FDA-approved Betrixaban Binds cGAS and Reactivates ERVs to Engage the Dual Nucleic Acid-Sensing Pathway and Promote Antiviral Immunity

Broad-spectrum host-directed antivirals are urgently needed as virus-targeted drugs often suffer from narrow specificity and rapid resistance. Here, we reported that Betrixaban (BT), an FDA-approved oral Factor Xa inhibitor, induced a robust antiviral state through dual innate immune pathways. Mechanistically, we identified BT directly bound and activated the DNA sensor cGAS to induce cGAMP production, representing BT as the first small-molecule cGAS agonist. Concurrently, BT inhibited histone deacetylases (HDACs), leading to chromatin de-repression of endogenous retroviruses (ERVs) and production of immunostimulatory double-stranded RNA (dsRNA) that engaged RIG-I/MDA5. These combined signalings triggered strong type I interferon responses and conferred broad-spectrum antiviral protection against RNA and DNA viruses in vitro and in vivo. These findings unveil a unique host-directed antiviral strategy wherein a small molecule drug engage dual nucleic acid-sensing pathway, and suggest repurposing BT as an orally broad-spectrum antiviral.