Identification and Validation of Novel Lactylation‐Related Gene Signature in Dilated Cardiomyopathy

ABSTRACT Dilated cardiomyopathy (DCM) is a progressive myocardial disorder with limited therapeutic options. Recent studies suggest that metabolic reprogramming, including lactate accumulation and protein lactylation, contributes to heart failure pathogenesis, but their roles in DCM remain poorly defined. We analyzed the global burden of cardiomyopathy and myocarditis using GBD data and performed transcriptomic profiling using GSE120895 and GSE5406 datasets. Weighted gene co‐expression network analysis (WGCNA), differential gene expression, and known lactylation‐related genes (LRGs) were integrated to identify key targets. LASSO regression was applied to construct a diagnostic model. Validation was conducted in an Lmna E82K transgenic mouse model using qRT‐PCR, Western blot analysis, immunofluorescence, and biochemical assays. Global analysis showed the rising age‐standardized prevalence of cardiomyopathy and myocarditis by 2021. Bioinformatics revealed 1988 DEGs in DCM, 11 of which overlapped with LRGs and WGCNA modules. LASSO modeling identified DDX39A , SPR , and HNRNPC as core diagnostic biomarkers. In vivo validation confirmed upregulation of these genes in Lmna E82K mice. Elevated lactate and protein lactylation levels were detected, alongside increased NEFA, MDA, and oxidative stress markers, implicating lactylation in metabolic dysfunction. We identify DDX39A , SPR , and HNRNPC as novel lactylation‐associated biomarkers of DCM and reveal a pathophysiological link between lactate‐driven protein lactylation, oxidative stress, and cardiac dysfunction. These findings offer new molecular targets for DCM diagnosis and intervention.