Tangeretin Targets Macrophage M1 Polarization to Alleviate Liver Injury in a Murine Model of Hepatic Sinusoidal Obstruction Syndrome

Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening liver microvascular disorder characterized by hepatic sinusoidal endothelial cells (HSECs) injury, for which safe and effective pharmacological treatments are currently lacking. Tangeretin (TAN), a natural polymethoxylated flavone, exhibits anti-inflammatory, antioxidant, and hepatoprotective properties. However, its therapeutic potential and mechanisms in HSOS remain unclear. This study investigated the protective role and molecular mechanisms of TAN against monocrotaline (MCT)-induced HSOS. In the murine HSOS model, TAN intervention alleviated hepatic sinusoidal congestion, lobular injury and elevated serum transaminase levels in a dose-dependent manner. Mechanistic studies revealed that TAN blocks the binding of Keap1 and Nrf2, inhibits Keap1-mediated ubiquitination and degradation of Nrf2, and facilitates its nuclear translocation. Activated Nrf2 enhances mitophagy and restores mitochondrial homeostasis, thereby suppressing NLRP3 inflammasome activation and M1 macrophage polarization to alleviate hepatic sinusoidal endothelial cell injury. Furthermore, genetic ablation of NLRP3, or pharmacological blockade of Nrf2 (ML385) and mitophagy (Mdivi-1), markedly attenuated the protective effects of TAN in restraining M1 macrophage polarization and ameliorating HSOS pathological lesions. In conclusion, TAN activates the Keap1-Nrf2 pathway and promotes mitophagy, which further inhibits NLRP3 inflammasome activation and M1 macrophage polarization, ultimately alleviating MCT-induced hepatic sinusoidal obstruction syndrome. These findings suggest that TAN may serve as a potential candidate drug for the treatment of HSOS.