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Despite success in improving cancer survival rates, anthracyclines have dose-limiting cardiotoxicity that prevents more widespread clinical utility. Currently, the therapeutic options for these patients are limited to the iron-chelating agent dexrazoxane, the only FDA-approved drug for anthracycline cardiotoxicity. However, the clinical use of dexrazoxane has failed to replicate expectations from preclinical studies. A limited list of GPCRs have been identified as pathogenic in anthracycline-induced cardiotoxicity, including receptors (frizzled, adrenoreceptors, angiotensin II receptors) previously implicated in cardiac remodeling in other pathologies. The RNA sequencing of iPSC-derived cardiac myocytes from patients has increased our understanding of the pathogenic mechanisms driving cardiotoxicity. These data identified changes in the expression of novel GPCRs, heterotrimeric G proteins, and the regulatory pathways that govern downstream signaling. This review will capitalize on insights from these experiments to explain aspects of disease pathogenesis and cardiac remodeling. These data provide a cornucopia of possible unexplored potential pathways by which we can reduce the cardiotoxic side effects, without compromising the anti-cancer effects, of doxorubicin and provide new therapeutic options to improve the recovery and quality of life for patients undergoing chemotherapy.<\/jats:p>","DOI":"10.3390\/cells14030169","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T09:52:20Z","timestamp":1737539540000},"page":"169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Role of GPCR Signaling in Anthracycline-Induced Cardiotoxicity"],"prefix":"10.3390","volume":"14","author":[{"given":"Nimish","family":"Biswal","sequence":"first","affiliation":[{"name":"School of Medicine, Xavier University at Aruba, Oranjestad, Aruba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ritika","family":"Harish","sequence":"additional","affiliation":[{"name":"Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minahil","family":"Roshan","sequence":"additional","affiliation":[{"name":"School of Medicine, Xavier University at Aruba, Oranjestad, Aruba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathvik","family":"Samudrala","sequence":"additional","affiliation":[{"name":"School of Medicine, Xavier University at Aruba, Oranjestad, Aruba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanmao","family":"Jiao","sequence":"additional","affiliation":[{"name":"School of Medicine, Xavier University at Aruba, Oranjestad, Aruba"},{"name":"Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3244-8777","authenticated-orcid":false,"given":"Richard G.","family":"Pestell","sequence":"additional","affiliation":[{"name":"School of Medicine, Xavier University at Aruba, Oranjestad, Aruba"},{"name":"Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA"},{"name":"The Wistar Institute, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6063-1566","authenticated-orcid":false,"given":"Anthony W.","family":"Ashton","sequence":"additional","affiliation":[{"name":"School of Medicine, Xavier University at Aruba, Oranjestad, Aruba"},{"name":"Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA"},{"name":"Division of Perinatal Research, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW 2065, Australia"},{"name":"Division of Cardiovascular Medicine, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1158\/1055-9965.EPI-19-1318","article-title":"Prevalence of Healthy Behaviors among Cancer Survivors in the United States: How Far Have We Come?","volume":"29","author":"Arem","year":"2020","journal-title":"Cancer Epidemiol. Biomark. 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