EPO Enhances Adaptation to Hypoxic Environment in the Freshwater Teleost (<i>Micropterus salmoides</i>) through the PI3K/AKT Pathway

Hypoxia has become one of the most common environmental stress events in the life history of aquatic organisms due to accelerated global warming. Exploring the adaptation mechanisms of aquatic organisms in hypoxic environments is important to deepen our understanding of environmental toxicology and to design breeding programs. In this study, the largemouth bass <i>Micropterus salmoides</i> exhibited greater hypoxic adaptability after 4 weeks of intermittent hypoxic exposure (IHE), with the O₂ tension for loss of equilibrium decreased from 1.17 ± 0.20 to 0.66 ± 0.10 mg/L. Combined transcriptomics, biochemical detection, and immunostaining results revealed that the hypoxia-tolerant phenotype driven by IHE was strongly correlated with the activation of erythropoietin (EPO). EPO promoted phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling to alleviate hepatic damage under acute hypoxic exposure (AHE) by selectively regulating the expression of genes related to antioxidant defense, antiapoptosis, and cell proliferation, which plays an important role in regulating hypoxic adaptation. The inhibition of <i>EPO</i> impaired cell survival in hypoxic environments, but intervention with the PI3K agonist 740 Y-P reversed this process. This novel finding provides insights into exploring how aquatic organisms cope with the challenges of hypoxia under increasing environmental risks.