Metabolic-epigenetic rewiring in rheumatoid arthritis: from pathogenic memory to precision restoration

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 “pathogenic memory.” In this Review, we provide a comprehensive framework illustrating how the hostile, nutrient-deprived synovial microenvironment acts as a metabolically restrictive microenvironment. Driven by “metabolic parasitism” and mitochondrial collapse, the massive accumulation of intermediate metabolites—most notably lactate, acetyl-CoA, and succinyl-CoA—transcends their traditional roles as bioenergetic waste to function as potent epigenetic regulators. We decode the emerging “PTM multiverse,” 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 “epigenetic scars” 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—from transient immune blockade to precise metabolic-epigenetic restoration.