Melatonin attenuates diquat-induced acute liver injury by modulating Nrf2-Associated antioxidant signaling and ferroptosis-related processes
Lei Xia, Guanghe Liu, Yunpeng Duan, Yuxin Dong, Fang Chen, Ziang Li, Yancun Liu, Songtao ShouObjective
Diquat (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.
Methods
Male C57BL/6J mice were used in an experimental DQ-induced acute liver injury model. DQ was administered intraperitoneally, with an LD 50 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.
Results
DQ increased serum ALT and AST, inflammatory cytokines, ROS, lipid peroxidation, and hepatic Fe 2+ 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, Fe 2+ 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.
Conclusions
Melatonin 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.