Vitamin K3 attenuates STING-agonist-induced signaling and imiquimod-induced psoriasis-like inflammation.

Abstract

Cytosolic DNA sensing through the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis is an important component of innate host defense, whereas sustained pathway activation has been implicated in inflammatory and autoimmune diseases. Although several potent STING inhibitors are in preclinical development and ASP5502 has entered clinical evaluation, no STING inhibitor has received regulatory approval. Screening of an FDA-approved compound library identified vitamin K3 (VK3; menadione), a synthetic vitamin K analogue, as a compound that attenuated cellular responses elicited by SR717 and 2'3'-cGAMP. VK3 reduced IRF3 phosphorylation and the expression of interferon-related and inflammatory genes. In a cellular thermal shift assay (CETSA), VK3 did not produce detectable thermal stabilization of STING; therefore, its direct molecular target remains undefined. VK3 did not significantly reduce short-term THP-1 cell viability at the concentration used for signaling experiments. In LPS-challenged THP-1 cells, VK3 attenuated the induction of selected inflammatory transcripts, indicating that effects beyond STING-agonist-stimulated signaling cannot be excluded. In mice, topical VK3 attenuated imiquimod (IMQ)-induced psoriasis-like skin inflammation, reduced IL-17 and IL-23 expression, and did not appreciably affect body weight or the measured organ indices. Among the vitamin K analogues examined, VK3 showed the most consistent attenuation of STING-agonist-induced signaling. These findings support further investigation of VK3 as a topical modulator of inflammatory signaling in skin disease.