Department of Orthopaedics, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China.
Sir Run Run Shaw Hospital, Hangzhou 310000, China.
Int Immunopharmacol. 2024 Aug 20;137:112531. doi: 10.1016/j.intimp.2024.112531. Epub 2024 Jun 21.
The role of oxidative stress and ferroptosis in osteoarthritis (OA) pathogenesis is increasingly recognized. Notably, 4-octyl Itaconate (OI) has been documented to counteract oxidative stress and inflammatory responses, highlighting its therapeutic potential in OA. This study explored the effects of OI on GPX4 methylation, oxidative stress, and ferroptosis in chondrocytes affected by OA. Our results demonstrated that OI mitigated IL-1β-induced chondrocyte degeneration in a dose-dependent manner. It also suppressed reactive oxygen species (ROS) production and sustained GPX4 expression, thereby attenuating the degenerative impact of IL-1β and Erastin on chondrocytes by curtailing ferroptosis. Moreover, we observed that blocking GPX4 methylation could alleviate IL-1β-induced degeneration, oxidative stress, and ferroptosis in chondrocytes. The regulatory mechanism of OI on GPX4 expression in chondrocytes involved the inhibition of GPX4 methylation. In a mouse model of OA, OI's protective effects against OA were comparable to those of Ferrostatin-1. Thus, OI reduced chondrocyte degeneration, oxidative stress, and ferroptosis by inhibiting GPX4 methylation, offering a novel mechanistic insight into its therapeutic application in OA.
氧化应激和铁死亡在骨关节炎（OA）发病机制中的作用越来越受到重视。值得注意的是，4-辛基衣康酸（OI）已被证明可对抗氧化应激和炎症反应，这凸显了其在 OA 中的治疗潜力。本研究探讨了 OI 对 OA 影响的软骨细胞中 GPX4 甲基化、氧化应激和铁死亡的影响。我们的研究结果表明，OI 可呈剂量依赖性减轻 IL-1β诱导的软骨细胞退化。它还抑制活性氧（ROS）的产生并维持 GPX4 的表达，从而通过抑制铁死亡来减轻 IL-1β和 Erastin 对软骨细胞的退行性影响。此外，我们观察到阻断 GPX4 甲基化可以减轻 IL-1β诱导的软骨细胞退化、氧化应激和铁死亡。OI 对软骨细胞中 GPX4 表达的调节机制涉及对 GPX4 甲基化的抑制。在 OA 小鼠模型中，OI 对 OA 的保护作用与 Ferrostatin-1 相当。因此，OI 通过抑制 GPX4 甲基化减少软骨细胞退化、氧化应激和铁死亡，为其在 OA 中的治疗应用提供了新的机制见解。
