Bisphenol A (BPA) is a widespread environmental pollutant whose exact effects on prostate cancer (PCa) progression remain understudied. This study aims to investigate the effect and underlying molecular mechanisms between BPA exposure and PCa in a comprehensive approach. The multicenter cohort study found that BPA exposure plays an important role in promoting biochemical recurrence and death of PCa. BPA exposure significantly promoted PCa progression in both the animal model and in vitro experiments. RNA sequencing revealed a disruption of mitochondrial energy homeostasis in BPA-treated cells. In multiple datasets, 17 prognostic genes such as PFKFB4 were obtained to construct and verify a mitochondrial energy metabolism Score system. Based on network toxicology methods and transcriptome sequencing data, ESR1 was identified as a potential transcription factor targeting glycolytic enzyme PFKFB4 under BPA exposure. With the support of lncRNA and circRNA sequencing data, a molecular regulatory network of BPA promoting prostate cancer through mitochondrial energy metabolism reprogramming was constructed. Further molecular docking revealed that BPA has higher binding free energy to ERα than its natural ligand estradiol. Given the widespread presence of BPA in the environment, minimizing exposure to this chemical could represent a feasible approach in improving clinical outcomes.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.