Cadmium Exposure Aggravates SREBP-1c-Mediated Hepatic Steatosis and Liver Injury in High-Fat Diet-Fed Mice

Abstract Cadmium (Cd) is a persistent environmental heavy metal that bioaccumulates and is associated with diverse toxicities. Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent, and steatotic metabolic stress may increase vulnerability to toxicological insults. In this study, we used a free fatty acid (FFA)-treated hepatocyte model and high-fat diet (HFD)-fed steatotic mice to characterize hepatic responses to a short-term CdCl2 toxicological challenge under lipid overload conditions. In FFA-treated QSG-7701 cells, CdCl2 exposure was associated with increased lipid droplet accumulation, elevated oxidative stress, and increased apoptosis. In HFD-fed steatotic mice, short-term CdCl2 administration was associated with worsened liver injury and greater hepatic lipid accumulation compared with parallel steatotic controls. These phenotypic changes were accompanied by increased expression of lipogenesis-related markers, including SREBP-1c and SCD1, consistent with enhanced lipogenic signaling under steatotic stress. CdCl2 exposure was also associated with increased α-SMA and TGF-β, consistent with early fibrogenic activation in this short-term model rather than staged fibrosis. Rapamycin-treated mice exhibited attenuation of multiple injury- and lipid-related readouts compared with parallel CdCl2-treated groups, supporting its use as a pharmacological probe in this acute setting. Collectively, these observations support a model in which short-term CdCl2 challenge aggravates steatotic liver injury under lipid overload.