CD36-mediated fatty acid metabolic reprogramming activates synovial fibroblasts and promotes rheumatoid arthritis...

The main pathological features of rheumatoid arthritis (RA) are synovial hyperplasia and inflammation. The abnormal activation of fibroblast-like synoviocytes (FLSs) is a crucial factor contributing to synovial inflammation and joint damage. Fatty acid metabolism is closely associated with the inflammatory, proliferative, migratory, and invasive phenotypes of RA-FLSs. CD36, a key regulator of intracellular fatty acid homeostasis, is involved in fatty acid metabolism, intracellular signal transduction, and various physiological and pathological processes. Our previous studies revealed that CD36 is associated with the risk of cardiovascular events in patients with RA; however, its role in RA progression remains unclear. This study demonstrated that CD36 expression is increased in synovial tissues and primary RA-FLSs from patients with RA. In vitro experiments revealed that CD36 knockdown or inhibition in RA-FLSs led to mitochondrial dysfunction and the reprogramming of fatty acid metabolism. Knockdown or inhibition promoted RA-FLS apoptosis; inhibited proliferation, migration, and invasion; and reduced the secretion of proinflammatory cytokines. AMPK and the PI3K/AKT/mTOR signaling pathway are involved in this process. Moreover, in arthritis animal models, inhibition of CD36 has been confirmed to have therapeutic effects on joint inflammation, bone erosion, and bone destruction. In summary, this study reveals a novel molecular mechanism through which CD36 participates in RA-FLS activation through the regulation of fatty acid metabolism, suggesting that CD36 may serve as a potential therapeutic target for alleviating joint inflammation and damage in patients with RA, providing a new direction for clinical treatment.