STING inhibitors(Shanghai Jiao Tong University)

The stimulator of interferon genes (STING) plays a critical role in innate immunity, where precise regulation of its activity is essential for pathogen clearance and avoiding harmful immune responses. The development of STING inhibitors has been proposed to alleviate a variety of autoimmune and inflammatory diseases. In this study, using cell line models, we demonstrate that midazolam, a commonly used anesthetic, inhibited STING signaling in macrophages and epithelial-derived cell lines. Specifically, midazolam or translocator protein (TSPO) silencing impaired STING trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus in a proteasome-dependent manner. Furthermore, midazolam effectively suppressed STING over-activation and type I interferons (IFNs) signaling activation induced by STING mutations or excessive DNA accumulation in three-prime repair exonuclease 1 knockout (Trex1^-/-) mouse embryonic fibroblasts. Of note, midazolam reduced type I IFNs expression and protected mice against Listeria monocytogenes-induced infection in vivo. These findings suggest that midazolam or TSPO inhibitors could be a promising therapeutic agent for modulating STING activation and treating related inflammatory diseases.

The regulation of the STING (stimulator of interferon genes) pathway represents a promising target for a range of inflammatory diseases. This review provides an overview of the structure of STING and discusses the mechanisms by which the cyclic GMP-AMP synthase (cGAS)-STING pathway is associated with various autoinflammatory and autoimmune diseases. We explore how targeting STING inhibition or degradation can alleviate excessive inflammatory signaling and improve efficacy. Emerging strategies include inhibiting STING expression by covalently binding compounds or using ligands that target the binding pocket. In addition, selective degradation of STING via the ubiquitin-proteasome system or the lysosomal pathway shows promise. In addition, we explore the implications of modulating the cGAS-STING pathway in the context of various inflammatory diseases. Finally, we summarize the chemical properties of recently developed STING compounds and their potential clinical applications. By comprehensively reviewing the current understanding of the role of STING in inflammation and the therapeutic potential of targeting STING, we aim to identify new avenues of intervention that could improve outcomes for patients with inflammatory diseases. This review highlights the important role of STING in the regulation of inflammation and its potential as a target for innovative therapeutic strategies.