Zhao Xia, Peng Yixue, Wang Mengsong, Tan Qishuang
Institute of Respiratory and Co-occurring Diseases, West China Hospital of Sichuan University, Chengdu, China.
Anaesthesia Surgery Centre, West China Hospital of Sichuan University, Chengdu, China.
Arch Rheumatol. 2025 May 28;40(2):197-210. doi: 10.5152/ArchRheumatol.2025.11031.
Background/Aims: Osteoarthritis typically features cartilage degeneration, synovial fibrosis, and bone remodeling. While clinical Western medicine therapies can restore joint functions, long-term use may exacerbate cartilage damage. This study was designed to investigate the impact of peroxiredoxin 3 (PRDX3) on ferroptosis and oxidative stress in osteoarthritis cartilage injury and its potential mechanism. Materials and Methods: In the osteoarthritis model, the expression of PRDX3 was downregulated. Single-cell analysis revealed that the PRDX3 gene was expressed in bone cells of osteoarthritis patients. Results: Sh-PRDX3 promoted osteoarthritis cartilage injury in the mouse model via the induction of oxidative stress. PRDX3 suppressed reactive oxygen species accumulation and mitochondria-dependent ferroptosis in the in vitro model or mice model of osteoarthritis. PRDX3 induced SIRT3 to reduce SIRT3 ubiquitin. Moreover, METTL3-mediated m6A modification decreases PRDX3 mRNA stability by YTHDF1 in the osteoarthritis cartilage injury model. Conclusion: These findings indicate that METTL3-mediated m6A modification decreases PRDX3 mRNA stability to relieve ferroptosis and oxidative stress in the model of osteoarthritis cartilage injury in a YTHDF1-dependent manner. Targeting METTL3 is thus a potentially effective therapeutic strategy for patients with osteoarthritis cartilage injury.
背景/目的：骨关节炎的典型特征是软骨退变、滑膜纤维化和骨重塑。虽然临床西医治疗可以恢复关节功能，但长期使用可能会加剧软骨损伤。本研究旨在探讨过氧化物酶体增殖物激活受体3（PRDX3）对骨关节炎软骨损伤中 ferroptosis 和氧化应激的影响及其潜在机制。材料与方法：在骨关节炎模型中，PRDX3 的表达下调。单细胞分析显示 PRDX3 基因在骨关节炎患者的骨细胞中表达。结果：Sh-PRDX3 通过诱导氧化应激促进小鼠模型中的骨关节炎软骨损伤。PRDX3 在骨关节炎的体外模型或小鼠模型中抑制活性氧积累和线粒体依赖性 ferroptosis。PRDX3 诱导 SIRT3 以减少 SIRT3 泛素化。此外，在骨关节炎软骨损伤模型中，METTL3 介导的 m6A 修饰通过 YTHDF1 降低 PRDX3 mRNA 的稳定性。结论：这些发现表明，METTL3 介导的 m6A 修饰以 YTHDF1 依赖的方式降低 PRDX3 mRNA 的稳定性，以减轻骨关节炎软骨损伤模型中的 ferroptosis 和氧化应激。因此，靶向 METTL3 是治疗骨关节炎软骨损伤患者的一种潜在有效治疗策略。
