STING棕榈酰化修饰调控心肌缺血/再灌注损伤诱导的心肌细胞和成纤维细胞不同命运及其机制研究
STING palmitoylation regulates differential fates of cardiomyocytes and cardiac fibroblasts in myocardial ischemia-reperfusion injury and its underlying mechanisms
摘要
目的：干扰素基因刺激因子（Stimulator of interferon genes，STING）通路是介导天然免疫应答的核心信号通路，其异常激活广泛参与心肌缺血/再灌注损伤（Myocardial ischemia-reperfusion，MIRI）进程。STING棕榈酰化修饰是启动通路激活的关键翻译后修饰，其介导MIRI病理进展的具体分子机制目前尚不明确。本研究旨在明确STING棕榈酰化修饰在MIRI进程中的核心调控作用，并揭示其差异调控心肌细胞与成纤维细胞命运的分子机制。方法：构建小鼠冠状动脉结扎MIRI体内模型以及人心肌细胞、成纤维细胞氧糖剥夺再复氧体外模型，检测STING棕榈酰化修饰水平及其通路激活变化；采用STING棕榈酰化修饰抑制剂H-151体内外干预验证，通过蛋白质组学、转录组学等技术探究分子机制。结果：MIRI后心肌细胞与成纤维细胞中STING棕榈酰化修饰显著上调并激活下游通路，H-151干预有效减轻心肌损伤与纤维化。机制研究发现STING棕榈酰化修饰调控两种细胞的不同命运：在成纤维细胞中，通过上调细胞间黏附分子1表达并增强其与整合素α5的相互作用，促进迁移体生成及细胞活化；在心肌细胞中则通过上调干扰素刺激基因15表达并增强其与STING的相互作用，促进细胞凋亡；H-151可同时抑制上述两种效应，发挥心肌保护与抗纤维化双重作用。结论：STING棕榈酰化修饰是MIRI的关键调控靶点，可通过差异调控心肌细胞与成纤维细胞命运共同促进损伤进展。
Abstract
Objective: The stimulator of interferon genes (STING) pathway is a core signaling cascade mediating innate immune responses, and its aberrant activation is widely implicated in the progression of myocardial ischemia-reperfusion injury (MIRI). Palmitoylation is a critical post-translational modification essential for STING pathway activation, yet the detailed molecular mechanisms through which STING palmitoylation drives MIRI pathogenesis remain elusive. This study aimed to delineate the central regulatory role of STING palmitoylation in MIRI and elucidate the molecular mechanism by which it differentially controls the fates of cardiomyocytes and cardiac fibroblasts. Methods: The in vivo mouse MIRI model was established via coronary artery ligation, and in vitro oxygen-glucose deprivation/reoxygenation (OGD/Re) models were constructed with human cardiomyocytes and cardiac fibroblasts to examine alterations in STING palmitoylation and pathway activation. The STING palmitoylation inhibitor H-151 was applied for in vivo and in vitro intervention validation, and the underlying molecular mechanisms were explored using proteomics, transcriptomics and other techniques. Results: STING palmitoylation was markedly upregulated in both cardiomyocytes and cardiac fibroblasts following MIRI, accompanied by activation of downstream signaling pathways. H-151 treatment effectively attenuated myocardial injury and fibrosis. Mechanistic investigations revealed that STING palmitoylation differentially modulated the fates of the two cell types: in cardiac fibroblasts, it upregulated intercellular adhesion molecule 1 (ICAM1) expression and enhanced its interaction with integrin α5, thus promoting migrasome biogenesis and cell activation; in cardiomyocytes, it upregulated interferon-stimulated gene 15 (ISG15) expression and potentiated its binding to STING, thereby facilitating cellular apoptosis. H-151 inhibited both pathological effects simultaneously, exerting dual cardioprotective and antifibrotic actions. Conclusion: STING palmitoylation acts as a critical regulatory node in MIRI, and it collectively aggravates injury progression by differentially governing the fates of cardiomyocytes and cardiac fibroblasts.关键词
心血管药理学/心肌缺血/再灌注损伤/STING棕榈酰化修饰/迁移体/细胞凋亡Key words
cardiovascular pharmacology/myocardial ischemia-reperfusion injury/STING palmitoylation/migrasome/cell apoptosis引用本文复制引用
张佳莹,张慧灵.STING棕榈酰化修饰调控心肌缺血/再灌注损伤诱导的心肌细胞和成纤维细胞不同命运及其机制研究[EB/OL].(2026-07-21)[2026-07-23].http://www.paper.edu.cn/releasepaper/content/202607-24.学科分类
基础医学/临床医学
