Small molecule HCY-NBD stabilizes GSTM2 via cys174 sulfenylation to attenuate high glucose induced endothelial cell senescence and calcification

Exogenous 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 SO 2 -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. • The small molecule HCY-NBD binds to GSTM2 and stabilizes its protein levels. • HCY-NBD upregulates the sulfenylation of GSTM2, inhibiting its K48-linked ubiquitination. • Cys174 is the critical residue for HCY-NBD-mediated regulation of GSTM2 sulfenylation and non-lysine ubiquitination. • HCY-NBD up-regulates GSTM2 inhibiting high-glucose-induced vascular endothelial cell senescence and calcification. • HCY-NBD up-regulates GSTM2 inhibiting vascular senescence and calcification in db/db mice.