| Summary: | Kai Chen,1 Yaohui Yu,1 Yishu Wang,1 Yi Zhu,1 Chaoren Qin,1 Jintao Xu,1 Xiangjie Zou,2 Tianqi Tao,1 Yang Li,1 Yiqiu Jiang1 1Department of Sports Medicine and Joint Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Yiqiu Jiang, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, People’s Republic of China, Email jyq_3000@163.comBackground: Astragalus membranaceus (AM) shows promise as a therapeutic agent for osteoarthritis (OA), a debilitating condition with high disability rates. OA exacerbation is linked to chondrocyte ferroptosis, yet the precise pharmacological mechanisms of AM remain unclear.Methods: We validated AM’s protective efficacy in an anterior cruciate ligament transection (ACLT) mouse model of OA. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database was utilized to identify AM’s active components and their targets. FerrDb (a database for regulators and markers of ferroptosis and ferroptosis-disease associations) pinpointed ferroptosis-related targets, while GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenomics Knowledgebase (PharmGKB), Therapeutic Target Database (TTD), and DrugBank sourced OA-related genes. Molecular docking analysis further validated these targets. Ultimately, the validation of the results was accomplished through in vitro experiments.Results: AM exhibited anabolic effects and suppressed catabolism in OA chondrocytes. Network pharmacology identified 19 common genes, and molecular docking suggested quercetin, an AM constituent, interacts with key proteins like HO-1 and NRF2 to inhibit chondrocyte ferroptosis. In vitro experiments confirmed AM’s ability to modulate the NRF2/HO-1 pathway via quercetin, mitigating chondrocyte ferroptosis.Conclusion: This study elucidates how AM regulates chondrocyte ferroptosis, impacting OA progression, providing a theoretical basis and experimental support for AM’s scientific application.Keywords: systematic pharmacology, osteoarthritis, ferroptosis, Astragalus membranaceus, quercetin
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