On October 2, 2025, Professor Ji Yong's team from our university reports a previously unrecognized, enzymatic-activity–independent (non-catalytic) role of S-nitrosoglutathione reductase (GSNOR) in diabetic vascular complications. The study, published in Science Translational Medicine as “S-nitrosoglutathione reductase as a therapeutic target for diabetic vascular complications in rodent models,” also presents NYY-001, an orally available small molecule that targets GSNOR and improves endothelial dysfunction in rodent models of diabetes.
Diabetes is a significant public health problem that severely endangers human health. Various vascular complications caused by diabetes are the leading causes of patient mortality and disability. In clinical practice, glycemic control alone does not fully prevent these complications, underscoring the need for mechanism based interventions that complement standard care.
GSNOR is a key enzyme in the metabolism of S-nitrosoglutathione (GSNO) and plays a crucial role in regulating the homeostasis of nitric oxide and protein S-nitrosylation within cells. However, its role in diabetic endothelial dysfunction remained unclear. This study, through proteomic screening, found that GSNOR expression was significantly increased in the endothelial cells of diabetic patients and model animals. Endothelial cell-specific knockout of GSNOR promoted blood flow recovery and angiogenesis in the ischemic hindlimbs of diabetic mice, and improved vascular permeability and vasodilation. Further mechanistic studies revealed that GSNOR promotes the nuclear export of the transcription factor ETS-related gene (ERG) via the chromosomal region maintenance 1 (CRM1)-dependent pathway, thereby inhibiting the transcription of ERG downstream genes related to vascular homeostasis, ultimately leading to endothelial dysfunction. Importantly, this action does not depend on GSNOR’s catalytic (enzymatic) activity. Based on this mechanism, the research team designed and synthesized a novel small-molecule compound–NYY-001. This compound exhibits good oral absorption and safety profile, effectively blocks the interaction between GSNOR and ERG, promotes blood flow recovery and angiogenesis in the ischemic hindlimbs, and improves vascular permeability in diabetic mice.
Professor Ji’s group has long investigated GSNOR in cardiovascular disease. Earlier work identified GSNOR as a regulator of pathological cardiac hypertrophy through S-nitrosylation of muscle LIM protein (MLP) and HSP90 (Circulation 2020;141:984–1000; Acta Pharmacol Sin 2022;43:1979–1988); uncovered NEDD4-mediated ubiquitination and degradation of GSNOR in hypertrophy (Circ Res 2025;136:422–438); and reported mitochondrial GSNOR localization modulating ANT1 S-nitrosylation in heart failure (Circ Res 2023;133:220–236). The present study extends this program by revealing a non-catalytic GSNOR mechanism at the core of diabetic vascular remodeling.This research was completed through the collaboration of Professor Ji Yong's team from Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Professor Xie Liping from the School of Basic Medical Sciences at Nanjing Medical University, and Professor Han Yi from the Second Affiliated Hospital of Harbin Medical University. Associate Professor Zhao Shuang, Dr. Song Tianyu, and Associate Professor Tang Xin from the School of Pharmacy at Nanjing Medical University are the co-first authors of the paper. The study received strong support from Academician Han Yaling and Professor Yan Chenghui of the General Hospital of Northern Theater Command; Professor Chen Feng, Professor Chen Hongshan, Professor Gao Yuanqing, Professor Yin Guoyong, and Professor Wang Liansheng of Nanjing Medical University; Professor Wang Dongjin of the Affiliated Drum Tower Hospital of Nanjing University Medical School; Professor Wang Hong of Temple University School of Medicine; Professor Cao Yu of the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; Professor Wang Xiujie of the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences; and Professor Yu Bo and Professor Zhang Zhiren of Harbin Medical University.
Link to the original article: https://www.science.org/doi/10.1126/scitranslmed.adn9216
(Drafted by Prof. Ji Yong’s Group; Reviewed by Chen Hongshan; Translation revised by Wu Wenbo)
