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<p>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 as the first small molecule to directly bind and activate the DNA sensor cGAS to induce cGAMP production. 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 engages dual nucleic acid-sensing pathway, and suggest repurposing BT as an orally broad-spectrum antiviral.</p>

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Betrixaban activates cGAS and ERVs to promote dual nucleic-sensing antiviral immunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Xingyu Chen,
  • Yang Zhao,
  • Yunfei Xie,
  • Tianyi Liu,
  • Haocheng Wang,
  • Xiao Wang,
  • Xuefei Guo,
  • Fuping You

摘要

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 as the first small molecule to directly bind and activate the DNA sensor cGAS to induce cGAMP production. 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 engages dual nucleic acid-sensing pathway, and suggest repurposing BT as an orally broad-spectrum antiviral.