HIF-1α-mediated glycolytic reprogramming facilitates decapod iridescent virus 1 pathogenesis in Macrobrachium rosenbergii: Central role of hexokinase in viral metabolic hijacking

Decapod iridescent virus 1 (DIV1) poses a severe threat to global aquaculture, yet the mechanisms underlying its metabolic hijacking of host pathways remain poorly understood. Here, we demonstrate that DIV1 infection in Macrobrachium rosenbergii induces a hypoxia-inducible factor 1α (HIF-1α)-mediated Warburg-like metabolic reprogramming, with hexokinase (MrHK) serving as a central metabolic hub. Proteomic profiling of DIV1-infected shrimp hemocytes identified 902 differentially expressed proteins (DEPs), revealing striking upregulation of glycolysis pathway. The temporal analysis confirmed stage-specific induction of MrHK and synchronized activation of downstream glycolytic enzymes, mirroring full-pathway metabolic hijacking. Evolutionary and structural analyses revealed MrHK's conservation across crustaceans and identified two functional HK domains. Targeting MrHK with the inhibitor 2-deoxy-D-glucose (2-DG) reduced viral copies and improved survival rates from 21.21 % to 43.33 %. Mechanistically, DIV1 stabilizes HIF-1α under normoxia to transactivate MrHK via three hypoxia-response elements (HREs), with mutagenesis of the core HRE motif abolishing promoter activity. Silencing MrHIF-1α attenuated MrHK expression and activity, viral copies, and improved survival, highlighting the axis's therapeutic potential. These findings establish HIF-1α-driven glycolytic reprogramming as a deliberate viral strategy, advancing our understanding of the molecular mechanisms behind DIV1 infection and offering actionable targets for metabolic interventions and host-directed therapies to combat DIV1 outbreaks in aquaculture.