2. Academic Validation
  3. Revealing Ferroptosis Induction by Bisphenol A and Bisphenol S through Distinct Protein Targets

Revealing Ferroptosis Induction by Bisphenol A and Bisphenol S through Distinct Protein Targets

  • Environ Sci Technol. 2025 Oct 21;59(41):21898-21909. doi: 10.1021/acs.est.5c08855.
Yanwei Wang 1 2,  Jiahui Zhao 1 3,  Yong Chen 1,  Xuesong Liu 1,  Tengfei Xu 1,  Mingliang Fang 4 5
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Department of Pharmacology, College of Medicine, Jiaxing University, Jiaxing 314001, China.
  • 3 School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • 4 Department of Environmental Science and Engineering, Fudan University, Shanghai 200433, China.
  • 5 Shanghai Key Laboratory of Atmospheric Particle Pollution and prevention(lap3), National Observations and Research Station for Wetland Ecosystems of the Yangtze Estuary, Department of Environmental Science & Engineering, Fudan University, Shanghai 200443, China.
PMID: 41068997 DOI: 10.1021/acs.est.5c08855
Abstract

Chronic bisphenol exposure is a recognized disruptor of liver function, and although Ferroptosis has been implicated, the underlying molecular mechanisms remain poorly defined. Here, integrative chemical proteomics and untargeted metabolomics were used to elucidate mechanisms of Ferroptosis induced by bisphenol A (BPA) and bisphenol S (BPS) in hepatic cells. BPA elicited a pronounced ferroptotic phenotype, whereas BPS elicited a moderate phenotype in hepatocytes. Glutathione Peroxidase 4 (GPX4) and Pyruvate Kinase M2 isoform (PKM2) were identified as critical targets, respectively. Validation through cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and molecular docking confirmed that BPA specifically binds to GPX4 (KD = 37.6 μM), while BPS exhibits moderate affinity for PKM2 (KD = 14.4 μM). Functional rescue experiments demonstrated that GPX4 overexpression effectively reversed BPA-induced Ferroptosis and partially alleviated BPS-induced effects, whereas PKM2 overexpression specifically mitigated BPS-triggered cytotoxicity. Mechanistically, BPA inhibited GPX4 activity, impairing lipid peroxide detoxification and triggering ferroptosis; BPS suppressed PKM2, promoting glucose flux toward the methylglyoxal (MGO) pathway, depleting glutathione, and activating oxidative stress, thereby inducing Ferroptosis indirectly. This study clarifies bisphenol-induced Ferroptosis via target heterogeneity, providing mechanistic insights that may inform future safety evaluations.

Keywords

GPX4; bisphenol A; bisphenol S; chemical proteomics; ferroptosis; metabolomics.

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