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The exogenous activation of autophagy was reported to exert cardioprotective effects in preclinical models of cardiovascular diseases. We tested whether restoration of autophagy by different pharmacological approaches can reduce DOX-induced cardiomyopathy. A validated preclinical murine model of DOX-induced cardiotoxicity (final cumulative dose of 15\u00a0mg\/kg) was used to test the cardiac effects of both natural (trehalose and spermidine) and synthetic (Tat-Beclin 1 D11) activators of autophagy. Cardiac function was evaluated by echocardiographic analyses. We performed histological analyses (Masson trichrome staining, TUNEL assay) to investigate fibrosis and apoptosis. Biomolecular analyses, confocal and transmission electron microscopy were used to assess levels of autophagy, autophagic flux, mitophagy and mitochondrial alterations. We also evaluated the effects of autophagy activators in a validated syngeneic model with subcutaneous injection of breast cancer cells treated with DOX. We found that DOX-induced cardiotoxicity is associated with impaired autophagic flux (accumulation of LC3-II and p62). Reactivation of autophagic flux by trehalose or spermidine rescues cardiac function and cardiomyocyte survival in mice treated with DOX, along with an overall amelioration of mitochondrial health and mitophagy. Selective reactivation of autophagy by Tat-Beclin 1 D11 also recapitulates the protective effects exerted by trehalose and spermidine. Autophagy activators preserve cardiac function without affecting the antineoplastic effects of DOX in mice with cancer. Boosting autophagic flux is a suitable therapeutic approach to prevent cardiotoxicity induced by anthracyclines.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s00395-026-01174-9","type":"journal-article","created":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T05:33:41Z","timestamp":1774762421000},"page":"523-539","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacological reactivation of autophagic flux by natural compounds or synthetic cell-permeable peptide prevents doxorubicin-induced cardiomyopathy"],"prefix":"10.1007","volume":"121","author":[{"given":"Leonardo","family":"Schirone","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Vecchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Valenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Picchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Schiavon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"D\u2019Ambrosio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"di Nonno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selenia","family":"Miglietta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Relucenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Madaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Palmerio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Cozzolino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Litterio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianmarco","family":"Sarto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Simeone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Moro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shazia","family":"Tahir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Zaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe Biondi","family":"Zoccai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"De Falco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Petrozza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Greco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Frati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Forte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Sciarretta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"key":"1174_CR1","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1089\/ars.2013.5416","volume":"21","author":"AM Andres","year":"2014","unstructured":"Andres AM, Hernandez G, Lee P, Huang C, Ratliff EP, Sin J, Thornton CA, Damasco MV, Gottlieb RA (2014) Mitophagy is required for acute cardioprotection by simvastatin. 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