{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:57:39Z","timestamp":1790668659280,"version":"4.1.0"},"reference-count":76,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Fatty acid synthase (FAS), the rate-limiting enzyme of de novo lipogenesis, is now recognized as a multifunctional regulator of cardiovascular homeostasis; its roles extend beyond simple FA biosynthesis to encompass calcium signalling, cholesterol trafficking, and inflammatory modulation. This review synthesizes current understanding of FAS molecular biology, tissue-specific expression, and pathophysiological contributions to cardiovascular disease. Circulating FAS (cFAS) associates with lipoproteins and promotes macrophage foam cell formation independently of low-density lipoprotein cholesterol concentration, establishing a novel atherogenic mechanism. cFAS is primarily hepatic in origin and is released under conditions of enhanced de novo lipogenesis and insulin resistance. Adipose tissue may also contribute through extrusion of FAS. In macrophages, Fasn deletion enhances cholesterol efflux through liver X receptor alpha induction and ATP-binding cassette transporter A1 upregulation, reducing atherosclerosis by 20\u201340% in preclinical models without affecting serum lipids. Vascular smooth muscle cells up-regulate FAS during phenotypic switching, facilitating transformation into foam cells within plaques. Clinical studies have established cFAS as a diagnostic biomarker for peripheral arterial disease, with higher concentrations present in affected individuals; elevated cFAS may also discriminate more severe disease. Despite its pathogenic roles in atherosclerosis, cardiac FAS serves essential stress-adaptive functions through calcium\/calmodulin-dependent protein kinase II regulation, as cardiac-specific Fasn knockout mice exhibit profound stress intolerance and accelerated aging-related cardiac dysfunction, demonstrating that FAS-mediated de novo lipogenesis is indispensable for myocardial stress responses. This observation necessitates tissue-specific therapeutic approaches. Pharmacological FAS inhibitors, including TVB-2640 (denifanstat), demonstrate acceptable safety profiles in clinical trials and reduce hepatic de novo lipogenesis by 50\u201370%, while platensimycin reduces atherosclerotic burden in preclinical models. These findings position FAS as both a mechanistic driver and promising therapeutic target for cardiovascular disease. However, the divergent consequences of FAS modulation across tissues underscore the need for targeted delivery strategies that suppress pathological lipogenesis while preserving essential cardiac functions.<\/jats:p>","DOI":"10.1093\/cvr\/cvag200","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:45:50Z","timestamp":1789127150000},"source":"Crossref","is-referenced-by-count":0,"title":["Fatty acid synthase in cardiovascular disease: from molecular mechanisms to therapeutic targeting"],"prefix":"10.1093","author":[{"given":"Dina","family":"Ibrahim","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Vascular Surgery, Washington University in St. Louis School of Medicine , Campus Box 8109, 660 South Euclid Avenue, St. Louis, Missouri 63110-1093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S","family":"Zaghloul","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Vascular Surgery, Washington University in St. Louis School of Medicine , Campus Box 8109, 660 South Euclid Avenue, St. Louis, Missouri 63110-1093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bera","family":"Koklu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Vascular Surgery, Washington University in St. Louis School of Medicine , Campus Box 8109, 660 South Euclid Avenue, St. Louis, Missouri 63110-1093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Elahi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Vascular Surgery, Washington University in St. Louis School of Medicine , Campus Box 8109, 660 South Euclid Avenue, St. Louis, Missouri 63110-1093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8338-1798","authenticated-orcid":false,"suffix":"Jr.","given":"James L","family":"Januzzi","sequence":"additional","affiliation":[{"name":"Cardiology Division, Massachusetts General Hospital , Boston, Massachusetts ,","place":["USA"]},{"name":"Harvard Medical School , Boston, Massachusetts ,","place":["USA"]},{"name":"Baim Institute for Clinical Research , Boston, Massachusetts ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9860-3584","authenticated-orcid":false,"given":"Marc P","family":"Bonaca","sequence":"additional","affiliation":[{"name":"CPC Clinical Research, Department of Medicine Division of Cardiology, University of Colorado School of Medicine , Aurora, Colorado 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