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Previous studies have suggested that the key enzyme in this pathway, farnesyl diphosphate synthase (FDPS), regulates the cardiovascular system. We used human samples and mice that were deficient in cardiac FDPS (<jats:italic>c\u2010Fdps<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice) to investigate the role of FDPS in cardiac homeostasis. Cardiac function was assessed using echocardiography. Left ventricles were examined and tested for histological and molecular markers of cardiac remodeling. Our results showed that FDPS levels were downregulated in samples from patients with cardiomyopathy. Furthermore, <jats:italic>c\u2010Fdps<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice exhibited cardiac remodeling and dysfunction. This dysfunction was associated with abnormal activation of Ras and Rheb, which may be due to the accumulation of geranyl pyrophosphate. Activation of Ras and Rheb stimulated downstream mTOR and ERK pathways. Moreover, administration of farnesyltransferase inhibitors attenuated cardiac remodeling and dysfunction in <jats:italic>c\u2010Fdps<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. These results indicate that FDPS plays an important role in cardiac homeostasis. Deletion of FDPS stimulates the downstream mTOR and ERK signaling pathways, resulting in cardiac remodeling and dysfunction. \u00a9 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5789","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T02:45:48Z","timestamp":1630464348000},"page":"438-450","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Cardiac\u2010specific deletion of <scp>FDPS<\/scp> induces cardiac remodeling and dysfunction by enhancing the activity of small <scp>GTP<\/scp>\u2010binding proteins"],"prefix":"10.1002","volume":"255","author":[{"given":"Xiying","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology The First Affiliated Hospital, College of Medicine, Zhejiang University  Hangzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology The First Affiliated Hospital, College of Medicine, Zhejiang University  Hangzhou PR 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