Linoleic acid accelerates osteoarthritis progression in male rats by targeting iron-sulfur clusters to drive ferroptosis in chondrocytes.

The development of osteoarthritis (OA) is accompanied by various metabolic disorders, highlighting the need for further investigation into metabolism-related pathogenesis and targeted therapeutic strategies. Herein, we found that linoleic acid (LA), the most abundant essential fatty acid in the diet, accumulates in the blood, synovial fluid, and cartilage tissue of elderly and OA individuals. Notably, LA not only induces ferroptosis in chondrocytes, but it also serves as a risk metabolite, driving OA onset and accelerating the progression of traumatic OA in male rat models. Mechanistically, LA can directly bind to iron-sulfur cluster assembly enzyme (ISCU) to induce its autophagic degradation and inhibit iron-sulfur cluster synthesis, which subsequently activates IRP1-mediated translational regulation to drive the ferroptosis process. Furthermore, upregulating or supplementing ISCU in cartilage tissue contributes to mitigating LA accumulation and trauma-induced OA progression, and this strategy can further enhance the therapeutic efficacy of moderate exercise in OA treatment by effectively inhibiting ferroptosis. Taken together, our findings identify LA as a key metabolite involved in the onset and progression of OA by driving ferroptosis and propose a targeted therapeutic strategy based on ISCU supplementation.