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Targeting IRE1 alone reduced tumor growth and, combined with doxorubicin, did not interfere with the oncologic efficacy of this drug. We observed that increased activation of caspase\u20103 was consistently activated by IRE1 in tumors regardless of diet and combination treatment. Furthermore, the blockade of IRE1 mitigated chemotherapy\u2010induced cardiotoxicity by preserving systolic dysfunction, reducing cardiac fibrosis, and preventing cell death. The potential difference in cell death mechanisms observed between the heart and tumors may be associated with different levels of oxidative stress as measured by 4HNE in our in\u00a0vivo model. Thus, systemic IRE1 suppression protected cardiac tissue while preserving the oncologic efficacy of anthracyclines.<\/jats:p>","DOI":"10.14814\/phy2.70400","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T05:35:09Z","timestamp":1758519309000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dietary influences on chemotherapy sensitivity and cardiotoxicity modulated by <scp>IRE1<\/scp> targeting in triple\u2010negative breast cancer in female mice"],"prefix":"10.14814","volume":"13","author":[{"given":"Yismeilin R.","family":"Feliz\u2010Mosquea","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Department of Surgery Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam S.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Surgery Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nildris","family":"Cruz\u2010Diaz","sequence":"additional","affiliation":[{"name":"Department of Surgery Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie S.","family":"Payne","sequence":"additional","affiliation":[{"name":"Department of Surgery Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine L.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Surgery Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Department of Cancer Biology Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0107-7678","authenticated-orcid":false,"given":"David R.","family":"Soto\u2010Pantoja","sequence":"additional","affiliation":[{"name":"Department of Surgery Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Department of Cancer Biology Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,21]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"142","article-title":"The epidemic of obesity and diabetes: Trends and treatments","volume":"38","author":"Barnes A. 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