Identification of lactylation-related hub genes as novel therapeutic and diagnostic targets for thoracic aortic dissection.

Abstract

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with high mortality rates. Although lactylation has garnered increasing attention, its role in TAD remains poorly understood. METHODS: Lactylation-related genes (LRGs) were obtained from the MsigDB database. Lactylation-related hub genes (LRHGs) were identified by intersecting LRGs with differentially expressed genes and WGCNA results. Lactylation was assessed in a β-aminopropionitrile (BAPN)-induced mouse model and human aortic tissues. Two single-cell RNA sequencing (scRNA-seq) from the GEO database were utilized to evaluate lactylation patterns across cell populations and intercellular communication networks. Biomarkers were evaluated using receiver operating characteristic (ROC) analysis. RESULTS: Elevated lactylation levels were observed in both TAD tissues and synthetic phenotype vascular smooth muscle cells. Through integrated analysis, we identified 12 LRHGs, which includes LDHA. In the BAPN-induced mouse model, LDHA inhibitors (Oxamate and FX11) significantly reduced mortality rates and decreased aortic lactate levels and protein lactylation. ScRNA-seq analytic results revealed that monocytes and macrophages exhibited the highest lactylation activity, which likely enhanced their inflammatory pathways and intercellular communication. ROC analysis showed the lowest AUC of 12 LRHGs is 0.8893. CONCLUSIONS: This study highlights the critical role of lactylation-related hub genes in TAD, identifying potential therapeutic targets and diagnostic biomarkers, which provides novel insights into the molecular mechanisms underlying TAD.