The IKKε-GABPA axis regulates STING transcription to orchestrate antiviral immunity and inflammation.

The cGAS-STING pathway plays a critical role in antiviral defense and inflammatory homeostasis. While posttranslational regulation of STING is well characterized, the transcriptional networks directly governing Sting1 expression remain unclear. Here, we identify the transcription factor GA-binding protein alpha (GABPA) as a critical regulator of STING-dependent type I IFN (IFN-I) responses in macrophages. Mechanistically, GABPA directly binds to the Sting1 promoter, thereby transcriptionally sustaining basal STING expression. Upon viral infection, activated IκB kinase epsilon (IKKε) phosphorylates GABPA at S447, which further enhances its transcriptional activity and amplifies the STING-IFN-I signaling cascade. Notably, Gabpa deficiency protects mice from DSS-induced colitis, and this protective effect is abolished upon Sting1 deletion. Strikingly, patients with inflammatory bowel disease (IBD) or systemic lupus erythematosus (SLE) exhibit elevated GABPA expression that positively correlates with STING hyperactivation and enhanced inflammatory signatures. Moreover, a GABPA-blocking peptide effectively suppresses aberrant IFN-β production in peripheral blood mononuclear cells (PBMCs) from SLE patients, highlighting its therapeutic potential for interferonopathies.