Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tamoxifen, a breast cancer therapeutic agent, raises environmental concerns due to its persistence and bioaccumulation potential, but its role as an endocrine disruptor in IPF pathogenesis remains unclear. Materials and Methods: We integrated computational toxicity prediction (ProTox-3.0/ADMETlab-3.0), FDA Adverse Event Reporting System (FAERS) pharmacovigilance, and Mendelian randomization (MR) to establish causal tamoxifen–IPF links. Network toxicology identified shared targets, with protein–protein interactions network construction revealing seven hubgenes. Multi-omics validation included: transcriptomics (GSE110147/GSE53845) for hubgenes expression, immune infiltration and single-cell RNA (scRNA) sequencing (GSE159354) for cellular associations, and machine learning (least absolute shrinkage and selection operator/support vector machine-recursive feature elimination/random forest) for biomarker identification. Mechanistic studies involved miRNA expression data (GSE27430) to explore the upstream regulators of key genes, and molecular docking to validate drug targets. Finally, in vivo validation was performed in C57BL/6 mice administered intraperitoneal tamoxifen, with assessment of pulmonary inflammation and fibrosis using bronchoalveolar lavage fluid protein exudation, cell counts, lung wet/dry weight ratio, and Ashcroft score, along with evaluation of epidermal growth factor receptor (EGFR)/phosphorylated EGFR (p-EGFR) and miRNA-432-3p expression. Results: Computational toxicity prediction revealed tamoxifen’s high respiratory toxicity potential, corroborated by FAERS-reported lung fibrosis associations, and MR confirmed causal IPF risk. Network toxicology identified seven hubgenes functionally enriched in miRNA regulation, with multi-omics validation revealing a critical EGFR dysregulation pattern where transcriptional downregulation contrasted with post-translational hyperactivation evidenced by elevated p-EGFR in fibrotic lungs. Mechanistically, miR-432-3p was upregulated in IPF and confirmed to directly target EGFR, while molecular docking demonstrated tamoxifen’s preferential binding to miR-432-3p over EGFR. This tamoxifen–miRNA–EGFR axis drove pulmonary fibrosis with concurrent p-EGFR and mmu-miR-432 elevation in vivo . Conclusion: Tamoxifen promotes IPF via miR-432-3p-mediated EGFR suppression, establishing it as a pulmonary toxicant. Integrated network toxicology identifies EGFR as a diagnostic biomarker, highlighting environmental and clinical risks of tamoxifen exposure.
Sun et al. (Fri,) studied this question.