Thapsigargin suppresses porcine hemagglutinating encephalomyelitis virus replication by disrupting host energy metabolism.

Coronaviruses (CoVs) are a large family of human and animal pathogens that cause significant health and economic burdens worldwide. Thapsigargin (Tg) is a plant-derived sesquiterpene lactone with potent antiviral effects; however, the underlying mechanism remains unclear. Here, we show that Tg exhibited strong antiviral activity against the neurotropic swine CoV porcine hemagglutinating encephalomyelitis virus (PHEV) both in vivo and in vitro. Tg also exhibited inhibitory activity against other three swine coronaviruses in cell lines. Specifically, Tg treatment significantly inhibited the replication and transcription of genomic RNA in the viral life cycle but did not directly inactivate PHEV. Transcriptome analysis and glycolysis/mitochondrial stress testing confirmed that Tg alters intracellular metabolic flux, and suppresses glycolysis and oxidative phosphorylation (OXPHOS). Furthermore, metabolic reprogramming is associated with the antiviral effect of Tg and is required for productive PHEV infection. Overall, our findings highlight that Tg plays a crucial role in combating viral infections by targeting host energy metabolism shared by pathogenic microorganisms, suggesting that targeting key nodes of host metabolic processes may be a strategy for designing antiviral drugs against coronaviruses.