Integrated Network Toxicology and Experimental Validation Reveal the Mechanism of Bisphenol A‐Induced Kidney Injury: Targeting Macrophage Esr1 Expression and Apoptosis

ABSTRACT Bisphenol A (BPA), an endocrine‐disrupting chemical ubiquitously present in environmental matrices, has emerged as a critical public health concern due to its potential multiorgan toxicity. Although epidemiological and experimental evidence associates BPA exposure with diverse pathologies including metabolic syndrome, carcinogenesis, and hepatorenal dysfunction, the molecular pathogenesis underlying BPA‐induced nephrotoxicity remains poorly characterized. To systematically elucidate these mechanisms, we employed an integrative network toxicology approach interrogating multiple pharmacological databases (ChEMBL, STITCH) and disease repositories (GeneCards, OMIM) to identify putative molecular targets. Through rigorous protein‐protein interaction network construction (STRING database, Cytoscape), three pivotal hub genes (Esr1, Esr2, Cyp19a1) were prioritized for further investigation. Subsequent multi‐omics interrogation encompassed functional enrichment analysis (GO/KEGG), molecular docking simulations, Summary data‐based Mendelian randomization (SMR), and immune infiltration analysis. Notably, macrophage‐specific Esr1 downregulation was identified as a key molecular event in BPA‐exposed renal. Both in vivo and in vitro experiments demonstrated that BPA‐mediated Esr1 suppression significantly impaired renal filtration capacity and promoted pro‐inflammatory macrophage apoptosis. These findings collectively demonstrate that estrogen receptor alpha (Esr1) serves as a critical molecular nexus linking environmental BPA exposure to macrophage apoptosis‐driven renal pathophysiology.