cGAS Inhibits ALDH2 to Suppress Lipid Droplet Function and Regulate MASLD Progression

Abstract Cyclic GMP‐AMP synthase (cGAS) is a cytosolic DNA sensor essential for host defense against microbial infections, but its role beyond innate immunity remains unclear. Here, a non‐canonical function of cGAS in regulating aldehyde metabolism and lipid homeostasis is identified. This is demonstrated that cGAS directly binds to and suppresses ALDH2 (aldehyde dehydrogenase 2), a key enzyme in ethanol metabolism and lipid peroxidation. Loss of cGAS activates ALDH2, thereby enhancing ethanol tolerance in mice. Elevated ALDH2 activity upon cGAS loss increases aldehyde conversion into acetyl‐CoA, promoting histone acetylation and transcription of lipid synthesis genes, which drives lipid droplet accumulation in cells and in cGas ‐/‐ mouse livers. These lipid droplets confer resistance to ferroptosis but simultaneously induce ER stress, impairing STING (stimulator of interferon genes) activation. Functionally, cGas ‐/‐ mice fed with a modified high‐fat diet develop exacerbated metabolic dysfunction‐associated steatotic liver disease (MASLD), characterized by excessive lipid droplet accumulation in livers compared to wild‐type controls. In human MASLD patient cohorts, increased cGAS but reduced ALDH2 mRNA expression is observed relative to healthy individuals. Together, this findings uncover a previously unrecognized role of cGAS in metabolic regulation, independent of its innate immune function. By suppressing ALDH2, cGAS controls lipid droplet biogenesis and stress responses, with direct implications for MASLD pathogenesis.