{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:36:46Z","timestamp":1790811406964,"version":"4.1.0"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis that may progress to irreversible joint destruction and disability, thereby substantially impairing quality of life. RA results from complex interactions among genetic predisposition, environmental exposures, and immune dysregulation; however, current therapies are not curative, and many patients continue to experience pain, morning stiffness, and recurrent inflammation. In recent years, epigenetic mechanisms have emerged as key modulators of RA heterogeneity and disease persistence. Reversible regulatory layers\u2014including non-coding RNAs, RNA modifications, DNA methylation, histone modifications, and microbiota\u2013host interactions\u2014provide a conceptual framework linking environmental cues to cell-type-specific inflammatory programs. This review summarizes recent advances in the epigenetic regulation of RA and outlines six interconnected dimensions. (1) miRNA-mediated post-transcriptional regulation: dysregulated miRNAs reshape inflammatory circuits and promote synovial activation through regulatory hubs. (2) RNA m\n                    <jats:sup>6<\/jats:sup>\n                    A modification: aberrant m\n                    <jats:sup>6<\/jats:sup>\n                    A remodeling alters immune metabolism and inflammatory gene expression, thereby reinforcing pathogenic responses. (3) DNA methylation: genome-wide profiling of synovium reveals differentially methylated loci that may activate disease-relevant pathways. (4) Histone modification and chromatin remodeling: altered activity of histone-modifying enzymes (e.g., HDACs) modulates inflammatory transcriptional programs and may contribute to epigenetic memory. (5) Hypoxia-driven metabolic\u2013epigenetic crosstalk: hypoxia-inducible factors (HIFs) coordinate metabolic adaptation and inflammatory amplification; for example, HIF-1\u03b1 supports the FLSs under hypoxic conditions. (6) Microbiome\u2013epigenome interactions: gut microbial metabolites (e.g., butyrate) regulate immune homeostasis, partly by promoting follicular regulatory T cell (TFR) differentiation and restraining inflammation. Collectively, these findings indicate that epigenetic networks exert multilevel control over RA pathogenesis and highlight translational opportunities for targeted epigenetic interventions, including RNA methylation modulators, DNA methyltransferase inhibitors, and histone deacetylase\u2013directed strategies.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1792863","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T05:36:03Z","timestamp":1773812163000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Multidimensional regulatory mechanisms and translational potential of epigenetic networks in the rheumatoid arthritis disease course"],"prefix":"10.3389","volume":"17","author":[{"given":"Yushan","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianjun","family":"Xiao","sequence":"additional","affiliation":[{"name":"College of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Guo","sequence":"additional","affiliation":[{"name":"The Affiliated Hospital of Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuantong","family":"Lei","sequence":"additional","affiliation":[{"name":"College of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Xiong","sequence":"additional","affiliation":[{"name":"College of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siying","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"He","sequence":"additional","affiliation":[{"name":"Affiliated Sichuan Provincial Rehabilitation Hospital of Chengdu University of Traditional Chinese Medicine, Sichuan Provincial Ba-yi Rehabilitation Center","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congjie","family":"Lei","sequence":"additional","affiliation":[{"name":"Affiliated Zigong TCM Hospital of Chengdu University of TCM","place":["Zigong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshen","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Health and Rehabilitation, Chengdu University of 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