PD146176 represses ferroptosis by upregulating AIFM2 to alleviate the progression of osteoarthritis

In osteoarthritis (OA), chondrocyte ferroptosis is a critical pathogenic mechanism. Although the 15-lipoxygenase (15-LOX) inhibitor PD146176 exhibits known anti-inflammatory properties, its role in modulating ferroptosis during OA progression remains unclear. An OA chondrocyte model was established using IL-1β. Protective effects of PD146176 on chondrocytes were assessed by analyzing extracellular matrix proteins, inflammatory cytokines, and cytoskeletal proteins. Furthermore, ferroptosis was induced in chondrocytes using IL-1β or FINO₂, and the inhibitory effects of PD146176 on ferroptosis were evaluated by measuring levels of malondialdehyde (MDA), Fe²⁺, reactive oxygen species (ROS), and lipid ROS, as well as by examining mitochondrial morphology. Our results showed that PD146176 not only mitigated IL-1β-induced ECM degradation and inflammation but also reversed FINO₂-driven ferroptosis damage. PD146176 significantly reduced levels of ferroptosis-related markers, including MDA, Fe²⁺, ROS, and lipid ROS, and attenuated mitochondrial injury. Mechanistically, we demonstrated that PD146176 directly binds to AIFM2 and upregulates its expression under inflammatory conditions, thereby suppressing ferroptosis and preserving chondrocyte homeostasis. In a mouse OA model induced by meniscal tear surgery, PD146176 treatment alleviated OA progression and counteracted FINO₂-aggravated joint damage in an AIFM2-dependent manner. These findings establish PD146176 as a promising therapeutic candidate for OA by targeting the AIFM2-mediated ferroptosis pathway.