In the context of autoimmune diseases, we found that targeting KDM4B–cGAS axis through either genetic approaches or pharmacological inhibition of KDM4B with JIB-04 effectively ameliorated disease manifestations in both Trex1-deficient mice and peripheral blood mononuclear cells from Aicardi-Goutieres syndrome (AGS) patients. The gene discussed is KDM4B; the disease is Aicardi-Goutières syndrome.