The novel GSDMD inhibitor GI-Y2 exerts antipyroptotic effects to reduce atherosclerosis

Abstract

	•We preliminarily confirmed GI-Y2 as a novel inhibitor of GSDMD via structure-based virtual screening and pharmacological validation.
	•GI-Y2 directly interacts with GSDMD and reduces the membrane binding of GSDMD-N via the Arg10 residue.
	•GI-Y2 inhibits the formation of atherosclerotic plaques by targeting GSDMD and GI-Y2 reduces pyroptosis and macrophage infiltration in atherosclerosis.
	•We constructed macrophage membrane-coated GI-Y2 nanoparticles to enhance the targeting of GI-Y2 to macrophages in atheromatous plaques and demonstrated its vascular protective effect in vivo.

Keywords

atherosclerosis / gasdermin D / macrophage / pyroptosis

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.