AI-driven discovery of bronopol for the treatment of pulmonary fibrosis via inhibition of fibroblast activation

Abstract

Aims: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Epigenetic regulation by p300 histone acetyltransferase plays a central role in fibroblast activation and fibrotic gene transcription. This study aimed to identify novel p300 inhibitors from an FDA-regulated compound library using integrated computational approaches and to evaluate their anti-fibrotic potential. Materials and methods: Candidate compounds were screened via p300 HAT activity assay. Bronopol was validated as a p300 inhibitor using Autodock vina, DiffDock AI-based blind docking, and molecular dynamics simulations. Anti-fibrotic efficacy was assessed in TGF-β–stimulated mouse (Mlg) and human (WI-38) lung fibroblasts and in a bleomycin-induced mouse model of pulmonary fibrosis. Key findings: Bronopol stably occupied the Acetyl-CoA–binding pocket of p300, forming persistent interactions with Arg1410 and Thr1411, and inhibited p300 enzymatic activity with greater potency than canonical inhibitor C646. In vivo, Bronopol inhibited endogenous p300 enzymatic activity in lung tissue, markedly reduced collagen deposition, myofibroblast activation, and overall fibrotic severity, accompanied by decreased histone H3 acetylation. Bronopol also inhibited p300 enzymatic activity and suppressed TGF-β–induced histone H3 acetylation, fibrotic gene expression, and fibroblast-to-myofibroblast activation in lung fibroblast cell lines. Significance: Bronopol, an FDA-regulated antimicrobial agent, exhibits potent anti-fibrotic effects through epigenetic inhibition of p300, highlighting its potential as a repurposed therapeutic candidate for IPF and other fibrotic diseases. © 2026 Elsevier Inc.