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

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 ApoE-/-mice. 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 CX3CR1+macrophage 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.