纳瑞鲁丁（Narirutin）通过靶向USP15促进KEAP1降解并抑制软骨细胞铁死亡，从而缓解骨关节炎症状。

Abstract

Narirutin suppresses IL-1β-induced ferroptosis and ECM degradation in chondrocytes. • Narirutin targets USP15 and inhibits USP15-mediated KEAP1 deubiquitination. • Narirutin promotes K48-linked ubiquitination and proteasomal degradation of KEAP1. • Narirutin alleviates cartilage degeneration in DMM-induced osteoarthritis. Background Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage degeneration and joint dysfunction, for which effective therapeutic options remain limited. Increasing evidence suggests that ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, contributes to chondrocyte injury and extracellular matrix (ECM) degradation during OA progression. Purpose This study aimed to investigate the protective effects of narirutin on OA and to elucidate its underlying mechanisms in regulating ferroptosis and ECM homeostasis in chondrocytes. Methods Primary chondrocytes were treated with interleukin-1β (IL-1β) to establish an in vitro OA model, and a destabilization of the medial meniscus (DMM) mouse model was used in vivo . Ferroptosis was assessed by Western blotting, BODIPY 581/591 C11, FerroOrange probe, DCFH-DA staining, and immunohistochemistry. ECM degradation was evaluated by Western blotting, Alcian blue staining, immunofluorescence, Safranin O staining, and immunohistochemistry. Mechanistically, molecular docking, cellular thermal shift assay, and ubiquitination assays were performed to identify the molecular target of narirutin. Results Narirutin significantly attenuated IL-1β-induced chondrocyte ferroptosis and ECM degradation. Mechanistically, narirutin targeted ubiquitin-specific protease 15 (USP15) and reduced its protein abundance, thereby inhibiting USP15-mediated deubiquitination of Kelch-like ECH-associated protein 1 (KEAP1). This promoted K48-linked ubiquitination and proteasomal degradation of KEAP1, leading to activation of the Nrf2 antioxidant pathway. C