Epigenetic and metabolic reprogramming in autoimmune rheumatology: toward immune tolerance reprogramming

Autoimmune rheumatic diseases arise when the immune system transitions from a flexible, self-regulating network into a metabolically and epigenetically fixed inflammatory attractor state. This review synthesizes emerging evidence that immune tolerance is governed by a coupled epigenetic-metabolic axis integrating mitochondrial fitness, chromatin accessibility, redox balance, and nutrient flux across lymphoid, myeloid, and stromal compartments. We examine how chronic cytokine signaling, hypoxia, and oxidative stress destabilize regulatory programs, imprint glycolytic effector states, and remodel enhancer landscapes, thereby sustaining autoreactive circuits even after inflammatory pathways are pharmacologically suppressed. Multi-omic and spatial analyses reveal that pathogenic chromatin architectures, persistent mitochondrial dysfunction, and intercellular metabolite exchange cooperate to establish self-sustaining inflammatory ecosystems in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjögren’s syndrome. We further highlight therapeutic strategies aimed at tolerance reprogramming, including metabolic correction, chromatin-targeted agents, chimeric antigen receptor regulatory T cells (CAR-Tregs), tolerogenic dendritic cells, and integrative biomarkers that quantify metabolic-epigenetic coherence. By reframing autoimmunity as a disorder of energetic and chromatin desynchronization rather than isolated immune activation, this review outlines a mechanistic path toward durable, drug-free remission through deliberate restoration of the molecular architecture that maintains immune self-recognition.