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

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

  • Redox Biol. 2026 Mar:90:104058. doi: 10.1016/j.redox.2026.104058.
Yangyang Zhang 1,  Xinyu Dong 2,  Xiaomeng Yan 3,  Congyao Zhao 4,  Xiaohui Chi 5,  Baoxiang Zhao 6,  Junying Miao 7,  Fanzhen Hong 8,  Zhaomin Lin 9
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Development and Regeneration, School of Life Science, Shandong University, Qingdao, 266237, PR China. Electronic address: [email protected].
  • 2 Shandong Provincial Key Laboratory of Development and Regeneration, School of Life Science, Shandong University, Qingdao, 266237, PR China. Electronic address: [email protected].
  • 3 Shandong Provincial Key Laboratory of Development and Regeneration, School of Life Science, Shandong University, Qingdao, 266237, PR China. Electronic address: [email protected].
  • 4 Shandong Provincial Key Laboratory of Development and Regeneration, School of Life Science, Shandong University, Qingdao, 266237, PR China. Electronic address: [email protected].
  • 5 Shandong Provincial Key Laboratory of Development and Regeneration, School of Life Science, Shandong University, Qingdao, 266237, PR China. Electronic address: [email protected].
  • 6 Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China. Electronic address: [email protected].
  • 7 Shandong Provincial Key Laboratory of Development and Regeneration, School of Life Science, Shandong University, Qingdao, 266237, PR China. Electronic address: [email protected].
  • 8 Institute of Medical Science, The Second Hospital of Shandong University, Jinan, 250033, PR China. Electronic address: [email protected].
  • 9 Institute of Medical Science, The Second Hospital of Shandong University, Jinan, 250033, PR China. Electronic address: [email protected].
PMID: 41637880 DOI: 10.1016/j.redox.2026.104058
Abstract

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 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.

Keywords

GSTM2; HCY-NBD; Senescence of endothelial cell; Sulfenylation; Ubiquitination.

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