AbMole丨H-151：高效STING拮抗剂抑制细胞和动物模型中的炎症反应

H-151（AbMole，M10126）是一种高效的STING信号通路拮抗剂，它通过抑制STING的棕榈酰化（palmitoylation）阻断其下游信号传导[1]。研究显示，H-151在多种细胞和动物模型中表现出显著的STING抑制活性。在细胞实验中，H-151可显著抑制单核细胞系THP-1中由2',3'-cGAMP诱导的干扰素调节因子（IRFs）的表达，其半数抑制浓度（IC50）低至11.5 nM[2]。此外，在人微血管内皮细胞（HMEC-1）中，H-151或STING siRNA能下调黏附分子和趋化因子的表达，并减少免疫细胞在TNF-α刺激下的黏附与迁移能力，同时降低转录因子STAT的磷酸化水平[3]。

H-151在角质形成细胞和免疫细胞中，通过抑制STING/NF-κB信号通路，减少促炎因子（如IL-17、IL-23和IL-6）的分泌，并抑制Th17细胞的分化[4]。在动物模型中H-151同样有着广泛的应用，例如，在C57BL/6J小鼠的激光诱导脉络膜新生血管（CNV）模型中，玻璃体内注射H-151可抑制CNV的发展和新生血管的荧光渗漏，同时降低cGAS-STING通路下游信号（如NF-κB磷酸化）的表达[5]。H-151在Imiquimod（咪喹莫特）诱导的银屑病样小鼠模型中，局部应用后能减轻皮肤病变，减少M1巨噬细胞浸润和Th17细胞活化[4]。此外，H-151在放射性肺损伤（RILI）模型中也表现出保护作用：C57BL/6J小鼠经20 Gy胸部照射后，腹腔注射H-151持续4周可显著减轻肺损伤程度[6]。在心肌缺血模型中，H-151（750 nmol）通过抑制cGAS-STING-IRF3通路，减少心肌细胞凋亡和纤维化[7]。

参考文献及鸣谢

[1] Shi, F.; Su, J.; Wang, J.; et al. Activation of STING inhibits cervical cancer tumor growth through enhancing the anti-tumor immune response. Mol Cell Biochem 2021, 476 (2), 1015-1024.

[2] Chang, P. W.; Wang, J. Y.; Wang, W. P.; et al. Analysis of structure-activity relationship of indol-3-yl-N-phenylcarbamic amides as potent STING inhibitors. Bioorganic & medicinal chemistry 2023, 95, 117502.

[3] Wu, B.; Xu, M. M.; Fan, C.; et al. STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion. Acta pharmacologica Sinica 2022, 43 (8), 2055-2066.

[4] Pan, Y.; You, Y.; Sun, L.; et al. The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-kappaB-mediated inflammation. British journal of pharmacology 2021, 178 (24), 4907-4922.

[5] Tanaka, M.; Yasuda, H.; Nakamura, S.; et al. H-151, a Selective STING Inhibitor, Has Potential as a Treatment for Neovascular Age-Related Macular Degeneration. Investigative ophthalmology & visual science 2024, 65 (8), 16.

[6] Ge, X.; Liu, Q.; Fan, H.; et al. STING facilitates the development of radiation-induced lung injury via regulating the PERK/eIF2alpha pathway. Translational lung cancer research 2024, 13 (11), 3010-3025.

[7] Hu, S.; Gao, Y.; Gao, R.; et al. The selective STING inhibitor H-151 preserves myocardial function and ameliorates cardiac fibrosis in murine myocardial infarction. International immunopharmacology 2022, 107, 108658.