Integrated Multi‐Omics Analysis Identifies PDK4 and ACOT1 as Metabolic Hub Genes Associated With Myocardial Fibrosis in Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a critical pathological driver of heart failure in diabetic patients, primarily characterized by progressive myocardial fibrosis. Nevertheless, the core molecular network linking upstream metabolic dysregulation to the aberrant activation of downstream cardiac fibroblasts remains largely elusive. In this study, we combined in vivo and in vitro approaches with bioinformatics analysis. A high‐fat diet‐induced mouse model of diabetic myocardial fibrosis was established, and transcriptome sequencing was performed to screen for hub genes, which were subsequently validated in two independent DCM datasets. Single‐cell RNA sequencing revealed that PDK4 and ACOT1 were upregulated in cardiac fibroblasts under pathological conditions. In vitro experiments confirmed that high glucose induced the expression of PDK4, ACOT1, and fibrotic markers in human primary cardiac fibroblasts. Molecular docking predicted a potential interaction between PDK4 and ACOT1. Collectively, our findings identify PDK4 and ACOT1 as evolutionarily conserved metabolic hub genes associated with myocardial fibrosis in DCM, suggesting a putative “metabolism–fibrosis axis” and providing potential therapeutic targets.