Bisphenol S accelerates the progression of high fat diet-induced NAFLD by triggering ferroptosis via regulating HMGCS2.

Bisphenol S (BPS) is a widely detected environmental toxin with the potential to increase the risk of non-alcoholic fatty liver disease (NAFLD). However, the effects of BPS on the progression of high fat diet (HFD)-induced NAFLD remain unclear. This study aimed to explore the role and underlying mechanisms of action of BPS in HFD-induced NAFLD. Our results showed that BPS exposure (50 and 500 μg/kg bodyweight/day) promoted the progression of NAFLD, which was evidenced by increased liver/body weight ratio, elevated serum alanine aminotransferase and aspartate aminotransferase levels, and more and larger lipid droplets in liver tissues. These phenomena were accompanied by abnormal expression levels of fatty acid uptake (Cd36), fatty acid synthesis (Pparγ, Scd-1, and Fasn), fatty acid oxidation (Pparα), and cytokines (TNFα, IL-1β, and IL-6). In vitro and in vivo studies showed that BPS exposure caused hepatic ferroptosis by regulating ferroptosis-related markers (GPX4, xCT, FTH, and ACSL4). Moreover, BPS exposure caused ROS overproduction, mitochondrial dysfunction, lipid peroxidation, and GSH suppression, all of which were restored by ferrostatin-1, a ferroptosis inhibitor. Moreover, BPS significantly upregulated HMGCS2 expression in the hepatocytes and liver tissues. 3-hydroxy-3-methylglutaryl coenzyme A synthetase 2 (HMGCS2) knockdown mitigated the effects of BPS on hepatocytes and reversed the expression of ferroptosis-related markers. Thus, BPS exposure aggravates HFD-induced NAFLD by regulating HMGCS2-mediated ferroptosis. Collectively, our study indicates that BPS exposure at environmentally relevant concentrations may aggravate NAFLD phenotypes under HFD conditions, highlighting the health risks of BPS to the liver.