Hypoxia Tolerance in Aquatic Animals: Physiological Basis, HIF ‐1α Signaling, and Nutritional Strategies for Aquaculture

ABSTRACT

Hypoxia is a major stressor in aquaculture and is increasingly intensified by warming, eutrophication, ammonia accumulation, acidification, and other co‐stressors. It impairs growth, feed intake, tissue integrity, immune homeostasis, and survival, making hypoxia tolerance a key trait for sustainable production. At the physiological level, tolerance reflects a balance between survival and cost, involving metabolic suppression, altered development, immune dysregulation, and reduced resilience under compound stress. At the molecular level, hypoxia responses are organized around hypoxia‐inducible factor‐1α (HIF‐1α) and related HIF‐α isoforms, whose activity depends on oxygen‐dependent hydroxylation, VHL‐mediated degradation, FIH‐dependent transcriptional restraint, and oxygen‐independent inflammatory/pathogen‐associated inputs, metabolic and epigenetic regulation, RNA‐level control, SET7‐mediated protein methylation, OTUB1‐related ubiquitin‐linkage control, and redox‐mediated crosstalk with the PHD‐HIF axis. This review evaluates nutritional strategies for hypoxia tolerance by distinguishing direct HIF evidence, indirect HIF‐related evidence, and phenotype‐based evidence. A three‐tier evidence framework is used to interpret protein and amino acid, carbohydrate, lipid, vitamin, mineral, plant‐derived additive, probiotic/prebiotic/postbiotic, and carotenoid interventions. We emphasize that improved hypoxia tolerance should not be equated with direct activation of HIF‐1α unless protein stabilization, nuclear localization, HRE activity, target‐gene regulation, or functional perturbation evidence is available. This evidence‐graded approach provides a clearer basis for translating nutritional and genetic strategies into aquaculture practice.