MK8722 alleviates osteoarthritis by activating Sesn2 and transcriptionally upregulating BNIP3 to promote mitophagy and inhibit chondrocyte ferroptosis

Introduction: Osteoarthritis (OA) is commonly accompanied by irreversible destruction of articular cartilage and is difficult to effectively relieve, primarily due to the unclear pathogenesis and the lack of effective therapeutic interventions. Sestrin 2 (Sesn2) is a highly conserved protein that regulates oxidative stress and cellular metabolism; however, its impact on the progression of OA and the detailed mechanisms underlying this process have not been elucidated.

Objectives: To investigate the critical role of Sesn2 in OA cartilage degradation and to clarify the underlying mechanism by which MK8722 promotes Mitophagy and inhibits chondrocyte Ferroptosis through the activation of Sesn2.

Methods: We utilized multi-omics data from both human and mouse models to investigate a potential association between Sesn2 and chondrocyte Ferroptosis. We established a murine OA model through destabilization of the medial meniscus surgery. Various molecular biological techniques, including western blot, immunofluorescence and flow cytometry, in combination with histological analyses, were employed to elucidate the pivotal role of Sesn2 in the progression of OA.

Results: Sesn2 expression is decreased in OA articular cartilage, and Sesn2 is a key gene regulating chondrocyte Ferroptosis. Intra-articular injection of adeno-associated virus overexpressed Sesn2 in chondrocytes to alleviate OA cartilage damage by inhibiting Ferroptosis. In addition, we identified a drug that activates Sesn2, MK8722, which inhibits chondrocyte senescence and Ferroptosis by promoting Mitophagy to alleviate cartilage destruction. MK8722 activates Sesn2 and transcriptionally upregulates Bcl-2 interacting protein 3 (BNIP3), promoting nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression, and then promoting Mitophagy. Upregulation of Mitophagy subsequently reduces cellular oxidative stress and Ferroptosis, thereby alleviating OA cartilage degeneration.

Conclusion: This study underscores the role of Sesn2 as a novel protein that maintains chondrocyte metabolic homeostasis and redox balance, and demonstrates that MK8722, which activates Sesn2, may serve as a promising therapeutic approach for OA.

BNIP3; Ferroptosis; MK8722; Mitophagy; Osteoarthritis; Sesn2.