• H₂S donor GYY4137 reverses Ang II-induced endothelial dysfunction by restoring SIRT6 expression and suppressing inflammation.
• Endothelial-specific CSE deficiency leads to vascular inflammation and dysfunction, which is rescued by H₂S supplementation.
• SIRT6 inhibitors abolish the protective effects of H₂S, confirming the pathway's necessity.
• The study identifies the H₂S-SIRT6 anti-inflammatory axis as a potential therapeutic target for hypertension-related endothelial damage.