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Vulnerable atherosclerotic plaques represent a critical pathological basis of acute cardiocerebrovascular events. Previous studies indicate that atherosclerotic plaques are more vulnerable under chronic kidney disease (CKD) milieus. Emerging evidence highlights that vascular smooth muscle cells (VSMCs) play a pivotal role in maintaining plaque stability, but the underlying mechanisms remain incompletely elucidated. Here, single-cell sequencing and functional enrichment analysis of arterial tissues from patients with CKD are performed, identifying lipid metabolism disorders in VSMCs. Further utilizing spatial and targeted lipidomics, apolipoprotein-E-deficient (ApoE ^-/-) mouse with CKD (CKD/ApoE ^-/- mouse) and bioinformatics analysis, we investigate the lipidomic profile of VSMCs and find that VSMCs in CKD-associated vulnerable plaques exhibit significant accumulation of polyunsaturated fatty acids (PUFAs), which induces VSMC ferroptosis and exacerbates plaque vulnerability. Mechanistically, the deficiency of ECH1 leads to the accumulation of PUFA in VSMCs, thereby inducing ferroptosis in fibrous cap VSMCs and fibrous cap thinning. Meanwhile, low expression of mRNA binding protein human antigen R (HuR) resulting from CKD milieus mediates the lack of ECH1 in VSMCs. In contrast, VSMC-specific overexpression of ECH1, inhibition of PUFA release using giripladib or suppression of PUFA lipid peroxidation with PRGL493 significantly alleviate VSMC ferroptosis and CKD-associated plaque vulnerability. These findings reveal that ECH1-deficiency-driven PUFA accumulation is responsible for VSMC ferroptosis and atherosclerotic plaque vulnerability. Targeted regulation of ECH1-mediated PUFA metabolism may be a promising preventive and therapeutic strategy for CKD-associated plaque vulnerability.