STING Degradation by PRRSV Activates HK(2)-Mediated Glycolysis to Facilitate Viral Replication.

Porcine reproductive and respiratory syndrome virus (PRRSV) infection relies on glycolytic reprogramming to support replication, but the mechanisms driving this metabolic shift remain poorly understood. The stimulator of interferon genes (STING), an innate immune adaptor, recently emerged as a metabolic regulator by directly binding and inhibiting hexokinase-2 (HK(2)), a key rate-limiting enzyme in glycolysis. Whether PRRSV exploits the STING-HK(2) axis to unleash glycolysis for its own replication is unknown. Here we demonstrate that PRRSV infection induced STING degradation and promoted HK(2) suppression, activating glycolysis for viral replication. In PRRSV-infected Marc-145 cells, lactate production (a glycolysis marker) and HK(2) expression increased time-dependently, peaking at 48 h post-infection (hpi). Conversely, STING protein levels decreased significantly at 36 hpi and further at 48 hpi, suggesting a correlation between STING downregulation and glycolytic activation. The HK(2) inhibitor 2-deoxy-D-glucose reduced lactate production and viral load, while the glycolysis activator PS48 enhanced both. STING knockdown via siRNA increased HK(2) expression, lactate secretion, and PRRSV nucleocapsid protein levels, whereas STING overexpression suppressed these phenotypes. Co-immunoprecipitation and confocal microscopy demonstrated direct STING-HK(2) interaction and cytoplasmic co-localization, maintained during PRRSV infection. HK(2) overexpression promoted viral replication without altering STING levels, confirming HK(2) as a downstream effector. In conclusion, PRRSV-triggered degradation of STING enhances HK(2) expression, promoting lactate accumulation and accelerating viral replication. These findings suggest that the STING-HK(2) axis can act as a critical viral metabolic checkpoint and highlight targeting metabolic-immune crosstalk as a potential anti-viral strategy.