{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T23:09:50Z","timestamp":1792537790746,"version":"4.5.0"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"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>Rheumatoid arthritis (RA) is a systemic autoimmune disorder wherein sustained, drug-free remission remains an elusive clinical goal. Frequent disease flares upon treatment withdrawal indicate that conventional immunosuppression fails to eradicate a deeply ingrained \u201cpathogenic memory.\u201d In this Review, we provide a comprehensive framework illustrating how the hostile, nutrient-deprived synovial microenvironment acts as a metabolically restrictive microenvironment. Driven by \u201cmetabolic parasitism\u201d and mitochondrial collapse, the massive accumulation of intermediate metabolites\u2014most notably lactate, acetyl-CoA, and succinyl-CoA\u2014transcends their traditional roles as bioenergetic waste to function as potent epigenetic regulators. We decode the emerging \u201cPTM multiverse,\u201d highlighting how aberrant lactylation, acetylation, and RNA modifications (ac4C) persistently rewire chromatin architecture and critical non-histone sensors (e.g., cGAS). Amplified by hyperactive acetyltransferases and the hypoxia-induced collapse of Sirtuin deacetylases, these modifications engrave resilient \u201cepigenetic scars\u201d that lock innate immune and stromal cells into highly destructive phenotypes via trained immunity. We further integrate this localized articular inflammation into a holistic meta-organ model, tracing disease origins to mucosal gene-environment interactions and detailing systemic regulation via the gut-microbiota-joint axis and chronobiological rhythms. Ultimately, we explore how deciphering these integrated networks translates into next-generation prognostic biomarkers (e.g., AMPAs and GlycA) and heralds a critical therapeutic paradigm shift\u2014from transient immune blockade to precise metabolic-epigenetic restoration.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1836618","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T05:39:10Z","timestamp":1777354750000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Metabolic-epigenetic rewiring in rheumatoid arthritis: from pathogenic memory to precision restoration"],"prefix":"10.3389","volume":"17","author":[{"given":"Shu","family":"Li","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Anhui University of Chinese Medicine","place":["Hefei, 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