Mitochondrial dysregulation in rheumatoid arthritis: From pathogenic mechanisms to therapeutic innovations

The pathogenesis of rheumatoid arthritis (RA) involves complex interactions among genetic predisposition, environmental factors, and immune dysregulation. Emerging evidence indicates that mitochondrial dysfunction plays a central role in RA pathology and its systemic complications, including rheumatoid arthritis-associated interstitial lung disease. This review systematically examines the synergistic effects of mitochondrial DNA mutations, oxidative stress, and metabolic reprogramming in promoting RA progression, with particular focus on activation mechanisms of key signaling pathways including NLRP3 inflammasome and cGAS-STING. We evaluate the therapeutic potential of various interventions targeting mitochondrial function, including natural compounds, conventional DMARDs, and biological agents. Innovatively, this review explores the estrogen-mitochondrial regulatory axis, elucidating its bidirectional modulation of immunometabolism through nuclear and mitochondrial receptors, thereby providing a molecular explanation for sexual dimorphism in RA incidence. The analysis further describes how environmental exposures interacting with genetic susceptibility induce mitochondrial damage to drive disease pathogenesis. Therapeutically, we summarize emerging stem cell therapies and physical interventions that ameliorate mitochondrial function, and discuss the precision medicine potential of estrogen-based therapies leveraging mitochondrial protective effects. Additionally, we analyze novel combination strategies targeting immunosenescence through multi-organelle interactions to overcome current treatment limitations. These advances provide deeper insights into RA pathogenesis and establish a foundation for developing mitochondrial-targeted precision therapies.