Ginsenoside Rh1 attenuates chondrocyte senescence and osteoarthritis via AMPK/PINK1/Parkin-mediated mitophagy.

Osteoarthritis (OA) is the most common joint disease characterized by disruption of extracellular matrix (ECM) homeostasis, chronic inflammation, and upregulation of senescent phenotypes. Ginsenoside Rh1 (Rh1) exerted various pharmacological activities, including anti-inflammatory, anti-cancer, and neuroprotective effects. Herein, we aimed to explore the role and mechanism of Rh1 in OA. In IL-1β-induced OA chondrocytes, Rh1 alleviated the imbalance of ECM and senescence phenotypes. Furthermore, we found that Rh1 mitigated mitochondrial damage and the impaired mitophagy of chondrocytes induced by IL-1β, and these effects could be prevented by Mdivi-1 (a mitophagy inhibitor). Knockdown of PINK1 or Parkin partially abolished Rh1-mediated chondroprotection, indicating that Rh1 exerts its therapeutic effects via PINK1/Parkin-dependent mitophagy. Based on molecular docking, Compound C (an AMPK inhibitor), and AMPK siRNA, we found that Rh1 regulated PINK1/Parkin-mediated mitophagy through AMPK. Besides, Rh1 alleviated OA by promoting AMPK-mediated mitophagy in the anterior cruciate ligament transection (ACLT) rats. In conclusion, Rh1 alleviated OA progress by regulating AMPK/PINK1/Parkin-mediated mitophagy and is a potentially effective therapeutic target for age-related OA.