Chen Haitao, Zhao Danyang, Liu Siyi, Zhong Yongkang, Wen Yinxian, Chen Liaobin
Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Int Immunopharmacol. 2025 Jun 26;159:114911. doi: 10.1016/j.intimp.2025.114911. Epub 2025 May 22.
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.
骨关节炎（OA）是最常见的关节疾病，其特征是细胞外基质（ECM）稳态破坏、慢性炎症和衰老表型上调。人参皂苷Rh1（Rh1）具有多种药理活性，包括抗炎、抗癌和神经保护作用。在此，我们旨在探讨Rh1在OA中的作用和机制。在白细胞介素-1β（IL-1β）诱导的OA软骨细胞中，Rh1减轻了ECM和衰老表型的失衡。此外，我们发现Rh1减轻了IL-1β诱导的软骨细胞线粒体损伤和受损的线粒体自噬，而Mdivi-1（一种线粒体自噬抑制剂）可以阻止这些作用。敲低PINK1或Parkin部分消除了Rh1介导的软骨保护作用，表明Rh1通过PINK1/Parkin依赖性线粒体自噬发挥其治疗作用。基于分子对接、化合物C（一种AMPK抑制剂）和AMPK小干扰RNA，我们发现Rh1通过AMPK调节PINK1/Parkin介导的线粒体自噬。此外，Rh1通过促进前交叉韧带横断（ACLT）大鼠中AMPK介导的线粒体自噬减轻OA。总之，Rh1通过调节AMPK/PINK1/Parkin介导的线粒体自噬减轻OA进展，是与年龄相关的OA潜在有效的治疗靶点。
