Bisphenol S facilitates breast cancer progression through DRP1-mediated mitophagy

To investigate the pro‑metastatic effects of low-dose bisphenol S (BPS) and characterize the underlying molecular pathway in breast cancer (BC). HER2‑amplified MMTV‑Erbb2 mice received BPS‑laced drinking water (50 μg/L) to assess tumor growth and metastasis. BC cell migration, invasion, and proliferation were evaluated after BPS treatment. RNA‑seq and bioinformatics identified key pathways. PINK1 or DRP1 knockdown, together with pharmacological inhibition of DRP1 (Mdivi‑1), were employed to verify the role of mitophagy in vitro and in vivo. Clinical relevance was assessed via immunohistochemistry and public databases (TCGA, GEO). Environmentally relevant BPS exposure accelerated BC progression in mice, increasing primary tumor burden, lung/liver metastasis and an EMT‑like signature (upregulated FN, MMP‑2, Snail; downregulated E‑cadherin) with elevated oxidative stress. In vitro, BPS promoted migration and invasion without affecting proliferation in MCF-7 and BT474 cells. RNA‑seq revealed transcriptomic changes; KEGG enrichment identified mitophagy as a central pathway. BPS induced mitochondrial dysfunction (depolarization, ROS accumulation, ATP depletion) and activated PINK1/Parkin‑mediated mitophagy (increased MAP1LC3B-II, reduced P62/TOM20). Genetic knockdown of PINK1 or DRP1, as well as pharmacological inhibition of DRP1 by Mdivi‑1, reversed BPS‑induced mitophagy, restored mitochondrial homeostasis (mitochondrial length and membrane potential), and suppressed the pro‑migratory and pro‑invasive phenotypes. In vivo, Mdivi‑1 attenuated BPS‑driven tumor progression and metastasis. Clinically, elevated DRP1 and PINK1 in BC tissues correlated with lymph node metastasis, advanced TNM stage, and worse overall survival. Environmental‑level BPS exposure promotes BC metastasis via DRP1/PINK1‑dependent mitophagy. DRP1 and PINK1 are identified as potential prognostic biomarkers and therapeutic targets for reducing cancer risk from environmental carcinogens.