Liraglutide attenuates doxorubicin-induced cardiomyocyte ferroptosis via DHHC7-mediated STAT3 palmitoylation.

AIMS: This study aimed to investigate liraglutide's protective effects against doxorubicin (DOX)-induced cardiotoxicity and ferroptosis, and to elucidate the underlying mechanisms involving signal transducer and activator of transcription 3 (STAT3) signaling and its post-translational palmitoylation. MATERIALS AND METHODS: In vivo models of chronic DOX-induced cardiotoxicity were established in male C57BL/6 J mice. Cardiac function was assessed via echocardiography. Ferroptosis markers such as malondialdehyde (MDA), glutathione (GSH), iron (Fe), reactive oxygen species (ROS), mitochondrial ultrastructure) were evaluated in myocardial tissue and H9c2 cardiomyocytes. Bioinformatics analysis of the GSE193861 dataset identified ferroptosis-related differentially expressed genes. STAT3 and DHHC7 were modulated using short hairpin RNA (shRNA) knockdown and cardiomyocyte-specific adeno-associated virus 9 (AAV9)-mediated overexpression. Molecular interactions were assessed via co-immunoprecipitation, acyl-biotin exchange assays, and western blotting. KEY FINDINGS: Liraglutide administration significantly attenuated DOX-induced cardiac dysfunction and cardiomyocyte ferroptosis. Bioinformatics identified STAT3 as a central regulator, with liraglutide restoring DOX-impaired STAT3 phosphorylation and nuclear translocation, thereby enhancing transcription of the anti-ferroptotic enzyme glutathione peroxidase 4 (GPX4). STAT3 knockdown abolished liraglutide's protection. Mechanistically, liraglutide upregulated the palmitoyltransferase DHHC7, rescuing DOX-suppressed STAT3 palmitoylation. DHHC7 knockdown and palmitoylation inhibition abrogated liraglutide-mediated STAT3 phosphorylation and anti-ferroptotic effects. Crucially, cardiomyocyte-specific DHHC7 overexpression replicated liraglutide's cardioprotection, mitigating DOX-induced ferroptosis and dysfunction. SIGNIFICANCE: We demonstrate a novel cardioprotective axis wherein liraglutide enhances DHHC7-dependent STAT3 palmitoylation, facilitating its phosphorylation, nuclear translocation, and transcriptional activation of GPX4 to suppress ferroptosis. This study provides the first evidence that DHHC7-mediated STAT3 palmitoylation is essential for liraglutide's efficacy, identifying a promising therapeutic target for DOX cardiotoxicity.