Melatonin Alleviates Diquat-Induced Acute Liver Injury by Inhibiting Oxidative Stress and Ferroptosis via Activation of the Nrf2/HO-1 Pathway

Diquat poisoning leads to severe liver injury in clinical settings, whose mechanism is closely associated with oxidative stress. Melatonin possesses antioxidant and cytoprotective properties, but its role in diquat-induced liver injury remains unclear. In this study, we established a mouse model of acute diquat-induced liver injury and determined the LD₅₀ (42.7 mg/kg) through survival analysis. We evaluated liver function, inflammatory cytokines, oxidative stress levels, iron metabolism, and mitochondrial function to assess the protective effects of melatonin. The Nrf2 inhibitor ML385 was employed to validate the role of the Nrf2/HO-1 pathway. Diquat exposure resulted in severe liver dysfunction, inflammation, oxidative stress, iron accumulation, and mitochondrial damage. Melatonin treatment significantly improved these parameters, reversed the abnormal expression of ferroptosis-related proteins, and activated the Nrf2/HO-1 pathway. ML385 inhibited this pathway and attenuated the protective effects of melatonin. In conclusion, our study demonstrates that melatonin alleviates diquat-induced acute liver injury by activating the Nrf2/HO-1 pathway to suppress oxidative stress and ferroptosis, highlighting its potential as a therapeutic strategy.