XPNPEP2 regulates angiogenesis via modulation of mitochondrial function through SLC25A6

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 involvement in the pathogenesis of angiogenesis remain unclear. In this study, we revealed that XPNPEP2 is essential for EC function and angiogenesis via modulation of mitochondrial function. <i>In vivo</i>, 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. <i>In vitro</i>, XPNPEP2 deficiency impaired EC proliferation, migration, and tubulogenesis, which was accompanied by diminished mitochondria-associated membranes and dysfunctional mitochondria, including insufficient ATP, excessive mitochondrial reactive oxygen species (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 via Siah E3 ubiquitin protein ligase 1 (SIAH1)-mediated degradation. Additionally, attenuated EC angiogenesis was achieved solely by silencing SLC25A6. Our findings highlight that XPNPEP2 regulates angiogenesis via modulation of mitochondrial function, which may represent a new strategy for the treatment of angiogenesis-related diseases.