Oxygen levels in the ocean have decreased worldwide as a result of climate change and nutrient contamination, which has had a significant impact on marine ecosystems. Although deep-sea fish that reside in oxygen minimum zones (OMZs) demonstrate remarkable adaptations to hypoxia, the molecular mechanisms that underlie their resilience are still inadequately understood. The hypoxia-inducible factors (HIFs), regulated by the hypoxia signaling pathway, play a crucial role in maintaining cellular and systemic oxygen homeostasis in response to changes in oxygen supply. In this study, we investigated the HIFs pathway in three deep-sea fish species: Pseudoliparis swirei, Ilyophis sp., and Liparis tanakai. We found that Ilyophis sp. HIF-1α shows stronger transcriptional activity and upregulates hypoxia-response genes more efficiently than the other species. Mutational analysis revealed that the deletion mutation of the nuclear export signal (NES) in Ilyophis sp . HIF-1α may enhance its stability, while Plk3 may function as a negative regulator of deep-sea fish HIF-1α under hypoxic conditions. This study reveals divergent evolutionary strategies in hypoxia adaptation among deep-sea fishes, highlighting how structural and regulatory mechanisms enable survival in oxygen-deprived environments, and provides novel insights into the genetic mechanisms enabling survival in OMZs, advancing our understanding of marine hypoxia resilience and its implications for ecosystem dynamics under global deoxygenation.
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