Fatty Acid Metabolic Reprogramming in Rheumatoid Arthritis: Integrating Inflammation, Resolution Failure, and Joint Destruction

Abstract

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis and progressive structural joint damage. Its pathology involves immune-cell infiltration, pannus formation, cartilage degradation, and bone destruction. Although autoantibodies, inflammatory cytokines, and aberrant immune activation are central to RA pathogenesis, they do not fully explain the persistence of synovitis, defective inflammation resolution, or structural joint damage in some patients. Emerging evidence indicates that fatty acid metabolic reprogramming may actively shape RA-related cellular dysfunction by linking lipid substrate availability, membrane remodeling, mitochondrial metabolism, oxidative stress, and lipid mediator generation. This review organizes current evidence within a cell-specific immune–synovial–bone destruction framework. In immune cells, alterations in fatty acid uptake and transport, de novo lipogenesis, fatty acid oxidation, and lipid mediator generation influence monocyte/macrophage-driven inflammatory amplification, T-cell effector responses and regulatory imbalance, and potential B-cell contributions to autoimmunity. In RA fibroblast-like synoviocytes, reprogrammed fatty acid metabolism supports proliferation, migration, invasion, inflammatory mediator production, and matrix degradation, thereby promoting synovial aggression. In osteoclast-lineage cells, fatty acid oxidation and related metabolic adaptations facilitate precursor fusion and bone resorption. In addition, an imbalance between arachidonic acid-derived pro-inflammatory mediators and eicosapentaenoic acid- and docosahexaenoic acid-derived specialized pro-resolving mediators may contribute to persistent inflammation and defective resolution. By integrating inflammatory amplification, defective resolution, synovial aggression, and bone destruction, this review highlights fatty acid metabolism as a context- and cell-dependent regulator of RA progression. Potential therapeutic approaches include limiting excessive fatty acid uptake and de novo lipogenesis, selectively modulating fatty acid oxidation, restoring pro-resolving lipid mediator balance, targeting relevant lipid-sensing receptors, and modulating microbiota-derived fatty acid metabolites. These strategies may complement existing anti-inflammatory and immunomodulatory therapies, although successful translation will require cell-selective targeting, disease-stage stratification, biomarker-guided patient selection, and careful safety evaluation.