91). These tools allow targeted installation or removal of m⁶A marks on selected transcripts and may help determine the causal roles of specific m⁶A sites. For PF research, such technologies could be used to validate disease-relevant targets such as KCNH6, DDIT4, FBXW7, NREP and ECM-associated transcripts. However, clinical application remains limited by delivery efficiency, off-target effects, immunogenicity, long-term safety and the complexity of fibrotic lung tissue. Tissue-specific delivery systems have also advanced through nanocarriers, biomembrane modification and molecular targeting strategies. Examples include PLGA nanoparticles loaded with METTL3 inhibitors, engineered small extracellular vesicles delivering YTHDF1 small interfering (si)RNA, mesenchymal stem cell-derived exosomes co-delivering YTHDF1 siRNA and chemotherapeutic agents and exosome-liposome hybrid nanoparticles delivering ALKBH5 mRNA in tumor models (92-95). These systems demonstrate the feasibility of cell- or tissue-targeted m⁶A modulation, but most data are derived from cancer models. For PF, future studies should focus on lung-targeted delivery, epithelial- or fibroblast-specific uptake, inhalable formulations and safety in chronically injured lung tissue. From a patient-centered perspective, m⁶A-targeted therapy should be evaluated according to clinically meaningful outcomes, including slowing lung function decline, reducing symptom burden, preventing acute exacerbation, improving exercise capacity and enhancing quality of life. Preclinical target validation in PF also includes METTL3 silencing in KCNH6-dependent fibroblast activation (18), modulation of the METTL14/DDIT4 axis in aging-related epithelial senescence (16), and manipulation of the ALKBH5/FBXW7 and YTHDF1/NREP axes in toxicant-induced PF (17,25). These studies establish mechanistic target validity, whereas STM2457 currently provides direct small-molecule evidence among the compounds discussed in the present review.

Studies have revealed that m⁶A modification may interact with other epigenetic and post-translational mechanisms in PF. For example, m⁶A interacts with histone lactylation, particularly H3K18 lactylation, in alveolar epithelial cells. Extracellular lactate from myofibroblasts increases H3K18 lactylation, which promotes YTHDF1 transcription, enhances NREP translation and increases TGF-β1 secretion, thereby facilitating fibroblast-to-myofibroblast transition (25). m⁶A modification is also linked to protein SUMOylation and ubiquitination; SUMOylation of ALKBH5 leads to its degradation, increases m⁶A modification of FBXW7 mRNA and promotes TRF2 degradation, alveolar epithelial senescence and fibrosis (17). m⁶A also acts in concert with circRNA methylation in silica-induced PF. Specifically, METTL3-dependent m⁶A modification of hsa_circ_0000672 and hsa_circ_0005654 promotes pulmonary fibroblast activation and migration. Both circRNAs converge on eIF4A3, producing a synergistic pro-fibrotic effect (24). These examples suggest that m⁶A should be understood as part of a multilayer regulatory network involving RNA methylation, histone modification, non-coding RNA regulation and post-translational modification. Single-cell m⁶A profiling technologies provide new opportunities for understanding PF heterogeneity. Techniques such as single cell DART-sequencing and single nucleus-m⁶A-CUT&Tag enable mapping of m⁶A RNA modifications at single-cell or single-nucleus resolution (96,97). These technologies may help identify cell-type-specific m⁶A landscapes in alveolar epithelial cells, fibroblast subpopulations, macrophages, endothelial cells and immune-cell subsets. In IPF, single-cell transcriptomic analysis has already revealed disease-associated epithelial, stromal and immune-cell states (98). Future integration of single-cell transcriptomics, spatial transcriptomics and m⁶A profiling may clarify whether m⁶A dysregulation occurs early in disease initiation, during fibrotic progression or as a secondary response to tissue remodeling. From a translational medicine perspective, m⁶A-related biomarkers have been investigated in several cancers. Examples include m⁶A-related lncRNA signatures associated with prognosis and immune-response patterns in lung adenocarcinoma, as well as m⁶A-based signatures linked to drug resistance, cancer stemness and immunotherapy response in other malignancies (99-103). In PF, m⁶A regulators may help classify patients according to dominant pathological processes, such as epithelial senescence (16), fibroblast activation (104), inflammatory remodeling (105) or environmental exposure-associated injury (23). However, direct evidence for m⁶A-related prognostic biomarkers in PF remains limited. Large independent cohorts, standardized detection methods and comparison with established indicators such as HRCT features, pulmonary function decline, MMP7, KL-6 and surfactant proteins are required before clinical translation.

Previous reviews have discussed m⁶A in non-coding RNAs, fibrotic diseases and collagen-related disorders (26-29). The contribution of the present review is more precise, as it provides a PF-focused synthesis of m⁶A regulatory mechanisms, emphasizing pulmonary cell-type specificity, validated transcript targets, context-dependent regulator function, multilayer epigenetic crosstalk and patient-centered translational implications. The translational research perspective, the review integrates evidence showing how m⁶A regulators participate in fibroblast activation, epithelial plasticity, macrophage-associated inflammation, oxidative stress, aging-related epithelial senescence and ECM remodeling. These mechanisms involve writers such as METTL3 and METTL14, erasers such as FTO and ALKBH5 and readers such as YTHDF1, YTHDF3 and IGF2BP2 across epithelial cells, fibroblasts and macrophages (16-25,36). In addition, for the patient-centered care perspective, the present review connects m⁶A biology with patient-prioritized needs, including early diagnosis, risk stratification, prevention of progression and development of therapies that may eventually affect lung scarring, lung function and quality of life (14). The discussion of biomarkers therefore avoids overclaiming clinical readiness and emphasizes the need for validation in large patient cohorts. From the perspective of novel advances in interstitial lung disease, the present review highlights multilayer crosstalk between m⁶A and H3K18 lactylation, SUMOylation, ubiquitination and circRNA methylation (17,24,25). These mechanisms are not presented as universal pathways, but as specific examples showing how m⁶A machinery can be integrated into broader epigenetic and post-translational regulatory networks in PF. Overall, the present review does not claim that m⁶A is the sole or dominant driver of PF. Instead, it positions m⁶A as a dynamic regulatory hub that connects RNA metabolism with pulmonary cell fate, fibrotic signaling and potential translational strategies.