Selenium restored mitophagic flux to alleviate cadmium-induced hepatotoxicity by inhibiting excessive GPER1-mediated mitophagy activation

Cadmium (Cd) is a common environmental pollutant, while selenium (Se) can ameliorate heavy metal toxicity. Consequently, this study aimed to investigate the protective effects of Se against Cd-induced hepatocyte injury and its underlying mechanisms. To achieve this, we utilized the Dongdagou-Xinglong cohort, BRL3A cell models, and a rat model exposed to Cd and/or Se. The results showed that Se counteracted liver function injury and the decrease in GPER1 levels caused by environmental Cd exposure, and various methods confirmed that Se could protect against Cd-induced hepatotoxicity both in vivo and in vitro. Mechanistically, Cd caused excessive mitophagy activation, evidenced by the colocalization of LC3B, PINK1, Parkin, P62, and TOMM20. Transfection of BRL3A cells with mt-keima adenovirus indicated that Cd inhibited autophagosome–lysosome fusion, thereby impeding mitophagic flux. Importantly, G1, a specific agonist of GPER1, mitigated Cd-induced mitophagy overactivation and hepatocyte toxicity, whereas G15 exacerbates these effects. Notably, Se supplementation attenuated Cd-induced GPER1 protein reduction and excessive mitophagy activation while facilitating autophagosome–lysosome fusion, thereby restoring mitophagic flux. In conclusion, this study proposed a novel mechanism whereby Se alleviated GPER1-mediated mitophagy and promoted autophagosome–lysosome fusion, thus restoring Cd-induced mitophagic flux damage, and preventing hepatocyte injury. Environmental Implication I think this study are of great significance to the environment. Specifically, this study considers the cadmium as a hazardous material because environmental cadmium exposure can cause liver dysfunction in rural residents near mining and smelting areas. Additionally, we evaluated the estrogen-like effects of cadmium, which may play an important role in the abnormal liver function caused by cadmium. This study further verified the protective effect of selenium against cadmium-induced liver injury at the population, animal, and cellular levels, which has important ecological significance for promoting ecological restoration in heavy metal polluted areas and improving the health level of residents.