CSE‐Derived Hydrogen Sulfide Safeguards Vascular Iron Homeostasis by Coupling Ferritin Buffering to Vasoprotection

ABSTRACT Iron overload drives oxidative stress and vascular injury, yet the role of hydrogen sulfide (H 2 S) in systemic and vascular iron regulation remains unclear. We investigated how cystathionine γ‐lyase (CSE)‐derived H 2 S influences iron handling and vascular responses following acute iron overload. Wild‐type (WT) and CSE‐knockout (CSE‐KO) mice received PBS, low‐concentration (1×) or high‐concentration (3×) iron dextran intravenously. CSE‐KO mice exhibited elevated serum iron and transferrin saturation but impaired ferritin upregulation compared to WT. KO aortas showed greater iron deposition, elastin degradation, and inflammatory remodeling under high iron. Iron overload impaired phenylephrine‐induced vasocontraction and H 2 S‐mediated vasorelaxation, with CSE‐KO mice displaying the most severe vascular dysfunction and elevated blood pressure. WT mice compensated via CSE upregulation and increased H 2 S production. Our findings demonstrate that CSE/H 2 S deficiency disrupts ferritin‐mediated iron storage, exacerbates vascular iron accumulation, and worsens vasomotor dysfunction during iron overload. The CSE/H 2 S pathway may represent a therapeutic target for mitigating iron‐induced vascular damage.