Bisphenol S induces hepatic steatosis and insulin resistance through AMPK inhibition and endoplasmic reticulum stress.

Bisphenol S (BPS), a common substitute for bisphenol A, has emerged as a widespread environmental contaminant, yet its metabolic effects remain poorly understood. Increasing evidence links BPS exposure to metabolic dysfunction-associated steatotic liver disease (MASLD), although the underlying mechanisms are unclear. Here, we investigated the metabolic effects of chronic BPS exposure (4, 25, and 50 μg/kg/day for 12 weeks) in C57BL/6 mice and evaluated its impact on human Huh-7 hepatocytes. In vivo, exposure to 25 μg/kg/day exhibited obesogenic potential, while all doses induced insulin resistance and promoted hepatic micro- and macrovesicular steatosis. BPS triggered endoplasmic reticulum (ER) stress and suppressed AMP-activated protein kinase (AMPK) phosphorylation, disrupting hepatic lipid and glucose metabolism. Consistently, BPS exposure in Huh-7 cells induced ER stress, reduced AMPK activity, and impaired insulin-stimulated Akt phosphorylation, indicating decreased insulin sensitivity. Notably, pharmacological activation of AMPK attenuated BPS-induced inhibition of insulin signaling, identifying AMPK as a key mediator of BPS-driven metabolic dysfunction in hepatocytes. Collectively, these findings demonstrate that BPS promotes hepatic steatosis and insulin resistance by activating ER stress and inhibiting AMPK, highlighting BPS as a potential environmental contributor to MASLD and related metabolic disorders.