Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway

作者：Xiaoyu Jin, Xunhao Wang, Siyu Xu, Nuo Xu, Ziwei Wang, Chunqing Hu, Wei Liu, Zhaofeng Zhang, Xiyu Liu, Jingjing Fan, Ruiyang Jiang, Rui Wu, Zhongyang Lv, Dongquan Shi · 发表于：Journal of Orthopaedic Translation · 年份：2025 · DOI：10.1016/j.jot.2025.07.003 · 被引用次数：7 · 研究领域：Ferroptosis and cancer prognosis、Osteoarthritis Treatment and Mechanisms、interferon and immune responses

Background Osteoarthritis (OA) is the most common degenerative joint disease, characterized by cartilage deterioration, which is closely associated with chondrocyte ferroptosis. The aim of this study was to investigate the role and mechanism of previously unexplored gene, growth factor independence 1 ( Gfi1 ) in chondrocyte ferroptosis, in order to provide a new therapeutic target for OA. Methods The expression of ferroptotic hallmarks and Gfi1 were analyzed in human and mice OA cartilages and tert-butyl hydroperoxide (TBHP)-induced primary chondrocytes. Small interfering RNA or overexpression plasmids were used to knock down or overexpress Gfi1 to explore its role in chondrocyte ferroptosis and metabolism. Then, the role of Gfi1 in destabilization of medial meniscus (DMM) surgery-induced mice OA model was investigated with or without the intra-articular injection of adeno-associated virus-overexpressing Gfi1 (AAV- Gfi1 ). Furthermore, RNA sequencing analysis was performed to reveal the key downstream pathway of Gfi1 exerting its role in chondrocyte ferroptosis. Results The expression of Gfi1 was significantly decreased, while 4-HNE, a typical lipid peroxidation product, was significantly increased both in damaged human and DMM surgery-induced mice OA cartilages. Consistently, Gfi1 was remarkably downregulated in TBHP-induced ferroptotic chondrocytes. Moreover, Gfi1 knockdown aggravated chondrocyte ferroptosis by elevated levels of ferroptotic hallmarks, including total ROS, ...