Four‐Octyl Itaconate Protects Chondrocytes against H<sub>2</sub>O<sub>2</sub>‐Induced Oxidative Injury and Attenuates Osteoarthritis Progression by Activating Nrf2 Signaling
Peng Zhang, Xiaotong Wang, Qiliang Peng, Yesheng Jin, Gaolong Shi, Zhihai Fan, Zhiqiang Zhou
Abstract
Nrf2 is a critical regulator of the antioxidant defense systems in cellular protection. Emerging evidence has shown that four‐octyl itaconate (OI) activates Nrf2 cascade. In this study, the chondroprotective effects of OI on H 2 O 2 ‐stimulated chondrocytes and DMM‐induced osteoarthritis (OA) progression were investigated. In primary murine chondrocytes, OI interrupted the binding of Keap1 and Nrf2, leading to accumulation and nuclear translocation of Nrf2 protein, as well as transcription and expression of Nrf2‐dependent genes, such as HO-1 , NQO1 , and GCLC . Furthermore, OI inhibited cell death and apoptosis, as well as H 2 O 2 ‐stimulated ROS generation, lipid peroxidation, superoxide accumulation, and mitochondrial depolarization in chondrocytes, which were abolished by the silence or depletion of Nrf2. In addition, in vivo experiments revealed the therapeutic effects of OI on OA progression in a DMM mouse model. Collectively, these results suggested that OI might serve as a potential treatment for OA progression.