ResearchMar 29, 20261 views

Pharmacological reactivation of autophagic flux by natural compounds or synthetic cell-permeable peptide prevents doxorubicin-induced cardiomyopathy.

Peptides and autophagy are getting real attention in cardioprotection research. Schirone and colleagues just showed that a synthetic cell-permeable peptide, Tat-Beclin 1 D11, can prevent doxorubicin-induced cardiomyopathy by restoring autophagic flux in mice. This matters for anyone interested in limiting the side effects of anthracyclines, a mainstay in cancer therapy.

Basic Res Cardiol

by Schirone L, Vecchio D, Valenti V et al.

“Pharmacological reactivation of autophagic flux by natural compounds or synthetic cell-permeable peptide prevents doxorubicin-induced cardiomyopathy. Schirone L(#)(1), Vecchio D(#)(2), Valenti V(#)(2)(3), Picchio V(2), Schiavon S(4), D'Ambrosio L(4), di Nonno F(4), Miglietta S(5), Relucenti M(5), Madaro L(5), Palmerio S(6), Cozzolino C(2), Litterio M(4), Sarto G(7), Simeone B(7), Moro N(8), Tahir S(9), Zaglia T(8), Zoccai GB(2)(3), De Falco E(2)(3), Petrozza V(2), Greco E(1), Frati G(2)(4), Forte M(10), Sciarretta S(11)(12). Author information: (1)Department of Health and Life Sciences, European University of Rome, Rome, Italy. (2)Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso Della Repubblica 79, Latina, Italy. (3)Maria Cecilia Hospital, GVM Care and Research, Cotignola, Italy. (4)Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, Italy. (5)Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy. (6)Department of Medicine, University of Verona School of Medicine, Verona University Hospital Trust, Verona, Italy. (7)Cardiology Division, ICOT Istituto "Marco Pasquali" University Hospital, Latina, Italy. (8)Department of Biomedical Sciences, University of Padua, Padua, Italy. (9)University of Palermo, Palermo, Italy. (10)Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, Italy. Maurizio.forte@neuromed.it. (11)Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso Della Repubblica 79, Latina, Italy. Sebastiano.sciarretta@uniroma1.it. (12)Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, Italy. Sebastiano.sciarretta@uniroma1.it. (#)Contributed equally Therapeutic strategies to limit doxorubicin (DOX)-induced cardiomyopathy are still limited due to incomplete characterization of the underlying molecular mechanisms. 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 mg/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. © 2026. The Author(s). Conflict of interest statement: Declarations. Conflict of interest: Giuseppe Biondi-Zoccai has consulted for Aleph, Amarin, Balmed, Cardionovum, Crannmedical, Endocore Lab, Eukon, Guidotti, Innovheart, Meditrial, Menarini, Microport, Opsens Medical, Terumo, and Translumina, outside the present work. The remaining authors have nothing to disclose.”

The team compared natural autophagy activators (trehalose and spermidine) to a synthetic peptide. They used a mouse model hammered with doxorubicin, a chemo agent notorious for causing heart problems. The research didn’t just track heart function. The group dug deep with histology, advanced microscopy, and molecular analyses to get the full picture on fibrosis, apoptosis, mitophagy, and mitochondrial health.

Key takeaway: Restoring autophagy—whether with natural compounds or a research peptide—protected the heart without messing with doxorubicin’s anti-cancer effects.

Here’s what they found:

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Doxorubicin messes up autophagic flux (think LC3-II and p62 accumulation)

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Trehalose, spermidine, and Tat-Beclin 1 D11 all restored autophagy in the heart

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These interventions improved cardiac function and survival of heart cells

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Mitochondrial health and mitophagy were noticeably better

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The protective effect didn’t blunt the chemo’s cancer-fighting action

Big picture: This pushes the idea that autophagy activators, including synthetic research peptides like Tat-Beclin 1 D11, could be powerful tools for researchers working on cardioprotection during chemotherapy. The peptide approach matches or beats what’s possible with well-known natural compounds.

For peptide researchers, this is another green light to explore autophagy modulation as a strategy—especially in the context of complex diseases with multiple moving parts. The science is moving fast, and the peptide toolbox keeps growing.

Back to News Read original on Basic Res Cardiol

Pharmacological reactivation of autophagic flux by natural compounds or synthetic cell-permeable peptide prevents doxorubicin-induced cardiomyopathy.

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