Ferroptosis inhibitors in the treatment of osteoarthritis:diversity and multitarget characteristics

Chen Xinlong; Meng Tao; Wang Yaomin; Zhang Kefan; Li Jian; Shi Hui; Zhang Chenchen

doi:10.12307/2026.351

Abstract：BACKGROUND:Recent studies have shown that ferroptosis,a novel iron-dependent form of cell death,plays an important role in the progression of osteoarthritis. OBJECTIVE:To introduce the mechanisms of ferroptosis,including iron homeostasis imbalance,lipid peroxidation,and weakened antioxidant systems,and to summarize the potential applications of various ferroptosis inhibitors in the treatment of osteoarthritis. METHODS:Literature retrieval was conducted in the CNKI and PubMed databases using the keywords of"osteoarthritis,ferroptosis,lipid peroxidation,ferroptosis inhibitors,chondrocytes,reactive oxygen species,glutathione peroxidase 4"in Chinese and English,respectively.Retrieval time was from January 2012 to January 2025.A total of 90 articles were systematically reviewed and summarized. RESULTS AND CONCLUSION:(1)Ferroptosis,as an iron-dependent form of cell death,involves the following core mechanisms:(i)Iron homeostasis imbalance:Excess iron generates reactive oxygen species through the Fenton reaction,leading to lipid peroxidation and cell death;(ii)Lipid peroxidation:Reactive oxygen species attack polyunsaturated fatty acids in the cell membrane,causing membrane degradation and ferroptosis;(iii)Weakened antioxidant systems:Intracellular antioxidant systems(such as Xc-system/glutathione/glutathione peroxidase 4,nuclear factor E2-related factor 2,mitogen-activated protein kinase/nuclear factor κB signaling pathways)play a key role in ferroptosis.When the antioxidant capacity is insufficient to counteract lipid peroxidation,cells undergo ferroptosis.(2)In the context of osteoarthritis,various ferroptosis inhibitors have shown therapeutic potential.Iron chelators reduce Fenton reactions and lipid peroxidation by chelating excess iron,thereby inhibiting chondrocyte ferroptosis.Antioxidants alleviate chondrocyte damage by inhibiting lipid peroxidation and enhancing antioxidant capacity.Natural compounds modulate signaling pathways such as nuclear factor E2-related factor 2 and mitogen-activated protein kinase/nuclear factor κB to inhibit ferroptosis and slow osteoarthritis progression.(3)Additionally,inhibitors of acyl-CoA synthetase long-chain family member 4 exert chondroprotective effects by inhibiting lipid peroxidation and correcting iron metabolism disorders.(4)Although ferroptosis inhibitors show promising potential in the treatment of osteoarthritis,most current studies are still at the cellular and animal experimental stages,with a lack of large-scale clinical trials to verify their safety and efficacy.Future research should further explore the specific mechanisms of ferroptosis and promote the clinical application of ferroptosis inhibitors,providing new strategies for the treatment of osteoarthritis.