Mitochondrial-targeted therapy for osteoarthritis: Challenges and opportunities from basic research to clinical translation.

Osteoarthritis is a high-burden degenerative joint disease. Existing therapies only alleviate symptoms but fail to halt disease progression. Studies have identified mitochondrial dysfunction as a core driver of cartilage degeneration in OA. Key mechanisms include mitochondrial reactive oxygen species bursts that activate inflammatory and cell death pathways; imbalances in mitochondrial dynamics leading to fragmentation; autophagy defects causing damage accumulation; and reduced biogenesis coupled with hyperglycolysis, which exacerbates the energy crisis. Collectively, these processes accelerate cartilage destruction. This review focuses on mitochondrial-targeted therapeutic strategies, including antioxidants, dynamics regulators to restore fission-fusion balance, autophagy activators to clear damaged mitochondria, biogenesis enhancers to improve metabolism, and the emerging approach of mitochondrial transplantation to directly replenish functional units. While preclinical studies have demonstrated that these strategies can significantly slow cartilage degeneration, their clinical translation data in OA remain limited. Substantial, translational efforts face three major challenges: drug delivery barriers, disease heterogeneity, and limitations of animal models. Future work will require the development of intelligent delivery systems, patient stratification, and humanized models to promote clinical translation.