Osteoarthritis (OA) is an age-related chronic degenerative disease, and chondrocyte senescence has been established to play an important role in the pathological process. There is ample evidence to suggest that lipid metabolism plays an important role in the aging process. However, the effect of lipid metabolism on chondrocyte senescence and OA remains unclear. Accordingly, we constructed a TBHP-induced senescent chondrocytes model and a destabilization of the medial meniscus (DMM) mouse model. We found that lipid accumulation and fatty acid oxidation were enhanced in senescent chondrocytes. Interestingly, carnitine palmitoyltransferase 1A (Cpt1a), the rate-limiting enzyme for fatty acid oxidation, was highly expressed in senescent chondrocytes and murine knee cartilage tissue. Suppressing Cpt1a expression using siRNA or Etomoxir, an inhibitor of Cpt1a, could attenuate oxidative stress-induced premature senescence and OA phenotype of primary murine chondrocytes, decrease cellular ROS levels, restore mitochondrial function, and maintain mitochondrial homeostasis via activating mitophagy. In vivo, pharmacological inhibition of Cpt1a by Etomoxir attenuated cartilage destruction, relieved joint space narrowing and osteophyte formation in the DMM mouse model. Overall, these findings suggested that knockdown of Cpt1a alleviated chondrocyte senescence by regulating mitochondrial dysfunction and promoting mitophagy, providing a new therapeutic strategy and target for OA treatment.

骨关节炎（OA）是一种与年龄相关的慢性退行性疾病，软骨细胞衰老在病理过程中发挥着重要作用。有充分的证据表明脂质代谢在衰老过程中起着重要作用。然而，脂质代谢对软骨细胞衰老和 OA 的影响仍不清楚。因此，我们构建了 TBHP 诱导的衰老软骨细胞模型和内侧半月板 (DMM) 小鼠模型的不稳定。我们发现衰老的软骨细胞中脂质积累和脂肪酸氧化增强。有趣的是，脂肪酸氧化的限速酶肉碱棕榈酰转移酶 1A (Cpt1a) 在衰老的软骨细胞和小鼠膝关节软骨组织中高度表达。使用 siRNA 或 Etomoxir 抑制 Cpt1a 表达，一种 Cpt1a 抑制剂，可通过激活线粒体自噬来减弱氧化应激诱导的小鼠原代软骨细胞的过早衰老和 OA 表型，降低细胞 ROS 水平，恢复线粒体功能并维持线粒体稳态。在在体内，Etomoxir 对 Cpt1a 的药理抑制作用减弱了 DMM 小鼠模型中的软骨破坏，缓解了关节间隙变窄和骨赘形成。总体而言，这些研究结果表明，敲低 Cpt1a 通过调节线粒体功能障碍和促进线粒体自噬来缓解软骨细胞衰老，为 OA 治疗提供了新的治疗策略和靶点。