{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:51:18Z","timestamp":1790729478055,"version":"4.1.0"},"reference-count":71,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,3,3]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Doxorubicin (DOX), an effective chemotherapeutic drug for various cancers, has been demonstrated to induce cardiovascular toxicity in cancer survivors. Endothelial cell (EC) dysfunction is recognized to play a critical role in the onset and severity of cardiotoxicity associated with DOX. TFEB (transcription factor EB), a master regulator of autophagy and lysosome biogenesis, regulates cardiovascular homeostasis. In the present study, we aimed to test whether endothelial TFEB protects against EC damage and alleviates cardiac dysfunction induced by DOX treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      EC-specific TFEB transgenic mice, EC-specific TFEB knockout mice, and their corresponding littermate controls were administered DOX intravenously. Survival curves were generated, and cardiac functions were measured in mice. The effects of TFEB on mitochondrial reactive oxygen species production, autophagic flux, and apoptosis were evaluated in human and mouse cardiac microvascular ECs treated with DOX. RNA sequencing, single-cell RNA sequencing, and chromatin immunoprecipitation with quantitative polymerase chain reaction (ChIP-qPCR) was performed to dissect molecular mechanisms in DOX-treated ECs in vitro and in vivo. Mice with endothelium-specific deficiency of\n                      <jats:italic toggle=\"yes\">Dab2<\/jats:italic>\n                      gene (Disabled homolog 2) were subjected to measurement of cardiac function and fibrosarcoma growth under DOX treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      EC-specific TFEB transgenic mice showed significantly reduced mortality and improved cardiac function, together with attenuation of perivascular fibrosis after DOX treatment. By contrast, EC-specific TFEB knockout exacerbated DOX-induced cardiac dysfunction in mice. Furthermore, we observed that TFEB enhanced autophagy and reduced oxidative stress in cardiac microvascular ECs treated with DOX. In addition, TFEB preserved EC barrier integrity, alleviated proinflammatory cytokine release from cardiac microvascular ECs, and maintained the EC\u2013cardiomyocyte communication, contributing to the protective effects of EC TFEB on cardiomyocyte function. Mechanistically, DAB2, a clathrin- and cargo-binding endocytic adaptor protein, was identified as a TFEB target gene in ECs. Accordingly, DAB2 knockdown attenuated the inhibitory effects of TFEB on apoptosis and the secretion of proinflammatory cytokines from cardiac microvascular ECs. In vivo, EC-specific\n                      <jats:italic toggle=\"yes\">Dab2<\/jats:italic>\n                      deficiency abolished the protective effect of EC TFEB on DOX-induced cardiac dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Taken together, endothelial TFEB protects against EC damage and cardiac dysfunction, constituting a potential target for treating cardiotoxicity induced by DOX. Our study provides new mechanistic insights into cardiotoxicity associated with chemotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.124.071774","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T10:00:12Z","timestamp":1766052012000},"page":"653-672","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Endothelial Transcription Factor EB Protects Against Doxorubicin-Induced Endothelial Toxicity and Cardiac Dysfunction"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-7301","authenticated-orcid":true,"given":"Wa","family":"Du","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Vascular Diseases and Surgery, Davis Lung and Heart Institute (W.D., G.I.K., Y.F.), College of Medicine, The Ohio State University, Columbus."},{"name":"Department of Cancer Biology (W.D., M.R., G.I.K., L.E.T.E., C.W., J.-L.G., Y.F.), College of Medicine, University of Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7029-8630","authenticated-orcid":true,"given":"Madison","family":"Ringer","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology (W.D., M.R., G.I.K., L.E.T.E., C.W., J.-L.G., Y.F.), College of Medicine, University of Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darshini","family":"Desai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology, and Neurobiology (D.D., G.-C.F.), College of Medicine, University of Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Golam Iftakhar","family":"Khandakar","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Vascular Diseases and Surgery, Davis Lung and Heart Institute (W.D., G.I.K., Y.F.), College of Medicine, The Ohio 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