FUNDC1/PFKP-mediated mitophagy induced by KD025 ameliorates cartilage degeneration in osteoarthritis

Osteoarthritis (OA) is the most prevalent joint disease, yet no disease-modifying drugs have been approved for its treatment. Mitophagy plays a crucial role in maintaining mitochondrial homeostasis by selectively removing dysfunctional mitochondria, a process that may contribute to cartilage degeneration in OA. In this study, we present evidence of impaired mitophagy in OA chondrocytes, which exacerbates chondrocyte degeneration. Among the various mitophagy-regulating pathways and receptors, we identified FUNDC1 as a key player in preserving chondrocyte homeostasis by promoting mitophagy. In vitro knockdown of FUNDC1 and in vivo knockout models reduced mitophagy, worsened mitochondrial dysfunction, and accelerated chondrocyte degeneration and OA progression. In contrast, overexpressing FUNDC1 via intra-articular injection of adeno-associated virus alleviated cartilage degeneration in OA. Mechanistically, we found that PFKP interacts with and dephosphorylates FUNDC1 to trigger mitophagy in chondrocytes. Further analysis revealed KD025 as a potential drug that restores chondrocyte mitophagy by enhancing the FUNDC1-PFKP interaction, thereby alleviating cartilage degeneration in mice with DMM-induced OA. Our findings emphasize the importance of the FUNDC1-PFKP interaction in maintaining chondrocyte homeostasis through mitophagy and suggest that KD025 could be a promising therapeutic agent for OA by promoting mitophagy in chondrocytes.