The role of epigenetics in pulmonary fibrosis: recent advances in mechanistic insights and therapeutic implications

Abstract

Pulmonary fibrosis (PF) is a fatal disease characterized by progressive fibrosis of lung tissue, with a key pathological feature of excessive accumulation of extracellular matrix. PF occurs from complicated origins, while emerging findings have suggested the involvement of the environmental factors in the risk of PF through epigenetic regulation. This article will discuss how recent advances in epigenetic alterations of DNA methylation, RNA methylation, histone modifications, and non-coding RNAs contribute to PF development through molecular mechanisms and cellular processes, including fibroblast-to-myofibroblast transition (FMT), epithelial-to-mesenchymal transition (EMT), alveolar epithelial cell injury and immune cell interactions in the past 5 years.

Keywords: DNA methylation; RNA methylation; epigenetic regulation; histone modifications; idiopathic pulmonary fibrosis; non-coding RNA.

FIGURE 1

DNA and RNA Methylation Dynamics in PF Pathogenesis. TGF-β1 induces UHRF1 upregulation, promoting methylation of Beclin 1 promoter to inhibit autophagy and enhance FMT; DNA methylation reader MBD2 binds the methylated Erdr1 promoter to suppress its expression, amplifying TGF-β/Smad signaling and FMT. METTL3-mediated m6A modification drives MSC differentiation into myofibroblasts via the miRNA-21/PTEN pathway; YTHDF1 bind to m6A-modified Nrep mRNA enhances TGF-β1 secretion to accelerate FMT; PM2.5 exposure reduces miRNA-494-3p expression, allowing YTHDF2 to bind m6A-modified CDH1 mRNA and induce EMT; ZC3H13 promotes m6A methylation of Bax mRNA, reducing epithelial apoptosis via YTHDC1-mediated destabilization.

FIGURE 2

Histone Methylation Regulators in Fibroblast Activation and EMT. SETDB1 catalyzes H3K9me3 at the Snai1 promoter to repress EMT; DOT1L mediates H3K79me3 enrichment at the Jag1 promoter, activating Notch signaling and fibrotic responses; KMT2A catalyzes H3K4me3 at the PU.1 promoter, activating PU.1 and FMT; CBX5 and EHMT2 (G9a) induce H3K9me2 at the PGC1α promoter, promoting FMT by suppressing mitochondrial function.

FIGURE 3

Histone Deacetylation and Fibrotic Phenotypes. HDAC inhibitor SAHA induces myofibroblast apoptosis by upregulating Bak and downregulating Bcl-xL; protein phosphatase PHLPP1 dephosphorylates HDAC8 to enhance deacetylase activity, thereby suppress KLF4 expression in alveolar macrophages which otherwise promotes FMT; HDAC3 promotes EMT through multiple mechanisms: activating Notch1/STAT1 signaling via deacetylation of NICD1 and STAT1; regulating miRNA-224/FOXA1 axis to enhance mesenchymal gene expression; stabilizing GATA3 via deacetylation to sustain EMT.

FIGURE 4

MicroRNA Networks Controlling Fibroblast and Epithelial Cell Fate. (a) miRNA-542-5p targets Itga6 to inhibit FMT in silica-induced PF; (b) macrophage-derived exosomal miRNA-328 and miRNA-7219-3p accelerate FMT by targeting FAM13A and SPRY1, respectively; (c) miRNA-let-7d, miRNA-125b-5p, and miRNA-155-5p inhibit EMT by targeting HMGA2, BAK1, and GSK-3β/NF-κB, respectively; (d) miRNA-335-3p downregulation upregulates THBS1 to drive EMT progression; (e) MSC-derived exosomal miRNA-148a-3p and miRNA-30b suppress fibrosis via Hsp90b1 and RUNX1/SPRED2 pathways.

FIGURE 5

lncRNA-Mediated ceRNA and Chromatin Remodeling in PF. (a) lncRNA-LOC103691771 and lncRNA-IAPF promote FMT via TGF-β/SMAD signaling; (b) lncRNA-H19 accelerates macrophage M2 polarization and FMT via ceRNA mechanisms; (c) lncRNA-PFI and FENDRR inhibit fibrosis by binding SRSF1 to downregulate fibronectin or sponging miRNA-214 to upregulate MFN2; (d) lncRNA-ATB, lncRNA-XIST, lncRNA-UCA1, and lncRNA-FEZF1-AS1 promote EMT by sponging miRNAs to upregulate ZEB1; (e) lncRNA-sirt1-AS stabilizes SIRT1 to inhibit EMT in IPF.

FIGURE 6

circRNA-Mediated ceRNA and Mechanical Signal Transduction in PF. (a) pro-fibrotic circRNA-ANKRD42 and ELP2 enhance FMT and ECM deposition via YAP/TAZ signaling; (b) anti-fibrotic circRNA-TADA2A inhibits FMT through miRNA-526b/Cav1 and miRNA-203/Cav2 axes; (c) circRNA-0004214 alleviates EMT by inhibiting the JAK-STAT pathway in BeSO₄-induced fibrosis; (d) circRNA-CDR1as accelerates EMT by sponging miRNA-7 to release TGFBR2.