CPT1A exacerbates trastuzumab-induced cardiotoxicity via promotion of mitochondrial dysfunction.

Trastuzumab, a cornerstone therapy for HER2-positive breast cancer, is associated with significant cardiotoxicity, manifesting as left ventricular dysfunction and heart failure. This study aimed to identify mitochondrial-related genes pivotal to Trastuzumab-induced cardiotoxicity (TIC) using integrative bioinformatics and machine learning. Analysis of gene expression datasets identified 19 mitochondrial-related differentially expressed genes (MRDEGs), enriched in fatty acid metabolism and oxidative pathways. Machine learning algorithms (LASSO, MCODE, Cytohubba, WGCNA) prioritized four key genes: ACSL1, ECI2, LONP1, and CPT1A. Cross-validation revealed CPT1A as the most consistent biomarker, showing upregulated expression in TIC and strong diagnostic potential (AUC > 0.8). In vivo validation using trastuzumab-treated mice and in vitro cell experiments confirmed CPT1A's dose-dependent upregulation, correlating with impaired cardiac function. Transcriptome sequencing and immune infiltration analysis further linked CPT1A to altered T-cell subsets, suggesting immune-metabolic crosstalk in TIC. In vitro mechanistic studies revealed that CPT1A may promote mitochondrial damage and induce cardiomyocyte injury by interacting with Parkin. This study underscores the utility of multi-omics integration in elucidating TIC mechanisms and paves the way for personalized cardioprotective strategies in HER2-targeted therapy.