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Gcn2 deficiency triggers anemia and hypoxic intolerance in zebrafish

ABSTRACT: The Integrated Stress Response (ISR) is a critical signaling network that maintains intracellular homeostasis and enables cells to adapt to diverse stress conditions. While the ISR has been linked to ferroptosis, its physiological function in regulating hypoxic adaptation remains poorly understood. Here, we identify General Control Nonderepressible 2 (GCN2) is essential for maintaining redox homeostasis and suppressing ferroptosis. Gcn2-deficient zebrafish exhibit hypersensitivity to hypoxia, with increased mortality associated with excessive heme degradation and mitochondrial damage. Loss of Gcn2 leads to upregulation of hmox1a, reduced erythrocyte numbers, and elevated levels of free ionic iron, collectively contributing to the development of anemia. Mechanistically, loss of Gcn2 downregulates the amino acid transporter chaperone slc3a2b, resulting in disturbed cysteine metabolism. This defect impairs glutathione biosynthesis, triggering ferroptosis characterized by elevated oxidative stress and iron-dependent lipid peroxidation. GCN2-deficient also induces ferroptosis in HeLa cells. Our findings elucidate a critical role for GCN2 in protecting against ferroptosis and promoting hypoxic tolerance.

ORGANISM(S): Danio rerio

PROVIDER: GSE317952 | GEO | 2026/01/30

REPOSITORIES: GEO

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GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency

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