Chemico-biological interactions · 2026
GSTA1 depletes glutathione and exacerbates oxidative stress in α-Amanitin-induced hepatotoxicity.
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Liu Tao, Zhang Xu, Zhang Wei, Yang Dejin, Li Jipeng, Liu Lin
Аннотация
OBJECTIVE: α-Amanitin (α-AMA), the principal toxin of lethal mushrooms, induces severe liver injury by exacerbating oxidative stress. Glutathione S-transferase A1 (GSTA1), a crucial hepatic antioxidant enzyme, plays an ambiguous role in this process.
METHODS: A mouse model of α-AMA-induced liver injury was established. Hepatic damage was assessed via serum biochemistry (ALT, AST, T-BIL) and histopathology (H&E staining). Oxidative stress markers (SOD, CAT, MDA) were measured. Integrated transcriptomics and metabolomics were employed to identify critical pathways. The interaction between α-AMA and GSTA1 was evaluated using molecular docking and Drug Affinity Responsive Target Stability (DARTS) assays. In vitro mechanisms were further dissected in HUH7 cells using siRNA knockdown, and functional rescue experiments.
RESULTS: α-AMA caused significant liver injury, evidenced by elevated serum markers, worsened histopathology, and increased oxidative stress (reduced SOD/CAT, elevated MDA). Multi-omics analysis pinpointed GSTA1 and glutathione metabolism as central to the toxicity. Both molecular docking and DARTS assays confirmed a direct interaction between α-AMA and GSTA1. Mechanistically, α-AMA activated the NRF2 pathway, leading to upregulated GSTA1 expression. Paradoxically, GSTA1 silencing alleviated toxicity. This detrimental effect was mediated through GSTA1-driven depletion of cellular glutathione (GSH), resulting in reactive oxygen species (ROS) accumulation.
CONCLUSION: This study unveils a novel mechanism where α-AMA hijacks the NRF2-GSTA1 antioxidant axis, transforming GSTA1 from a detoxifier into a key perpetrator of hepatotoxicity via GSH depletion, ROS overproduction. GSTA1 emerges as a promising direct therapeutic target and potential diagnostic biomarker for α-AMA poisoning, highlighting a critical direction for future research.
METHODS: A mouse model of α-AMA-induced liver injury was established. Hepatic damage was assessed via serum biochemistry (ALT, AST, T-BIL) and histopathology (H&E staining). Oxidative stress markers (SOD, CAT, MDA) were measured. Integrated transcriptomics and metabolomics were employed to identify critical pathways. The interaction between α-AMA and GSTA1 was evaluated using molecular docking and Drug Affinity Responsive Target Stability (DARTS) assays. In vitro mechanisms were further dissected in HUH7 cells using siRNA knockdown, and functional rescue experiments.
RESULTS: α-AMA caused significant liver injury, evidenced by elevated serum markers, worsened histopathology, and increased oxidative stress (reduced SOD/CAT, elevated MDA). Multi-omics analysis pinpointed GSTA1 and glutathione metabolism as central to the toxicity. Both molecular docking and DARTS assays confirmed a direct interaction between α-AMA and GSTA1. Mechanistically, α-AMA activated the NRF2 pathway, leading to upregulated GSTA1 expression. Paradoxically, GSTA1 silencing alleviated toxicity. This detrimental effect was mediated through GSTA1-driven depletion of cellular glutathione (GSH), resulting in reactive oxygen species (ROS) accumulation.
CONCLUSION: This study unveils a novel mechanism where α-AMA hijacks the NRF2-GSTA1 antioxidant axis, transforming GSTA1 from a detoxifier into a key perpetrator of hepatotoxicity via GSH depletion, ROS overproduction. GSTA1 emerges as a promising direct therapeutic target and potential diagnostic biomarker for α-AMA poisoning, highlighting a critical direction for future research.