FX11

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.

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.

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.

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.

Endothelial‐to‐mesenchymal transition (EndMT) induced by dysfunctional pulmonary artery endothelial cells (PAECs) is regarded as an initiating and pivotal factor in pulmonary hypertension (PH). This study focuses on identifying a novel therapeutic target for regulating EndMT in PH. A comprehensive analysis of 2 hypoxic PAECs datasets yielded 310 overlapping upregulated and 229 downregulated differentially expressed genes (DEGs). These upregulated DEGs were primarily enriched in HIF‐1 signalling pathway and glycolysis/gluconeogenesis, while downregulated only in spliceosome, as indicated by KEGG. Through PPI network analysis and the application of MCC algorithms, 5 hub genes were identified among these upregulated DEGs: GAPDH, LDHA, ALDOA, PFKL, and PFKP. Their enrichment in the 2 aforementioned pathways was confirmed by cross‐pathway DEGs analysis and ClueGo. Among the hub genes, LDHA was chosen as the key gene based upon expression and correlation analysis of the validation set from PH patients. Subsequent GSEA also revealed the enrichment of LDHA in these 2 pathways. Additionally, the increased expression of LDHA protein in tissues and cells was confirmed, and the elevated enzymatic activity of LDHA in clinical serum samples was also verified. From 2 online databases, 4 LDHA inhibitors were filtered out, and the stable binding between the inhibitors and the LDHA protein was confirmed through molecular docking and molecular dynamics simulation. Finally, the experimental results indicated that one of the inhibitors FX11 reversed EndMT by inhibiting the lactate‐SNAI1 axis, thereby alleviating hypoxia‐induced PH. The potential of LDHA as a therapeutic target for PH by modulating EndMT was proposed in this study.