Importantly, we show that targeting cGAS demethylation, either through K350R mutation or KDM4B inhibition with JIB-04, ameliorates autoimmune manifestations in both Trex1−/− mice and AGS patient PBMCs, presenting a promising therapeutic strategy for self-DNA-induced autoimmune disorders. This evidence concerns the gene TREX1 and Aicardi-Goutieres syndrome.