Hydrogen sulfide promotes S-sulfhydration of TrxR1 and attenuates diabetic vascular remodeling

Abstract Diabetic vasculopathy represents one of the most serious complications of type 2 diabetes mellitus (T2DM). Growing evidence suggests that its pathogenesis is closely linked to chronic inflammation-driven phenotypic switching of vascular smooth muscle cells (VSMCs), which under hyperglycemic conditions exhibit heightened proliferative and migratory activity. While hydrogen sulfide (H₂S) is known for its antioxidant and anti-inflammatory roles in diabetic vasculopathy, the specific mechanisms by which H₂S alleviates these abnormal VSMCs phenotypes in T2DM remain unclear. Using T2DM mice and mouse aortic vascular smooth muscle cells (MOVAS) cultured under high-glucose-high-fat (HGHF) conditions, we observed a marked decrease in both the expression of the H₂S-synthesizing enzyme cystathionine γ-lyase (CSE) and endogenous H₂S production. These changes were accompanied by elevated oxidative stress, activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, and enhanced MOVAS proliferation and migration. Notably, the H₂S donor NaHS reversed these changes. Further investigation into protein S-sulfhydration revealed that H₂S promotes the S-sulfhydration of thioredoxin reductase 1 (TrxR1). Through pharmacological inhibition and rescue experiments, we demonstrated that H₂S mediates S-sulfhydration at the Cys611 residue of TrxR1, thereby regulating its enzymatic activity and influencing the thioredoxin 1 (Trx1)–thioredoxin-interacting protein (TXNIP)–NLRP3 signaling axis. This process leads to suppression of inflammasome activation and contributes to the antioxidant, anti-inflammatory, anti-migratory, and anti-proliferative effects observed in MOVAS. Our study reveals a novel pathway whereby H₂S alleviates diabetic vascular complications via TrxR1 S-sulfhydration at Cys611 and subsequent inhibition of the Trx1–TXNIP–NLRP3 axis, highlighting a promising therapeutic target.