ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Signaling
XPNPEP2 involved in angiogenesis through the modulation of mitochondrial function via SLC25A6
Provisionally accepted
Chenxi Yang1,2
Yijun Lu1,3Yu Xia1Bingying Wang1,4
Jie Xu1
Zhang Yuchen1,3Jiaxuan Yan3Min Liu3Ting Chen1
Xiaoxu Zhao5
Xiaohui Cang1
Jianhua Mao1
Pingping JIANG1,4*- 1Zhejiang University School of Medicine Children's Hospital National Clinical Research Center for Child Health, Hangzhou, China
- 2Northwest Women and Children's Hospital, Xi'an, China
- 3Zhejiang University School of Medicine, Hangzhou, China
- 4Zhejiang University, Hangzhou, China
- 5Shandong First Medical University, Jinan, China
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Abstract X-prolyl aminopeptidase 2 (XPNPEP2), which is abundantly expressed in vascular endothelial cells (ECs), has been reported to be associated with cardiovascular disease and angiogenesis. However, its function in ECs and its pathogenesis in angiogenesis remain unclear. Here, we revealed that, by modulating mitochondrial function, XPNPEP2 is essential for EC function and angiogenesis. In vivo, XPNPEP2 deletion led to pathological changes in the pulmonary artery wall and renal tissue, decreased venous blood vessel density in the proximal region of superficial retinal vessels, and significantly slowed wound healing and tumor growth in mice. In vitro, XPNPEP2 deficiency impaired EC proliferation, migration and tubulogenesis, which was accompanied by diminished mitochondria-associated membranes and dysfunctional mitochondria, including insufficient ATP, excessive mROS, and disrupted respiration chain function. XPNPEP2 was found to interact with SLC25A6. The overexpression of XPNPEP2 restored impaired EC angiogenesis and the reduction in SLC25A6 caused by XPNPEP2 ablation. Moreover, inhibition of XPNPEP2 downregulated SLC25A6 by E3 ubiquitin protein ligase SIAH1-mediated degradation. Additionally, attenuated EC angiogenesis was achieved solely by silencing SLC25A6. Our findings highlight XPNPEP2-mediated mitochondrial function in angiogenesis, which may suggest a new strategy for the treatment of angiogenesis-related diseases.
Keywords: interaction of SLC25A6, Mitochondria, mitochondria-associated membranes (MAMs), neoangiogenesis, Siah E3 ubiquitin protein ligase 1 (SIAH1), Xpnpep2
Received: 03 Sep 2025; Accepted: 05 Dec 2025.
Copyright: © 2025 Yang, Lu, Xia, Wang, Xu, Yuchen, Yan, Liu, Chen, Zhao, Cang, Mao and JIANG. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Pingping JIANG
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