Nano-selenium alleviates cadmium-induced ferroptosis in chicken liver by modulating the TRPM2 channel.

Cadmium (Cd), a prototypical environmental heavy metal pollutant, can induce severe hepatic pathological damage upon chronic exposure. Recent studies have demonstrated that nano-selenium (Nano-Se) exhibits remarkable advantages in alleviating Cd-induced liver injury due to its unique characteristics of high bioavailability and low toxicity. However, the precise hepatoprotective mechanisms of Nano-Se remain incompletely understood. In this study, we systematically investigated the molecular mechanisms of Cd-induced hepatotoxicity and elucidated the protective effects of Nano-Se on the liver, using Hyline white chicks as an in vivo model and LMH cell lines as an in vitro model. Our results demonstrate that Cd exposure significantly upregulates the expression of the transient receptor potential melastatin-2 (TRPM2) channel, promotes calcium influx, and leads to calcium overload in hepatocytes and mitochondria. This is accompanied by increased expression of arachidonate 5-lipoxygenase (ALOX5) and 15-lipoxygenase (ALOX15), which induces lipid peroxidation and ferroptosis, ultimately resulting in liver injury. Notably, Nano-Se effectively reversed Cd-induced TRPM2 upregulation, calcium overload, elevated ALOX5/ALOX15 expression, and alterations in ferroptosis-related markers. By specifically inhibiting TRPM2 expression, we confirmed that the protective effect of Nano-Se against Cd toxicity is TRPM2-dependent. This study not only elucidated the molecular mechanism of Cd inducing hepatic ferroptosis through TRPM2 activation, but also provided a novel intervention strategy for Cd-related liver disease, highlighting the potential therapeutic value of Nano-Se.