{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:01:59Z","timestamp":1789603319239,"version":"build-2803163510"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente grant, \u201cCardio-oncologia traslazionale e clinica: ricerca preclinica e clinica della cardiotossicit\u00e0 da farmaci anti-tumorali e strategie di cardioprotezione innovative \u201d LINEA 1\/13_26 funded by Ministero della Salute (Italy)."],"award-info":[{"award-number":["Ricerca Corrente grant, \u201cCardio-oncologia traslazionale e clinica: ricerca preclinica e clinica della cardiotossicit\u00e0 da farmaci anti-tumorali e strategie di cardioprotezione innovative \u201d LINEA 1\/13_26 funded by Ministero della Salute (Italy)."]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Ricerca Corrente grant, \u201cCardio-oncologia traslazionale e clinica: ricerca preclinica e clinica della cardiotossicit\u00e0 da farmaci anti-tumorali e strategie di cardioprotezione innovative \u201d LINEA 1\/13_26 funded by Ministero della Salute (Italy)."],"award-info":[{"award-number":["Ricerca Corrente grant, \u201cCardio-oncologia traslazionale e clinica: ricerca preclinica e clinica della cardiotossicit\u00e0 da farmaci anti-tumorali e strategie di cardioprotezione innovative \u201d LINEA 1\/13_26 funded by Ministero della Salute (Italy)."]}],"id":[{"id":"https:\/\/ror.org\/00789fa95","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Activating PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)\/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3K\u03b1-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium\u2013glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3K\u03b1-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3K\u03b1 inhibitor-induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 \u03bcM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (\u0394\u03a8m) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1\u03b2, IL-18, IL-6, TNF-\u03b1, and CCL2) were quantified by ELISA. Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3-mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1\u03b2, IL-18, IL-6, TNF-\u03b1, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. This study provides evidence that alpelisib-based therapy under hyperglycemic conditions is associated with oxidative, mitochondrial, and inflammatory stress responses in human cardiomyocytes, recapitulating key features of cardiometabolic stress relevant to PI3K\u03b1-targeted therapy. Importantly, dapagliflozin markedly attenuated these alterations, supporting a potential cardioprotective role that may extend beyond glycemic control. These findings provide a mechanistic rationale for further investigation of SGLT2 inhibition as a cardiometabolic protective strategy in patients receiving PI3K\u03b1 inhibitor-based cancer therapy.<\/jats:p>","DOI":"10.3390\/ijms27083597","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:30:36Z","timestamp":1776443436000},"page":"3597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SGLT2 Inhibitor Dapagliflozin Attenuates Cardiomyocyte Injury and Inflammation Induced by PI3K\u03b1-Selective Inhibitor Alpelisib and Fulvestrant Under Hyperglycemia"],"prefix":"10.3390","volume":"27","author":[{"given":"Vincenzo","family":"Quagliariello","sequence":"first","affiliation":[{"name":"Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-9148","authenticated-orcid":false,"given":"Massimiliano","family":"Berretta","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8941-1975","authenticated-orcid":false,"given":"Matteo","family":"Barbato","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Maurea","sequence":"additional","affiliation":[{"name":"Radiology Division, University of Aquila, 67100 Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0990-6397","authenticated-orcid":false,"given":"Maria Laura","family":"Canale","sequence":"additional","affiliation":[{"name":"U.O.C. Cardiologia, Ospedale Versilia, 55041 Lido di Camaiore (LU), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Paccone","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0689-0695","authenticated-orcid":false,"given":"Irma","family":"Bisceglia","sequence":"additional","affiliation":[{"name":"Servizi Cardiologici Integrati, Dipartimento Cardio-Toraco-Vascolare, Azienda Ospedaliera San Camillo Forlanini, 00152 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0315-3304","authenticated-orcid":false,"given":"Andrea","family":"Tedeschi","sequence":"additional","affiliation":[{"name":"Cardiology, \u201cGuglielmo da Saliceto\u201d Hospital, 29121 Piacenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marino","family":"Scherillo","sequence":"additional","affiliation":[{"name":"Cardiologia Interventistica e Unit\u00e0 di Terapia Intensiva Cardiologica (UTIC), A.O. 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Pascale, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.cell.2017.07.029","article-title":"The PI3K Pathway in Human Disease","volume":"170","author":"Fruman","year":"2017","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/nrd4204","article-title":"PI3K and cancer: Lessons, challenges and opportunities","volume":"13","author":"Fruman","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ascione, L., Zagami, P., Nicol\u00f2, E., Crimini, E., Curigliano, G., and Criscitiello, C. (2022). PIK3CAMutations in Breast Cancer Subtypes Other Than HR-Positive\/HER2-Negative. J. Pers. 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