Tirzepatide attenuates doxorubicin-induced cardiotoxicity by improving mitochondrial function in preclinical models

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 toxicity is primarily driven by mitochondrial dysfunction and reactive oxygen species (ROS) production. Current standard-of-care often falls short in preventing this severe side effect. 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, leveraging its known metabolic and anti-inflammatory properties.

Researchers established comprehensive in vitro and in vivo injury models to assess the cardioprotective effects of tirzepatide. 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 to evaluate bioenergetic function. The control arm received DOX without tirzepatide.

Tirzepatide treatment significantly attenuated DOX-induced cardiotoxicity across both cellular and animal models. It markedly improved left ventricular systolic function and reduced histopathological damage in myocardial tissue. Crucially, tirzepatide preserved mitochondrial integrity, a key finding given DOX's known mitochondrial toxicity. This was evidenced by TEM showing maintained cristae density and structure, which are vital for efficient energy production. Furthermore, tirzepatide effectively restored DOX-induced mitochondrial membrane potential (MMP) dissipation, indicating a rescue of mitochondrial bioenergetic function. This suggests a direct protective effect on the cellular powerhouses. The findings point to the amelioration of DOX-triggered mitochondrial dysfunction, specifically through the preservation of cristae integrity and restoration of MMP, as the primary mechanism. These results were consistent across both in vitro and in vivo models.

Tirzepatide preserved mitochondrial integrity, with TEM showing maintained cristae density and structure, and restored doxorubicin-induced mitochondrial membrane potential (MMP) dissipation.