Molecular Modulation of Threadfin Fish Brain to Hypoxia Challenge and Recovery Revealed by Multi-Omics Profiling

Migratory fish often encounter hypoxic zones during migration, which can lead to varying degrees of hypoxic stress. This issue has become increasingly severe due to human activities and climate change, which have resulted in the expansion of hypoxic zones in aquatic environments. However, there is limited research on how these species respond to hypoxic stress and subsequent recovery. In this study, we used Eleutheronema tetradactylum, a well-recognized migratory and economically valuable fish species, as a model organism. Histological analysis revealed extensive neuronal damage during hypoxia exposure, with limited recovery observed even after 12 h of reoxygenation. Differential gene expression analysis highlighted progressive alterations in genes associated with stress response, neuroactive ligand interactions, and cellular repair mechanisms. Time-series analysis of differentially expressed genes (DEGs) identified critical expression profiles throughout the hypoxia-recovery process and revealed hub genes for each stage. Furthermore, dynamic changes in miRNA expression and proteomic profiles indicated active regulation of several key biological pathways, including MAPK, HIF-1, and ECM-receptor interactions. Through miRNA-mRNA-protein correlation analysis, we propose a model that predicts key regulatory pathways and critical miRNA-mRNA-protein interactions across the various stages of hypoxia-recovery in the brain of E. tetradactylum. This study presents the first integrated analysis of miRNA, mRNA, and protein throughout the entire hypoxia-recovery process in fish brains. The molecular interactions and regulatory pathways identified in this model could serve as valuable biomarkers for future research on hypoxia-recovery mechanisms in fish. © 2025 by the authors.