The cGAS-STING pathway in systemic lupus erythematosus and lupus nephritis: a review of novel therapeutic targets

Systemic lupus erythematosus (SLE) is a prototypical autoimmune connective tissue disease in which the immune system is aberrantly activated, producing various autoantibodies that target the body's tissues, particularly the kidneys. Approximately 50% of patients with lupus nephritis (LN) eventually progress to end-stage renal disease. Despite the availability of multiple therapies, their effectiveness is often limited by individual patient differences. Recent studies have identified a new signaling pathway, the cyclic GMP-AMP synthetase (cGAS)-interferon gene stimulating factor (STING) innate immune pathway. Research has indicated that the serum levels of cGAS, STING, and type I interferon are significantly higher in mice with SLE or LN compared with normal populations. Experimental findings also suggest that the absence of cGAS and STING significantly reduces autoantibody production and alleviates tissue inflammation in autoimmune mouse models. These observations highlight the potential of targeting this pathway as a treatment for patients with SLE and LN. However, significant translational hurdles remain, including contradictory evidence from murine models, a complete lack of human trial data for leading candidates, and the inherent risk of viral reactivation owing to systemic immunosuppression. This article provides an overview of the cGAS-STING pathway, discusses its relevance to SLE and LN, and summarizes over 20 inhibitors targeting cGAS/STING. Furthermore, we emphasize the key clinical challenges and prospects of targeted drugs in this pathway.