传统医学宽胸气雾剂通过cGAS-STING途径减轻CX3CR1巨噬细胞凋亡，从而减轻动脉粥样硬化斑块炎症。

Traditional medicine Kuanxiong Aerosol alleviates atherosclerotic plaque inflammation by mitigating CX3CR1 macrophage apoptosis via the cGAS-STING pathway.

作者信息

Chen Yefeng, Wang Guowei, Jiang Yuanqing, Qian Kai, Liu Yajing, Qiu Cong, Huang Pintong

机构信息

Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Postdoctoral Research Center, Zhejiang Sukean Pharmaceutical Co., Ltd, Hangzhou 311228, China.

Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.

出版信息

Phytomedicine. 2025 Oct;146:157120. doi: 10.1016/j.phymed.2025.157120. Epub 2025 Jul 30.

DOI:10.1016/j.phymed.2025.157120

PMID:40753933

Abstract

BACKGROUND

Atherosclerosis (AS), a chronic inflammatory vascular disease, represents the leading cause of lethal cardiovascular events and demands innovative therapies targeting plaque inflammation. Kuanxiong Aerosol (KX), a clinically used traditional Chinese medicine for angina, exhibits potent anti-inflammatory activities.

PURPOSE

This investigation aimed to explore the therapeutic potential and mechanism of KX for AS.

STUDY DESIGN AND METHODS

KX was administered to ApoE mice subjected to high-fat diets. AS progression or regression was assessed via phenotypic analysis and histological examination. Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) in conjunction with serum-network pharmacology was employed to clarify the function of blood-derived chemicals originating from KX. Single-cell RNA sequencing was executed to explore the cellular mechanisms of KX therapy, while bioinformatics analysis and molecular docking were undertaken to identify molecular targets.

RESULT

KX suppressed AS progression and promoted regression in ApoEmice. The integrated serum pharmacochemistry analysis revealed anti-inflammatory effects of KX-derived compounds, as confirmed by reduced inflammatory cell infiltration and serum biomarkers. Further studies demonstrated that KX inhibited macrophage differentiation into CX3CR1 subpopulations and reduced apoptosis, thereby attenuating lesional inflammation. The mechanistic studies identified cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling as a critical effector for KX-induced reduction in the apoptotic CX3CR1 macrophages. Moreover, STING pathway activation reversed the effect of KX on AS progression and CX3CR1macrophage apoptosis in vivo and in vitro.

CONCLUSIONS

KX suppresses the cGAS-STING-P65 signaling pathway, causing the downregulation of the CX3CR1 macrophage subpopulation and apoptosis, thereby alleviating plaque inflammation and AS progression. This investigation is the first to illustrate the regulatory effect of KX on macrophage subpopulations and its anti-apoptosis function.

摘要

背景

动脉粥样硬化（AS）是一种慢性炎症性血管疾病，是致死性心血管事件的主要原因，需要针对斑块炎症的创新疗法。宽胸气雾剂（KX）是一种临床上用于治疗心绞痛的传统中药，具有强大的抗炎活性。

目的

本研究旨在探讨KX对AS的治疗潜力及其作用机制。

研究设计与方法

将KX给予高脂饮食的载脂蛋白E（ApoE）小鼠。通过表型分析和组织学检查评估AS的进展或消退情况。采用超高效液相色谱-高分辨率质谱（UHPLC-HRMS）结合血清网络药理学来阐明源自KX的血液化学物质的功能。进行单细胞RNA测序以探索KX治疗的细胞机制，同时进行生物信息学分析和分子对接以鉴定分子靶点。

结果

KX抑制ApoE小鼠的AS进展并促进其消退。综合血清药物化学分析揭示了KX衍生化合物的抗炎作用，炎症细胞浸润减少和血清生物标志物证实了这一点。进一步研究表明，KX抑制巨噬细胞分化为CX3CR1亚群并减少细胞凋亡，从而减轻病变炎症。机制研究确定环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激物（STING）信号通路是KX诱导凋亡的CX3CR1巨噬细胞减少的关键效应器。此外，STING通路激活在体内和体外逆转了KX对AS进展和CX3CR1巨噬细胞凋亡的影响。