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The pathological progression of AAA is closely attributed to the phenotypic switching of vascular smooth muscle cells (VSMCs). NFS1 is the rate\u2010limiting enzyme for the synthesis of iron\u2010sulfur proteins, and the roles of NFS1 in AAA initiation and development have not been explored. Angiotensin II (Ang II) infusion\u2010induced AAA animal model with\n                    <jats:italic>Apoe<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice combined with human thoracic aorta samples are used to analyze the role of NFS1 in AAA development. Gain or loss\u2010of\u2010function studies are conducted to investigate the regulatory roles of NFS1 on SMC phenotypic switching at both cellular and animal levels. CUT&amp;Tag is further performed for identifying the targets of NFS1 involved in AAA progression. NFS1 is downregulated in the abdominal aortic tissues from both patients and mice. Defects in NFS1 in VSMCs led to enhanced glycolysis and impaired mitochondrial function, contributing to the phenotypic transformation of VSMCs. Mechanistically, NFS1 functions as a transcriptional cofactor of SP2 for inducing the transcription of\n                    <jats:italic>Idh2<\/jats:italic>\n                    . Inhibition of IDH2 partially attenuated the protective effect of NFS1 on AAA. This study uncovers a crucial role for NFS1 in the development and progression of AAA, suggesting that NFS1 may serve as a novel therapeutic and prognostic marker for this condition.\n                  <\/jats:p>","DOI":"10.1002\/advs.202505240","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T19:01:26Z","timestamp":1770231686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NFS1 Regulates IDH2 to Attenuate Abdominal Aortic Aneurysms via Interacting With SP2"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7421-4767","authenticated-orcid":false,"given":"Luzheng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery Renji Hospital School of Medicine Shanghai Jiao Tong University  Shanghai 200127 P. R. 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