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Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>\n                    The loss of smooth muscle cell (SMC) contractile phenotype contributes to various diseases including atherosclerosis. However, its metabolic basis is not entirely elucidated. Since the transforming growth factor beta (TGF\u03b2) signaling is among principal regulators of SMC contractility, we studied metabolic regulation of TGF\u03b2 signaling in SMCs in vitro and atherosclerotic mouse models and human lesions. We found that TGF\u03b2 induced Ac-CoA synthetase 2 (ACSS2)-dependent Ac-CoA production, by suppressing pyruvate dehydrogenase kinase 4 (PDK4). This stabilized R-SMADs and TGF\u03b2 receptor 1, preserving SMC contractile phenotype. SMC-specific PDK4 knockout mimicked the effect of TGF\u03b2 signaling both metabolically and phenotypically, increasing glucose-derived synthesis of Ac-CoA and SMC contractile phenotype. SMC-specific\n                    <jats:italic toggle=\"yes\">Pdk4<\/jats:italic>\n                    knockout in\n                    <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                    knockout mice reduced atherosclerosis. Furthermore, human specimens demonstrated a strong correlation between PDK4 level and atherosclerosis severity. These findings indicate that continuous SMC TGF\u03b2 signaling, critical to the maintenance of the normal SMC contractile state, is regulated by PDK4 and carbohydrate metabolism.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aef6065","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:59:39Z","timestamp":1787767179000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic control of smooth muscle cell phenotype switching in atherosclerosis"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9904-7540","authenticated-orcid":true,"given":"Rong-Mo","family":"Zhang","sequence":"first","affiliation":[{"name":"Yale University, New Haven, CT, 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