{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:31:03Z","timestamp":1789183863434,"version":"build-2803163510"},"reference-count":451,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Doxorubicin, a secondary metabolite of\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">Streptomyces peucetius<\/jats:styled-content>\n                      var. caesius\n                    <\/jats:italic>\n                    and a member of the anthracycline family, exerts anticancer effects via DNA intercalation and topoisomerase II inhibition in tumor cells. However, its clinical application is limited by dose\u2010dependent and cumulative cardiotoxicity. The mechanisms underlying doxorubicin\u2010induced cardiotoxicity (DIC) include oxidative stress, lipid peroxidation, mitochondrial dysfunction, calcium dysregulation, disrupted iron homeostasis, nitric oxide release, and inflammatory mediator production. Emerging evidence highlights autophagy dysregulation, with doxorubicin upregulating cardiac autophagy by suppressing GATA4 and ribosomal protein S6 kinase beta\u20101(S6K1). Mitochondria\u2010dependent ferroptosis also plays a significant role, driven by downregulation of glutathione peroxidase 4 (GPX4), lipid peroxidation via DOX\u2010Fe\n                    <jats:sup>2+<\/jats:sup>\n                    complexes, and dysregulated iron metabolism. Additionally, DOX triggers pyroptosis in cardiomyocytes, involving proteins such as NLRP3 (NOD\u2010, LRR\u2010, and pyrin domain\u2010containing protein 3), caspase\u20103, and gasdermin D (GSDMD). Epigenetic alterations, including DNA hypomethylation (via downregulation of DNMT1 (DNA (cytosine\u20105)\u2010methyltransferase 1), changes in microRNA levels (e.g., upregulation of miR\u2010520h targeting HDAC19 (histone deacetylase 1), and histone deacetylase inhibition, exacerbate cardiac damage. Recent studies also emphasize the role of gut microbiota in doxorubicin\u2010induced cardiotoxicity. Doxorubicin induces dysbiosis, leading to cardiomyocyte apoptosis and elevated myocardial enzyme levels. Interventions such as dietary modifications, fecal microbiota transplantation, probiotics, and natural compounds like glabridin and emodin show promise. Glabridin reduces inflammation by modulating colonic macrophage polarization, while emodin inhibits ferroptosis via gut microbiota remodeling mediated by Nrf2. This review explores oxidative stress, lipid peroxidation, ferroptosis, apoptosis, inflammation, autophagy, epigenetics, and gut microbiota in DIC, alongside promising pharmacological strategies to mitigate its effects.\n                  <\/jats:p>","DOI":"10.1002\/jat.70131","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T08:20:35Z","timestamp":1773217235000},"page":"1801-1837","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Doxorubicin\u2010Induced Cardiotoxicity: Comprehensive Pathway Insights and Advanced Preclinical Therapeutics"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9641-4127","authenticated-orcid":false,"given":"Seema","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shri Vaishnav Vidyapeeth Vishwavidyalaya  Indore Madhya Pradesh 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