Bisphenol S promotes hepatic fibrosis through macrophage polarization- and autophagy-mediated activation of hepatic stellate cells.

The environmental endocrine disruptor bisphenol S (BPS) has emerged as a risk factor for non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide. However, the mechanism by which this chemical triggers fibrosis progression in NAFLD remains unclear. Using transgenic zebrafish with labeled macrophages, RAW264.7 macrophages, and human hepatic stellate cells (HSCs, LX2), this study investigated the profibrotic effects of BPS and demonstrated that it promoted hepatic fibrosis through both indirect and direct mechanisms. Results showed that 1 and 100 μg/L BPS exposure enhanced the migration of macrophages into zebrafish liver, especially in the presence of excessive toxic lipids. In vitro, BPS exerted limited direct effects on macrophage polarization, but it induced a shift toward the profibrotic M2 phenotype in lipopolysaccharide-induced inflammatory microenvironment, indirectly activating HSCs via the polarized macrophages. In parallel, BPS could also directly activate HSCs by stimulating autophagic processes and inducing the formation of more autophagosomes in LX2 cells. Overall, these findings indicated that BPS facilitated the progression of nonalcoholic steatohepatitis (NASH) to hepatic fibrosis through the dual mechanisms of macrophage polarization and autophagy-mediated HSC activation, highlighting an indispensable role of intercellular crosstalk in the pollutant-driven transition from NASH to liver fibrosis.