STING inhibitors (Discovery BioMed/Nitor Therapeutics)

Colitis-associated cancer (CAC) is a minor subtype of CRC, accounting for 2% of CRC cases. It is also one of the most common and severe complications in patients with chronic IBD. The exact pathogenic mechanisms of CAC remain unclear. Therefore, actively investigating the pathogenesis of CAC and developing novel therapeutic strategies are of great significance for its prevention and treatment.

The mouse model of UC and CAC was induced using DSS and AOM stimulation. The model was validated through H&E staining, Masson, AB-PAS staining, and ELISA assays. Additionally, the expression levels of key molecules, including cGAS and STING, were examined in model mice using qRT-PCR and immunohistochemistry. Later, based on the mouse CAC model, STING inhibitors and agonists were administered in combination with H&E staining, Masson, AB-PAS staining, and ELISA assays to explore the impact of key molecular expression levels on CAC progression in mice. Finally, in a mouse UC organoid model, STING agonists were used in combination with NLRP3 inhibitor. WB, CCK8, immunofluorescence staining, and intestinal permeability tests were employed to investigate the regulatory mechanisms of pyroptosis in CAC development.

DSS and AOM stimulation successfully induced the mouse UC and CAC model. Key proteins of the cGAS-STING pathway, including cGAS, p65, and IFN-I, were significantly upregulated in the mouse UC and CAC model. The STING agonist SR-717 markedly increased the expression of cGAS-STING pathway-related genes, such as cGAS, STING, p65, and IFN-I, exacerbating pathological features and serum inflammatory cytokine levels in the colonic cancer model. It also significantly upregulated pyroptosis marker proteins pro-caspase-1, GSDMD-N, and NLRP3, whereas the STING inhibitor H-151 effectively suppressed these effects. The NLRP3 inhibitor INF195 enhanced the proliferative capacity, membrane integrity, and intestinal barrier function of the mouse colon organoid model, providing partial protective effects. Meanwhile, the STING agonist SR-717 partially reversed the effects of INF195.

The cGAS-STING signaling pathway accelerates the progression of CAC by promoting pyroptosis in colonic epithelial cells through NLRP3/caspase-1 mediation.

In recent years, the cGAS-STING signaling pathway has emerged as a highly regarded mechanism for intracellular DNA recognition and innate immune activation. This pathway activates downstream interferon and inflammatory factor expression by recognizing Double-Stranded DNA (dsDNA) in the cytoplasm, thereby participating in the regulation of various physiological and pathological processes, including autophagy, apoptosis, and aging. In Central Nervous System (CNS) diseases, abnormal activation of the cGAS-STING pathway is closely associated with key pathological mechanisms such as neuroinflammation and neuronal injury. However, its specific mechanisms of action and regulatory networks in different diseases still require systematic investigation. This paper provides a systematic review summarizing the molecular activation mechanisms of the cGAS-STING signaling pathway, with a focus on elucidating its role and mechanisms of action in various central nervous system disorders. We further explored the potential and challenges of this pathway as a therapeutic target. This paper provides a comprehensive and categorized analysis of the composition, activation process, and functional roles of the cGAS-STING pathway in CNS diseases, based on the latest research findings. By reviewing preclinical research evidence, this study focuses on investigating the activation triggers of this pathway across various disease models and their impact on disease progression. While summarizing current pharmacological research advances targeting this pathway. Reviews indicate that the cGAS-STING pathway is activated in various CNS disorders, primarily exacerbating secondary neurological damage by inducing glial cells to polarize toward a proinflammatory phenotype and perpetuating neuroinflammation. Preclinical studies indicate that cGAS or STING inhibitors (such as C-176, H-151, RU.521, etc.) effectively reduce neuroinflammation and improve behavioral outcomes, suggesting significant therapeutic potential. However, the translational application of this pathway still faces significant challenges, including poor blood-brain barrier penetration of existing inhibitors, suboptimal pharmacokinetic properties, potential off-target toxicity, and the risk of immunosuppression that may arise from long-term inhibition. Moreover, this pathway may exert dual or even opposing effects across different disease stages and cell types, exhibiting significant context-dependent functionality. The cGAS-STING pathway plays a crucial role in neuroimmunoregulation of CNS diseases and represents a highly promising therapeutic intervention target. Despite the exciting preclinical evidence, its translation into clinical applications remains constrained by numerous challenges, including drug delivery, selectivity, safety, and potential interference with physiological immune function. Future research should focus on elucidating the precise regulatory network of this pathway in specific pathological contexts and developing novel modulators with high blood-brain barrier permeability, high selectivity, and favorable safety profiles. Concurrently, conduct systematic efficacy and safety validation in models more closely resembling human diseases to advance the ultimate realization of targeted therapeutic strategies for this pathway. Activation of the cGAS-STING signalling pathway and its role in central nervous system diseases. (ICH: Intracerebral hemorrhage; TBI: Traumatic brain injury).