This study investigates the role of pro-ferroptosis signaling in vascular smooth muscle cell (VSMC) senescence and arterial aging. Pro-ferroptosis signaling, characterized by lipid oxidation and ferrous iron accumulation, is activated in senescent VSMCs and aged arteries. The activation of pro-ferroptosis signaling leads to NAD+ loss, vascular remodeling, and aging. Pharmacological or genetic inhibition of pro-ferroptosis signaling ameliorates VSMC senescence, reduces vascular stiffness, and delays abdominal aortic aneurysm progression in mice. Mechanistically, pro-ferroptosis signaling promotes the nuclear-cytoplasmic shuttling of peroxisome proliferator-activated receptor-γ (PPARγ) and impairs ferritinophagy through the NCOA4-ferritin complex. Additionally, pro-ferroptosis signaling is correlated with arterial stiffness in a human proof-of-concept study. These findings highlight the therapeutic potential of targeting ferroptosis signaling to counteract vascular aging and associated cardiovascular diseases.This study investigates the role of pro-ferroptosis signaling in vascular smooth muscle cell (VSMC) senescence and arterial aging. Pro-ferroptosis signaling, characterized by lipid oxidation and ferrous iron accumulation, is activated in senescent VSMCs and aged arteries. The activation of pro-ferroptosis signaling leads to NAD+ loss, vascular remodeling, and aging. Pharmacological or genetic inhibition of pro-ferroptosis signaling ameliorates VSMC senescence, reduces vascular stiffness, and delays abdominal aortic aneurysm progression in mice. Mechanistically, pro-ferroptosis signaling promotes the nuclear-cytoplasmic shuttling of peroxisome proliferator-activated receptor-γ (PPARγ) and impairs ferritinophagy through the NCOA4-ferritin complex. Additionally, pro-ferroptosis signaling is correlated with arterial stiffness in a human proof-of-concept study. These findings highlight the therapeutic potential of targeting ferroptosis signaling to counteract vascular aging and associated cardiovascular diseases.