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Hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) is an endogenous gaseous transmitter that exerts cardioprotective effects via the regulation of oxidative stress and apoptosis and maintenance of mitochondrial function, among other mechanisms. AP39 is a novel mitochondria-targeted H<jats:sub>2<\/jats:sub>S donor that, at appropriate concentrations, attenuates intracellular oxidative stress damage, maintains mitochondrial function, and ameliorates cardiomyocyte injury. In this study, DOX-induced cardiotoxicity models were established using H9c2 cells and Sprague\u2013Dawley rats to evaluate the protective effect of AP39 and its mechanisms of action. Both in vivo and in vitro experiments showed that DOX induces oxidative stress injury, apoptosis, and mitochondrial damage in cardiomyocytes and decreases the expression of p-AMPK\/AMPK and UCP2. All DOX-induced changes were attenuated by AP39 treatment. Furthermore, the protective effect of AP39 was significantly attenuated by the inhibition of AMPK and UCP2. The results suggest that AP39 ameliorates DOX-induced cardiotoxicity by regulating the expression of AMPK\/UCP2.<\/jats:p>","DOI":"10.1371\/journal.pone.0300261","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T17:32:10Z","timestamp":1712165530000},"page":"e0300261","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["AP39, a novel mitochondria-targeted hydrogen sulfide donor ameliorates doxorubicin-induced cardiotoxicity by regulating the AMPK\/UCP2 pathway"],"prefix":"10.1371","volume":"19","author":[{"given":"Bin","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangxue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7304-6806","authenticated-orcid":true,"given":"Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,3]]},"reference":[{"key":"pone.0300261.ref001","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s12918-017-0464-7","article-title":"A systematic analysis of FDA-approved anticancer drugs.","volume":"11","author":"J Sun","year":"2017","journal-title":"BMC Syst Biol"},{"key":"pone.0300261.ref002","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jaccao.2022.01.101","article-title":"The role of cardioprotection in cancer therapy cardiotoxicity: JACC: cardiooncology state-of-the-art review.","volume":"4","author":"T Omland","year":"2022","journal-title":"JACC CardioOncol"},{"key":"pone.0300261.ref003","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13104-018-3260-6","article-title":"Pegylated and liposomal doxorubicin is associated with high mortality and causes limited cardiotoxicity in mice.","volume":"11","author":"C Stark","year":"2018","journal-title":"BMC Research Notes"},{"key":"pone.0300261.ref004","doi-asserted-by":"crossref","first-page":"111708","DOI":"10.1016\/j.biopha.2021.111708","article-title":"Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management.","volume":"139","author":"PS Rawat","year":"2021","journal-title":"Biomedicine & Pharmacotherapy"},{"key":"pone.0300261.ref005","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1093\/jpp\/rgac063","article-title":"Doxorubicin-induced cardiotoxicity: causative factors and possible interventions","volume":"74","author":"IC Jones","year":"2022","journal-title":"Journal of Pharmacy and Pharmacology"},{"key":"pone.0300261.ref006","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.biopha.2017.04.033","article-title":"Cardioprotective mechanisms of phytochemicals against doxorubicin-induced cardiotoxicity.","volume":"90","author":"AI Abushouka","year":"2017","journal-title":"Biomed Pharmacother"},{"issue":"10","key":"pone.0300261.ref007","doi-asserted-by":"crossref","first-page":"635","DOI":"10.3389\/fphar.2019.00635","article-title":"Mesenchymal Stem Cell Therapy for Doxorubicin-Induced Cardiomyopathy: Potential Mechanisms, Governing Factors, and Implications of the Heart Stem Cell Debate.","volume":"14","author":"AI Abushouk","year":"2019","journal-title":"Front Pharmacol."},{"key":"pone.0300261.ref008","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1159\/000501195","article-title":"Use of Cardioprotective Dexrazoxane Is Associated with Increased Myelotoxicity in Anthracycline- Treated Soft-Tissue Sarcoma Patients.","volume":"64","author":"MS Ceruso","year":"2019","journal-title":"Chemotherapy"},{"key":"pone.0300261.ref009","first-page":"934231","article-title":"Hydrogen sulfide: A new therapeutic target in vascular diseases.","volume":"13","author":"CL Zhu","journal-title":"Front. 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