Environmental Levels of Sodium p‐Perfluorous Nonenoxybenzene Sulfonate Induce Nephritis in Renal Proximal Tubular Epithelial Cells via Modulation of Estrogen Signaling Pathways

Sodium p‐perfluorous nonenoxybenzene sulfonate (OBS), widely used as an alternative to per‐ and polyfluoroalkyl substances, has been implicated in toxicity across multiple organ systems. Currently, its effects on renal health remain poorly characterized. In this study, we investigated the mechanisms underlying OBS‐induced nephritis by integrating network toxicology, cellular experiments, molecular docking, and molecular dynamics simulations. A total of 28 shared targets were identified by intersecting machine learning‐predicted OBS‐related targets with nephritis‐associated targets retrieved from databases. These targets were predominantly enriched in pathways related to estrogen signaling and cellular responses to estrogenic stimuli. Subsequent cellular experiments demonstrated that OBS exposure significantly upregulated the expression of ESR1 and ESR2 in renal proximal tubular epithelial cells. Molecular docking and molecular dynamics simulation analyses further revealed that OBS forms more stable complexes with ERα than with ERβ, suggesting a preferential interaction with ERα. Collectively, these findings indicate that OBS may induce nephritis through modulation of nuclear‐initiated estrogen signaling pathways.