Nature Immunology, Journal Year: 2024, Volume and Issue: unknown
Published: Oct. 4, 2024
Language: Английский
European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 291, P. 117632 - 117632
Published: April 15, 2025
Language: Английский
Citations
0
Human Molecular Genetics, Journal Year: 2025, Volume and Issue: unknown
Published: April 28, 2025
Abstract The stimulator of interferon gene (STING) is an important innate immune mediator the cytoplasmic DNA sensing pathway. As a known for its role in response to infections, STING also surprisingly at center variety non-infectious human diseases, including cancer, autoimmune diseases and neurodegenerative diseases. Recent studies have shown that has many signaling activities, type I (IFN-I) other IFN-independent which are poorly understood. unique property being continuous transported from ER Golgi then lysosome. Mutations or trafficking cofactors associated with affecting multiple non-immune organs. Here, we review recent advances mechanisms based part on STING-associated monogenic inborn error
Language: Английский
Citations
0
Journal of Autoimmunity, Journal Year: 2025, Volume and Issue: 154, P. 103434 - 103434
Published: May 6, 2025
Aberrant activation of the stimulator interferon genes (STING) pathway is a hallmark autoinflammatory disorders such as STING-associated vasculopathy with onset in infancy (SAVI), characterized by systemic inflammation affecting blood vessels, skin, and lungs. Despite its clinical significance, mechanisms linking STING to disease pathology remain poorly defined. In this study, we demonstrated that SAVI mice harboring N153S mutation exhibit diverse phenotypes, subset developing severe colitis diarrhea alongside exacerbated inflammation. These diarrheal showed pronounced dysbiosis, marked reduced short-chain fatty acid-producing bacteria an enrichment segmented filamentous bacteria. This microbial imbalance was accompanied elevated levels both host-derived cyclic dinucleotides (CDNs), potent activators pathway. Notably, antibiotic treatment ameliorated inflammation, underscoring role dysbiosis driving STING-mediated autoinflammation. Furthermore, patients, CDNs were observed. conditions lupus erythematosus (SLE)-a heterogeneous autoimmune potential involvement-systemic significantly correlated biomarkers, including type I scores anti-dsDNA antibodies. contrast, no correlations observed STING-independent like rheumatoid arthritis (RA). Importantly, study highlights are key drivers activation, suggesting personalized strategies could target cGAS or microbiome based on patient's specific CDN profile. findings position valuable biomarkers therapeutic targets for STING-driven diseases.
Language: Английский
Citations
0
Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown
Published: May 19, 2025
Stimulator of interferon genes (STING) is involved in various autoimmune diseases. However, it challenging to develop small-molecule STING inhibitors with potent activity. Herein, we designed a inhibitor and mutant-specific degrader by binding two coupled pockets dimer. Structure optimization selected SI-24, SI-42, SI-43 low nanomolar activity inhibit 2'3'-cyclic GMP-AMP (cGAMP)-induced activation release IFN-β CXCL-10, which were far more than reported inhibitors. Moreover, the three lead compounds suppressed cGAMP-induced oligomerization phosphorylation regulatory factor 3 (IRF3) STING. Surprisingly, promoted proteasome-independent degradation STINGS154 STINGM155. Subcutaneous or oral administration reduced serum CXCL-10 disease mouse model. Our dual-functional provide new strategy investigate function through both inhibition
Language: Английский
Citations
0
Nature Immunology, Journal Year: 2024, Volume and Issue: unknown
Published: Oct. 4, 2024
Language: Английский
Citations
2