DBT Modulates Copper‐Dependent Cuproptosis‐Related Injury in Experimental Alcoholic Cardiomyopathy

ABSTRACT

Alcoholic cardiomyopathy (ACM) is a severe cardiovascular complication of chronic alcohol consumption, but its underlying mechanisms remain incompletely understood. Cuproptosis is a recently identified copper‐dependent form of regulated cell death; however, its role in ACM remains unclear. In this study, male C57BL/6 mice were fed an ethanol‐containing Lieber‐DeCarli liquid diet to establish an ACM model, and RNA sequencing combined with bioinformatics analysis was performed to identify cuproptosis‐related genes. Among the candidate genes, dihydrolipoamide branched‐chain transacylase E2 (DBT) showed a consistent trend of downregulation across both independent RNA‐seq cohorts, and was further validated by qRT‐PCR and Western blotting. ACM mice exhibited increased serum and cardiomyocyte copper content, altered cuproptosis‐related markers and impaired cardiac function. In AC16 cells, DBT knockdown induced copper overload, cuproptosis‐related molecular alterations and mitochondrial dysfunction, which were markedly alleviated by the copper chelator tetrathiomolybdate. Conversely, DBT overexpression attenuated EtOH‐induced copper overload, cuproptosis‐related molecular alterations and mitochondrial dysfunction, with effects similar to those of tetrathiomolybdate. These findings suggest that DBT regulates ACM‐related cardiomyocyte injury through cuproptosis‐associated processes at the cellular level and may represent a potential therapeutic target for alcohol‐induced myocardial injury.