Integrated analyses of single-cell transcriptome and mendelian randomization reveal the role of lymphatic endothelial CD74 in the progression of atherosclerosis.

Authors

Heng-Xuan Cai, Guan-Peng Ma, Zhe Jia, Feng-Yi Liu, Gege Wu, Rong-Zhe Lu, Zhen-Ming Zhang, Yi-Shuo Xu, Zi-Qian Weng, Shan-Jie Wang, Zhao-Ying Li, Bo Yu, Shao-Hong Fang

Published in

Journal of geriatric cardiology : JGC. Volume 23. Issue 7. Pages 456-473. Jul 28, 2026.

Abstract

Lymphatic dysfunction plays a critical role in the development of atherosclerotic plaques, and targeting lymphatic regulation offers promising strategies for preventing and treating atherosclerosis (AS). This study aims to identify key genes influencing AS in lymphatic endothelial cells (LECs) followed by validation, and to explore potential intervention targets for AS treatment.
Single-cell data from the GEO database and Mendelian randomization was employed to identify genes in LECs that may either exacerbate or protect against AS. AS mouse models were established, followed by the assessment of key gene expression in lymphatic vessels within the plaque adventitia. In vitro, LECs were manipulated by silencing or overexpressing key genes to investigate the signaling pathways and mechanisms through which genes influence lymphangiogenesis.
Human carotid plaque data via the GEO database revealed that LEC-specific genes are closely associated with vasculogenesis, cell migration, and inflammatory responses during AS. Mendelian randomization analysis identified CD74 as a promoter of AS progression. In vivo experiments revealed a significant upregulation of CD74 expression during AS. Correlation analysis of CD74 in LECs with inflammatory genes from the GEO database, along with the in vitro construction of CD74 silencing and overexpression models in LECs, revealed the critical role of CD74 in the inflammatory response in AS. Gene correlation analysis and experimental validation revealed that CD74 promotes LEC pyroptosis through the NLRP3/SYK pathway. Additionally, in vitro results demonstrated that CD74 impairs lymphangiogenesis by inducing pyroptosis.
This study has identified the key gene CD74 in LECs that influence the progression of AS. Moreover, during AS, CD74 mediates NLRP3/SYK-dependent LEC pyroptosis, thereby inhibiting lymphangiogenesis and exacerbating the inflammatory response. These findings provide a novel molecular mechanism by which CD74 disrupts lymphatic function and accelerates AS progression, offering potential avenues for intervention in AS.

PMID:
42740889
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.

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