Oxysophocarpine attenuates acute liver injury by targeting FBP1 to suppress ferroptosis and enhance cellular resilience via the PPARα-GPX4 axis.

Acute liver injury (ALI) is a life-threatening clinical condition with limited therapeutic options. Through network pharmacology screening, we identified oxysophocarpine (OSC), a natural compound derived from traditional Chinese medicine, as a potent reactive oxygen species-scavenging agent. In LPS/D-GalN-induced ALI models, OSC administration dose-dependently improved survival, attenuated histopathological damage, reduced serum transaminase levels and inflammatory cytokines, and enhanced antioxidant capacity. Notably, we report for the first time that OSC directly bound to fructose-1,6-bisphosphatase (FBP1) and modulated its interaction with peroxisome proliferator-activated receptor alpha (PPARα), leading to upregulated glutathione peroxidase 4 (GPX4) expression and subsequent inhibition of ferroptosis, apoptosis, and endoplasmic reticulum stress. Collectively, this study reveals a multidimensional protective mechanism of OSC against ALI centered on FBP1 targeting, integrating anti-inflammatory, antioxidant, and anti-cell death activities, thereby providing a rationale for developing OSC as a promising natural product-based therapy for ALI.