Regulation of partial endothelial-to-mesenchymal transition by circATXN1 in ischemic diseases

Yue Li, Zhe Zheng, Yanze Li, Siyuan Fan, Lingyao Kong, Wanrong Fu, Zhonggen Li, Jianchao Zhang, Shuang Li, Zongtao Liu, Chao Liu, Jinhua Cao, Zhenxuan Hao, Lili Xiao, Youyou Du (), Xiaofang Wang () and Lu Gao ()
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Yue Li: Zhengzhou University
Zhe Zheng: Zhengzhou University
Yanze Li: Shandong First Medical University and Shandong Academy of Medical Sciences
Siyuan Fan: Zhengzhou University
Lingyao Kong: Zhengzhou University
Wanrong Fu: Zhengzhou University
Zhonggen Li: Zhengzhou University
Jianchao Zhang: Zhengzhou University
Shuang Li: Zhengzhou University
Zongtao Liu: Huazhong University of Science and Technology
Chao Liu: The First Affiliated Hospital of Zhengzhou University
Jinhua Cao: Zhengzhou University
Zhenxuan Hao: Zhengzhou University
Lili Xiao: Zhengzhou University
Youyou Du: Zhengzhou University
Xiaofang Wang: Zhengzhou University
Lu Gao: Zhengzhou University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Ischemic injury induces a partial mesenchymal shift in endothelial cells (ECs), contributing to impaired vascular regeneration. However, the molecular regulators of this transitional state remain poorly defined. To address this, we performed circular RNA profiling of endothelial cells under ischemic-like conditions and identified a marked upregulation of a circular RNA, named circATXN1. Functional studies revealed that circATXN1 knockdown modulates endothelial phenotype and vascular response after ischemia. Functional studies have shown that knockdown of circATXN1 can regulate the endothelial cell phenotype and vascular response after ischemia. Mechanistically, circATXN1 knockdown enhances the demethylase protein ALKBH5 to reduce the RNA methylation level of the key transcription factor SLUG, thereby stabilizing SLUG. In animal models, suppression of circATXN1 enhances angiogenesis and improves recovery following ischemic injury. Here, we show that circATXN1 regulates partial endothelial-to-mesenchymal transition (EndMT) and angiogenesis by controlling SLUG mRNA methylation dynamics, highlighting its potential as a therapeutic target in ischemic disease.

Date: 2025
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DOI: 10.1038/s41467-025-61596-2

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