H-151作為高效STING拮抗劑在抑制細(xì)胞和動(dòng)物模型中炎癥反應(yīng)中的應(yīng)用

H-151（AbMole，M10126）是一種高效的STING信號(hào)通路拮抗劑，它通過抑制STING的棕櫚�；�（palmitoylation）阻斷其下游信號(hào)傳導(dǎo)[1]。研究顯示，H-151在多種細(xì)胞和動(dòng)物模型中表現(xiàn)出顯著的STING抑制活性。在細(xì)胞實(shí)驗(yàn)中，H-151可顯著抑制單核細(xì)胞系THP-1中由2',3'-cGAMP誘導(dǎo)的干擾素調(diào)節(jié)因子（IRFs）的表達(dá)，其半數(shù)抑制濃度（IC50）低至11.5 nM[2]。此外，在人微血管內(nèi)皮細(xì)胞（HMEC-1）中，H-151或STING siRNA能下調(diào)黏附分子和趨化因子的表達(dá)，并減少免疫細(xì)胞在TNF-α刺激下的黏附與遷移能力，同時(shí)降低轉(zhuǎn)錄因子STAT的磷酸化水平[3]。

H-151在角質(zhì)形成細(xì)胞和免疫細(xì)胞中，通過抑制STING/NF-κB信號(hào)通路，減少促炎因子（如IL-17、IL-23和IL-6）的分泌，并抑制Th17細(xì)胞的分化[4]。在動(dòng)物模型中H-151同樣有著廣泛的應(yīng)用，例如，在C57BL/6J小鼠的激光誘導(dǎo)脈絡(luò)膜新生血管（CNV）模型中，玻璃體內(nèi)注射H-151可抑制CNV的發(fā)展和新生血管的熒光滲漏，同時(shí)降低cGAS-STING通路下游信號(hào)（如NF-κB磷酸化）的表達(dá)[5]。H-151在Imiquimod（咪喹莫特）誘導(dǎo)的銀屑病樣小鼠模型中，局部應(yīng)用后能減輕皮膚病變，減少M(fèi)1巨噬細(xì)胞浸潤和Th17細(xì)胞活化[4]。此外，H-151在放射性肺損傷（RILI）模型中也表現(xiàn)出保護(hù)作用：C57BL/6J小鼠經(jīng)20 Gy胸部照射后，腹腔注射H-151持續(xù)4周可顯著減輕肺損傷程度[6]。在心肌缺血模型中，H-151（750 nmol）通過抑制cGAS-STING-IRF3通路，減少心肌細(xì)胞凋亡和纖維化[7]。
 
參考文獻(xiàn)及鳴謝
[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.