Tirzepatide attenuates doxorubicin-induced cardiotoxicity via mitochondrial function improvement

Doxorubicin (DOX) is a highly effective anthracycline chemotherapeutic agent, but its clinical utility is severely limited by dose-dependent cardiotoxicity, which can lead to irreversible heart failure. This study investigated the cardioprotective potential of tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, against DOX-induced cardiac injury.

We established comprehensive in vitro and in vivo injury models. Cardiac systolic function was quantitatively assessed via transthoracic echocardiography, measuring left ventricular ejection fraction and fractional shortening. Histopathological evaluation of myocardial structure was performed using hematoxylin and eosin (H&E) staining. Mitochondrial ultrastructure integrity, particularly cristae morphology, was examined via transmission electron microscopy (TEM). Mitochondrial membrane potential (MMP) was measured using the fluorescent JC-1 probe.

Tirzepatide treatment significantly attenuated DOX-induced cardiotoxicity. It markedly improved left ventricular systolic function and reduced histopathological damage. Crucially, tirzepatide preserved mitochondrial integrity, evidenced by TEM showing maintained cristae density and structure, and effectively restored DOX-induced MMP dissipation, indicating rescued mitochondrial bioenergetic function.

Tirzepatide confers significant cardioprotection against DOX-induced toxicity in both cellular and animal models. The primary mechanism underlying this protection is the amelioration of DOX-triggered mitochondrial dysfunction, specifically through the preservation of cristae integrity and restoration of MMP. These findings strongly support further investigation of tirzepatide as a promising adjunctive therapy to enhance the cardiac safety profile of DOX chemotherapy.