Melatonin mitigates cadmium-triggered ferroptosis in hippocampal neurons and cognitive deficits by inhibiting mtROS-mediated ferritinophagy and increasing GPX4 expression via Nrf2 activation.

Cadmium (Cd), an environmental neurotoxic pollutant, is believed to have adverse effects on cognitive function in humans. Recent studies have linked the induction of ferroptosis to Cd-induced cytotoxicity. Melatonin (Mel) has been shown to exert anti-ferroptotic and neuroprotective effects in nervous system diseases. This study aims to investigate whether ferroptosis inhibition by Mel can ameliorate Cd-induced neuronal/synaptic injury in the hippocampus and cognitive dysfunction and to explore the underlying mechanisms involved. Daily intraperitoneal injections of Mel (20 mg/kg per day) for 8 weeks significantly mitigate Cd-evoked cognitive deficits. Furthermore, the reduction in the number of Nissl-positive neurons in the hippocampus and in the synaptic density following Cd exposure is prevented by Mel administration. Mechanistically, Mel supplementation significantly inhibits ferroptosis in Cd-treated mouse hippocampal HT-22 neurons and in the mouse hippocampus. Mel suppresses mtROS-ferritinophagy and thereby decreases Cd-induced cellular iron overload by activating Nrf2 in HT-22 neurons. Moreover, Nrf2 activation by Mel markedly restores GPX4 deficiency and prevented lipid peroxidation under Cd stress in vitro. However, the anti-mtROS-ferritinophagic and anti-ferroptotic effects of Mel are abolished by Nrf2 knockdown in vitro. Overall, exogenous Mel treatment relieves Cd-induced neuronal ferroptotic death in the hippocampus and cognitive impairment through the inhibition of mtROS-ferritinophagy and the increase in GPX4 expression via Nrf2 activation, suggesting that Mel may be a potential therapeutic agent for the treatment of neurotoxicity and neurobehavioral disorders associated with Cd exposure.