Structure-Related Activity of 4-Alkylphenols in Hepatic Lipogenesis Regulated by Estrogen Receptor Agonism and Oxidative Stress

Abstract 4-Alkylphenols (APs), as typical endocrine-disrupting chemicals (EDCs) widely present in the environment and the human body, have been implicated in the disruption of lipid metabolism. However, the structure-activity relationships (SARs) and underlying mechanisms of their hepatic lipotoxicity remain unclear. This study systematically evaluated the effects of nine 4-AP isomers with linear (4-n-APs) and branched (4-t-APs) para-alkyl substituents on hepatic lipid metabolism in HepG2 cells. The results showed that all 4-n-APs significantly promoted intracellular triglyceride (TG) accumulation in a dose-dependent manner, whereas 4-t-APs exerted no such effects. The lipogenic potency of 4-n-APs followed an inverted U-shaped curve with increasing linear alkyl chain length. Either ER antagonism or ROS inhibition effectively mitigated 4-n-AP-induced hepatic lipogenesis, demonstrating the coordinated actions of ER signaling and oxidative stress underlying the lipotoxic phenotype. Collectively, linear 4-n-APs induce hepatic lipid accumulation through the combined contributions of ER agonism and excessive ROS production, while branched 4-t-APs lack such activity due to structural differences. These findings clarify the SAR framework for hepatic lipogenesis triggered by 4-AP congeners and the underlying dual ER-ROS mechanism, providing a scientific basis for assessing their environmental health risks.