Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging

Dan Wu, Bo Tan, Zijie Cheng, Haoqi Li, Huimin Li, Yun Yin, Fenfen Ma, Tao Chen, Xin Dong, Wang Wang and Qingxun Hu ()
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Dan Wu: Shanghai University
Bo Tan: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine
Zijie Cheng: Shanghai University
Haoqi Li: Shanghai University
Huimin Li: Tongji University School of Medicine
Yun Yin: Tongji University School of Medicine
Fenfen Ma: Fudan University
Tao Chen: Northwest Institute of Plateau Biology
Xin Dong: Shanghai University
Wang Wang: University of Washington
Qingxun Hu: Shanghai University

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

Abstract: Abstract Reduced nicotinamide adenine dinucleotide phosphate (NADPH) metabolism is independently regulated in different compartments in endothelial cells (EC). The metabolic profile and functional impact of NADPH during EC senescence remain largely unknown. Using a genetically encoded fluorescent indicator, we find that cytosolic, but not mitochondrial, NADPH level increases during EC senescence. Upregulation of glucose-6-phosphate dehydrogenase (G6PD) further elevates cytosolic NADPH level during EC senescence. Suppression of G6PD S-nitrosylation at C385 potentiates G6PD activity. G6PD overexpression alleviates, while its knockdown aggravates, vascular aging. NADPH is indispensable for G6PD to protect against vascular aging through increasing reduced glutathione and inhibiting HDAC3 activity. Among 1419 FDA-approved drugs, folic acid, catalyzed by methylenetetrahydrofolate dehydrogenase to generate NADPH, effectively alleviates vascular aging in angiotensin II-infused mice and naturally aged mice. The connection between NADPH metabolism and EC senescence provides a unique angle for understanding vascular aging and an efficient target for therapy.

Date: 2025
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DOI: 10.1038/s41467-025-64652-z

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