Статья

Single-Cell Transcriptomics Identifies a Pivotal Role of SPHK1+ Macrophage-Driven Inflammation in Mechanism of Aortic Dissection and Highlights SPHK1 as a Therapeutic Target

Dianjun TangDepartment of Vascular Surgery, The First Hospital of China Medical University, No. 155, Nanjingbei Street, Shenyang, Liaoning, 110001, ChinaYanshuo HanDepartment of Vascular Surgery, Central Hospital of Dalian University of Technology, Dalian, ChinaHan JiangDepartment of Vascular Surgery, The First Hospital of China Medical University, No. 155, Nanjingbei Street, Shenyang, Liaoning, 110001, ChinaJ UzokovRepublican Specialized Scientific Practical Medical Center of Therapy and Medical Rehabilitation, Tashkent, UzbekistanFandong LiDepartment of Vascular Surgery, The Second Qilu Hospital of Shandong University, Jinan, ChinaZhong WangDepartment of Vascular Surgery, The First Hospital of China Medical University, No. 155, Nanjingbei Street, Shenyang, Liaoning, 110001, ChinaMario D’OriaDepartment of Vascular and Endovascular Surgery, Cardio-Thoraco-Vascular Department, University Hospital of Trieste ASUGI, Trieste, ItalyPhilipp ErhartDepartment of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, GermanyDittmar BoecklerDepartment of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, GermanyYu LunDepartment of Vascular Surgery, The First Hospital of China Medical University, No. 155, Nanjingbei Street, Shenyang, Liaoning, 110001, China. [email protected]Jian ZhangDepartment of Vascular Surgery, The First Hospital of China Medical University, No. 155, Nanjingbei Street, Shenyang, Liaoning, 110001, China. [email protected]

Inflammationjournal2026en

ABI

Аннотация

Macrophages are a key heterogeneous cell population involved in the pathogenesis and progression of acute aortic dissection (AD), though their mechanisms remain unclear. This study aims to identify the gene driving inflammatory damage in acute AD within a specific macrophage subcluster, highlighting potential therapeutic targets. Single-cell RNA sequencing (scRNA-seq) was employed to analyze the cellular heterogeneity in acute AD and normal aortic tissues. Bioinformatic analysis was conducted to identify the key gene. The role of sphingosine kinase 1 (SPHK1) was further explored using human acute AD tissue samples, macrophage cell line experiments, and AD mouse models. scRNA-seq identified six macrophage subclusters in AD tissues, with subcluster a exhibiting a pronounced pro-inflammatory phenotype. SPHK1 was significantly upregulated in this subcluster and was identified as the key regulatory gene. In vitro, inhibition of SPHK1 reduced macrophage-mediated inflammatory damage via the S1P-S1PR2/3-RhoA-ROCK1 signaling pathway. In vivo studies revealed a 40% reduction in the incidence of AD and significantly reduced severity in mice treated with PF-543 (a specific SPHK1 inhibitor). In this model, PF-543 reduced macrophage infiltration and the inflammatory damage caused by inflammatory factors and matrix metalloproteinases. This study identifies macrophage-driven inflammation, particularly via SPHK1, as a central mechanism in AD. Targeting SPHK1 and the associated S1P-S1PR2/3-RhoA-ROCK1 signaling pathway offers a potential therapeutic strategy for mitigating AD progression.

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Темы

Immune cells in cancer Connective tissue disorders research Aortic Disease and Treatment Approaches

Идентификаторы

DOI: 10.1007/s10753-026-02505-7

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