Paeonol inhibits ACSL4 to protect chondrocytes from ferroptosis and ameliorates osteoarthritis progression

作者：Siyang Cao, Yihao Wei, Ao Xiong, Yaohang Yue, Jun Yang, Deli Wang, Xiyu Liu, Hui Zeng, Dongquan Shi, Li Ye · 发表于：Journal of Orthopaedic Translation · 年份：2024 · DOI：10.1016/j.jot.2024.10.005 · 被引用次数：22 · 研究领域：Ferroptosis and cancer prognosis、Osteoarthritis Treatment and Mechanisms、Bone Metabolism and Diseases

Discovering an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein that triggers cell injury via ferroptosis, presents potential to minimize cellular damage. This study investigates paeonol (PAE), a traditional Chinese herbal medicine, as an ACSL4 inhibitor to prevent chondrocyte ferroptosis and protect against osteoarthritis (OA). We conducted in vitro experiments using mouse chondrocytes treated with PAE to mitigate ferroptosis induced by Interleukin-1 Beta (IL-1β) or ferric ammonium citrate (FAC), examining intracellular ferroptotic indicators, cartilage catabolic markers, and ferroptosis regulatory proteins. A mouse OA model was created via destabilized medial meniscus (DMM), followed by intra-articular PAE injections. After 8 weeks, micro-computed tomography and histological assessments evaluated PAE's protective and anti-ferroptotic effects in the OA model. In vitro results showed PAE significantly reduced IL-1β/FAC-induced damage by targeting ACSL4, including cell apoptosis, inflammatory responses, extracellular matrix degradation, and ferroptotic markers (oxidative stress, lipid peroxidation, and iron buildup). It also restored the expression of ferroptotic suppressors and mitigated mitochondrial damage. Additionally, PAE increased cartilage anabolic marker expression while reducing cartilage catabolic marker expression. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability analysis verified the bind...