Polybrominated Biphenyls Induce Liver Injury by Disrupting the KEAP1/Nrf2/SLC7A11 Axis Leading to Impaired GSH Synthesis and Ferroptosis in Hepatocytes

Overview

Journal Arch Toxicol

Specialty Toxicology

Date 2025 Feb 11

PMID 39934342

Authors

Longteng Jin

Ya Zhang

Yuhan Xia

Qifang Wu

Huanjuan Yan

Haibin Tong

Maoping Chu

Zhengwang Wen

Affiliations

Soon will be listed here.

Abstract

Polybrominated biphenyls (PBBs) are persistent organic pollutants (POPs) widespread in the environment, presenting significant health hazards due to their bioaccumulation, particularly in liver. Ferroptosis, an iron-dependent form of cell death, has not been previously linked to PBBs-induced hepatotoxicity. This study investigated whether PBBs induce hepatotoxicity through ferroptosis and the toxicological mechanism using mice and THLE-2 cells models exposed to PBB mixture (BP-6). Histopathological and biochemical analyses revealed that BP-6 exposure-induced hepatic injury, oxidative stress, and inflammatory response in mice. BP-6 exposure induced a significant increase in Fe content and a decrease in FTH1, SLC7A11 and GPX4 protein expression in hepatocytes, resulting in severe lipid peroxide accumulation and GSH depletion. Ferroptosis inhibitors, Fer-1 and DFO, reversed the iron metabolism disruption caused by BP-6, underscoring the critical role of ferroptosis in BP-6-induced liver injury. Mechanistically, BP-6 exposure impaired GSH synthesis by preventing Nrf2 nuclear translocation and Slc7a11 transcription through upregulating KEAP1 levels. Keap1 knockdown or Slc7a11 overexpression reversed BP-6-induced lipid peroxide accumulation and GSH depletion, confirming the involvement of ferroptosis in BP-6-induced hepatotoxicity. In addition, curcumin, a natural Nrf2 agonist, significantly alleviated BP-6-induced ferroptosis and liver injury in vitro and in vivo by restoring SLC7A11 protein expression and GSH synthesis. These findings elucidate the toxicological mechanism of PBBs and suggest potential therapeutic strategies to counteract PBBs exposure.

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