Melatonin attenuates diquat-induced acute liver injury by modulating Nrf2-Associated antioxidant signaling and ferroptosis-related processes.

Abstract

ObjectiveDiquat (DQ) poisoning can cause severe acute liver injury associated with oxidative stress. This experimental animal study investigated the involvement of ferroptosis-related processes and Nrf2-associated antioxidant signaling in the protective effects of melatonin against DQ-induced liver injury.MethodsMale C57BL/6J mice were used in an experimental DQ-induced acute liver injury model. DQ was administered intraperitoneally, with an LD50 of 42.70 mg/kg and 24 h selected as the peak-injury time point. Liver injury, inflammation, oxidative stress, iron homeostasis, mitochondrial damage, ferroptosis-related markers, and Nrf2 signaling were assessed. RSL3 and ML385 were used to challenge ferroptosis-related protection and inhibit Nrf2 signaling, respectively. Nrf2 nuclear accumulation, HO-1, NQO1, SLC7A11, and FSP1 were additionally evaluated. A post-exposure experiment tested melatonin administered 2 h after DQ.ResultsDQ increased serum ALT and AST, inflammatory cytokines, ROS, lipid peroxidation, and hepatic Fe2+ accumulation, while decreasing GSH and impairing mitochondrial function and morphology (all P < 0.05). DQ also reduced GPX4, FTH1, SLC7A11, and FSP1 and increased ACSL4 and TFR1. Melatonin significantly attenuated these changes, enhanced Nrf2 nuclear accumulation, and increased HO-1 and NQO1 expression. RSL3 weakened melatonin-associated protection and partially reversed improvements in liver injury, inflammation, Fe2+ accumulation, MDA, GSH, and GPX4. ML385 similarly attenuated Nrf2 nuclear accumulation, HO-1/NQO1 expression, restoration of SLC7A11 and FSP1, and protection against liver injury and ferroptosis-related alterations (P < 0.05 vs. FMDQ). Post-exposure melatonin also reduced ALT, AST, and histological liver injury.ConclusionsMelatonin attenuates DQ-induced acute liver injury. Pharmacological findings support contributions of Nrf2-associated antioxidant signaling and suppression of oxidative stress and ferroptosis-related processes, although they do not establish an exclusive causal pathway. Post-exposure efficacy further supports the potential translational relevance of melatonin.