Background <p>Despite advances in antihypertensive therapies, uncontrolled hypertension remains a major global health challenge, particularly among older adults. Ferroptosis, an iron-dependent programmed cell death, has been implicated in age-related vascular dysfunction, but its regulatory mechanisms in hypertension are unclear. This study investigates Sestrin2, a highly conserved stress-induced protein linked to cellular senescence, in regulating ferroptosis in hypertension.</p> Methods <p>Angiotensin II (Ang II)-induced hypertensive mouse model and human umbilical vein endothelial cells (HUVECs) were established. Blood pressure was measured via the tail-cuff system, and vascular injury was assessed by H&amp;E staining. Ferroptosis markers (ROS, Fe²⁺, MDA, and GSH) and mitochondrial morphology were analyzed. Co-immunoprecipitation assays (Co-IP) were used to analyze the interaction between Sestrin2 and AMPK in HUVECs cells.</p> Results <p>Sestrin2 and ferroptosis were elevated in hypertensive mice and HUVECs. Inhibition of ferroptosis using ferrostatin-1 (Fer-1) improved angiotensin II-induced hypertension. Furthermore, Sestrin2 colocalized with the endothelial cell marker CD31 in the thoracic aortas. Overexpression of Sestrin2 inhibited, whereas its knockdown promoted, ferroptosis in Ang II-induced HUVECs. Additionally, Sestrin2 overexpression partially restored normal mitochondrial morphology. Co-IP experiments revealed that Sestrin2 interacts with AMP-activated protein kinase (AMPK). Moreover, the AMPK inhibitor Compound C significantly downregulated nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and FTH1 expression, and upregulated Fe²⁺ levels. In vivo, Sestrin2 overexpression prevented Ang II-induced ferroptosis and hypertension.</p> Conclusions <p>Sestrin2 inhibits ferroptosis to prevent hypertension by activating the AMPK/Nrf2/GPX4 pathway, suggesting its potential as a therapeutic target for hypertension.</p>