Betrixaban Activates cGAS and ERVs to Promote Dual Nucleic-Sensing 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 signal cascades 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/669242v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@aa153dorg.highwire.dtl.DTLVardef@585d43org.highwire.dtl.DTLVardef@152ec59org.highwire.dtl.DTLVardef@11ada33_HPS_FORMAT_FIGEXP M_FIG C_FIG