{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T23:16:58Z","timestamp":1792279018624,"version":"4.4.0"},"reference-count":186,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Doxorubicin (DOX), a highly effective anthracycline chemotherapy drug, has its clinical application severely restricted by dose-dependent doxorubicin-induced cardiotoxicity (DIC). Ferroptosis, an iron-dependent, lipid peroxidation-driven regulated cell death, has been confirmed as a core pathological mechanism in DIC, where it synergistically participates with multiple cell death modalities in myocardial injury. This review systematically elaborates the multidimensional molecular mechanisms underlying DOX-induced myocardial ferroptosis, including: lipid peroxidation cascade self-amplification, bidirectional regulation by selective autophagy, multilayered GPX4 modification and stability regulation, and involvement of the gut microbiota-heart axis. Concurrently, we summarize evidence for natural phytochemicals\u2014including flavonoids, polyphenols, terpenoids, and traditional Chinese medicine compounds\u2014that inhibit myocardial ferroptosis via multi-target mechanisms, providing theoretical support for phytochemical-based DIC intervention. Critically, this review addresses the clinical translation dilemmas in ferroptosis regulation and proposes three innovative strategies: (1) time-decoupling strategy based on IFN-\u03b3 signaling; (2) cardiac-targeted nanodrug delivery system employing the OGF\/OGFR axis; (3) cross-regulation between ferroptosis and other regulated cell death pathways. These strategies aim to achieve tissue-selective ferroptosis intervention, simultaneously protecting myocardium while maintaining DOX anti-tumor efficacy, thereby providing molecular mechanistic basis and clinical translational directions for constructing precision ferroptosis-targeted cardioprotective strategies.<\/jats:p>","DOI":"10.3389\/fphar.2026.1852342","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T08:21:08Z","timestamp":1782980468000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Ferroptosis regulation in doxorubicin-induced cardiotoxicity: multi-mechanism interventions and translational strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"XiaoJie","family":"Chen","sequence":"first","affiliation":[{"name":"School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, Gansu, China"]},{"name":"Laboratory of Traditional Chinese and Western Medicine, Gansu Provincial Hospital","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YuYuan","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YiYuan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YuShun","family":"Kou","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YuanHui","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Gansu Provincial Hospital","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Yi","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, Gansu, China"]},{"name":"Chronic Disease Laboratory, Gansu University of Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"B1","first-page":"175","article-title":"Hesperidin alleviates doxorubicin-induced cardiotoxicity in rats","volume":"21","author":"Abdel-Raheem","year":"2009","journal-title":"J. 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