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Pollutant retrorsine induces hepatotoxicity through ATF3-mediated ferroptosis in mouse primary hepatocytes and Cyp3a4-HepG2 cells

ABSTRACT: Pyrrolizidine alkaloid (PA) contamination in food poses a global health risk, primarily entering the human food chain through contaminated food. Given that ferroptosis—a form of cell death characterized by glutathione depletion—is involved in toxicant-induced liver injury and that retrorsine (RTS, A typical toxic PA) depletes glutathione, we investigated whether RTS induces hepatotoxicity via ferroptosis. This study demonstrates that RTS induces acute hepatotoxicity and ferroptosis in vitro and in vivo, RTS triggers mitochondrial dysfunction and activates ATF3, which translocates to the nucleus to directly repress PLA2G6 expression. Genetic studies revealed ATF3's dual role in enhancing RTS-induced cytotoxicity and oxidative stress, while its target PLA2G6 confers protection, unveiling a novel mechanism of RTS-induced liver injury centered on the ATF3-PLA2G6 axis. These findings demonstrates that RTS-induced hepatotoxicity, driven by ferroptosis, is governed by the ATF3-PLA2G6 axis, thus revealing a pivotal mechanism and a promising therapeutic target for PA-related liver injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE312412 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Heavy metals residue in the natural ecosystem had become one global environmental problem that was eager to solve. Due to the non-biodegradability, organism could deposit excessive heavy metals elements into tissues. Existing literature proposed that prolonged heavy metals enrichment had comprehensive toxicity to multi-organs of vertebrates. However, little research focus on the molecular mechanism for the hepatotoxicity of heavy metal enrichment to Chiroptera. In the present study, ten Hipposideros armiger individuals from Yingde City (YD, relatively pollution-free) and Chunwan City (CW, excessive heavy metals emission) were dissected while environment samples were also obtained. To corroborate the toxicity mechanism of heavy metals to bats liver, multi-omics, pathology and molecular biology methods were performed. Our results showed that more Cd and Pb elements were significantly enriched in bats liver and food sources in the CW group. In addition, prolonged heavy metals accumulation disturbed the hepatic transcription profiling associated with solute carriers family, ribosome pathway, ATP usage and heat shock proteins. Excessive heavy metals enrichment also altered the relative abundance of typical gut microbe taxa to inhibit the tight-junction protein expression. We also found that the levels of superoxide dismutase, glutathione peroxidase and glutathione were decreased while ROS density and malondialdehyde content were elevated after excessive heavy metals enrichment. Besides, hepatic fat accumulation and inflammation injury were also observed under the excessive heavy metals enrichment while the metabolism biomarkers contents were decreased. Therefore, prolonged heavy metals enrichment would induce a series of hepatotoxicity by disturbing the microbes-gut-liver axis and hepatic transcription modes, which could decrease the overall metabolism level in bats. Our study provided protection strategy for biodiversity conservation and raised public attention to environment pollution.

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Pollutant retrorsine induces hepatotoxicity through ATF3-mediated ferroptosis in mouse primary hepatocytes and Cyp3a4-HepG2 cells

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