Bisphenol A Induces Endothelial Dysfunction via Oxidative Stress-Driven Ferroptosis and Nrf2 Suppression.

Abstract

Bisphenol A (BPA), a widespread environmental contaminant, induces endothelial dysfunction through multiple mechanisms; however, its role in triggering ferroptosis remains largely unexplored. In this study, we investigated the effect of BPA on ferroptosis induction in endothelial cells and its association with Nrf2 signaling and endothelial dysfunction. Human endothelial cells were exposed to BPA (10, 50, and 100 μM) for 24 h, and the expression of ferroptosis markers (GPX4, SLC7A11, ACSL4, TFR1, FPN, FTH), Nrf2 and its downstream antioxidant enzymes (SOD2, HO-1, NQO1, CAT), oxidative stress markers (P22PHOX, TXNIP), inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-18), and endothelial dysfunction markers (ENDO-1, ICAM-1, VCAM-1, vWF) were assessed by qRT-PCR and western blotting. BPA exposure downregulated GPX4, SLC7A11, FPN, and FTH while upregulating ACSL4 and TFR1, indicating ferroptotic activation. Ferroptosis induction was further confirmed by FerroOrange staining, demonstrating increased labile intracellular iron accumulation in BPA-treated endothelial cells. Concurrently, Nrf2 expression and nuclear translocation were suppressed, accompanied by Keap1 upregulation, reduced levels of antioxidant enzymes, and elevated oxidative stress and proinflammatory cytokine levels. Markers of endothelial dysfunction increased significantly at higher BPA concentrations (50-100 μM). Collectively, these findings identify ferroptosis as a critical mediator of BPA-induced endothelial dysfunction through disruption of Nrf2 signaling, highlighting potential therapeutic targets for BPA-associated cardiovascular pathologies.