Abstract

cGAS overactivation is linked to various inflammatory and autoimmune diseases. Recent studies identify HDACs as critical regulators of cGAS, suggesting that dual cGAS/HDAC inhibition could be a novel therapeutic strategy. Herein, we report the identification of an HDAC/cGAS dual inhibitor, 31h, containing a hydroxamic acid moiety. This compound exhibited potent inhibitory activity against human and mouse cGAS (IC50: 0.17 and 1.80 μM, respectively) and moderate activity against HDAC3 and HDAC6 (IC50: 1.2 and 0.4 μM, respectively). Mechanistically, 31h directly suppresses cGAS activity and increases its acetylation levels via HDAC3 inhibition. This dual-action profile resulted in robust therapeutic efficacy in murine models of inflammatory bowel disease and Aicardi-Goutières syndrome. Collectively, 31h represents the first cGAS/HDAC dual inhibitor, offering a promising lead for further investigation into cGAS-dependent disorders.