iProXProteomicsJunying MiaoHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0014675000miaojy@sdu.edu.cnShandong universityiProXExogenous Glutathione S-transferase Mu 2 (GSTM2) supplementation has emerged as a promising strategy to counteract aging. However, approaches to enhance endogenous GSTM2 expression remain underexplored. Here, we identify HCY-NBD, an SO₂-targeting small molecular that binds GSTM2 and stabilizes GSTM2 protein levels under high-glucose (HG)-induced vascular endothelial senescence. Mechanistically, HCY-NBD promotes sulfenylation at Cys174 of GSTM2 and inhibits its K48-linked ubiquitination at this residue, thereby stabilizing GSTM2 protein. In cellular studies, we observe that HCY-NBD upregulates GSTM2 and inhibits HG-induced senescence and calcification in vascular endothelial cells. Consistent with this, in vivo administration of HCY-NBD in db/db mice increases GSTM2 levels and mitigates senescence and calcification in the thoracic aorta. Collectively, our findings demonstrate that HCY-NBD inhibits HG-induced vascular senescence and calcification by stabilizing GSTM2 protein levels via enhancing Cys174 sulfenylation and suppression of site-specific ubiquitination-mediated degradation. Here, we first develop a new strategy to enhance endogenous GSTM2 and provide a novel therapeutic strategy for the prevention and treatment of vascular aging.Small molecule HCY-NBD stabilizes GSTM2 via cys174 sulfenylation to attenuate high glucose induced endothelial cell senescence and calcification.Zhang Yangyang Y, Dong Xinyu X, Yan Xiaomeng X, Zhao Congyao C, Chi Xiaohui X, Zhao Baoxiang B, Miao Junying J, Hong Fanzhen F, Lin Zhaomin ZfalseIdentification of ubiquitination sites on the GSTM2 proteinThe human GSTM2 protein was enriched, followed by mass spectrometry to identify its ubiquitination sites.Mon Dec 15 00:00:00 GMT 2025PXD071988960641637880