STING1 is a central hub protein of CGAS-STING1 signaling which is important signaling axis to sense DNA for the host against pathogens infection through regulating type I interferon (IFN-I) production. However, excessive STING1 activation-induced overproduced IFN-I triggers tissue damage and autoimmune disorders. Thus, the activity of STING1 must be precisely regulated for immune homeostasis. Here, we discovered SESN1 (sestrin 1) as an essential negative regulator of STING1 to maintain immune homeostasis. Upon herpes simplex virus-1 (HSV-1) infection, the expression of SESN1 was downregulated, which enhanced potentiality to virus defense for host. Consistently, SESN1-deficient mice exhibited stronger ability against HSV-1 infection compared to wild-type littermates. Additionally, we found the expression of SESN1 was decreased in systemic lupus erythematosus (SLE) patients and