• • GYY4137 (H₂S donor) reverses Ang II-induced endothelial damage by restoring SIRT6 expression, suppressing IL-6 and ICAM-1, and improving vasodilation; this identifies a druggable pathway for hypertension where current therapies fail to target inflammation.
• • Endothelial-specific CSE-deficient mice display spontaneous inflammation and endothelial dysfunction, reversed by H₂S supplementation, establishing CSE/H₂S as a critical endogenous brake on vascular inflammation.
• • SIRT6 inhibitors completely block the protective effects of H₂S, confirming that SIRT6 is the obligatory downstream mediator; this suggests SIRT6 activators could mimic H₂S benefits without gas-donor liabilities.
• • The study provides mechanistic evidence that H₂S supplementation restores NO bioavailability and reduces adhesion molecule expression, offering a potential adjunct to angiotensin receptor blockers for resistant hypertension.