IGFBP7 and CCT2 are novel lactylation-driven mediators of endothelial-to-mesenchymal transition in idiopathic pulmonary fibrosis.

Lactylation is a post-translational modification that can influence the onset and progression of various diseases.However, its role in Idiopathic Pulmonary Fibrosis (IPF) has not been systematically investigated. Single-cell sequencing and bulk RNA sequencing techniques were utilized to assess lactylation levels in IPF patients and health people. The clinical significance of lactylation was explored through survival and correlation analyses. Optimal feature genes of lactylation were identified using correlation analysis, multiple machine learning algorithms, Cox regression analysis and Mendelian randomization. The potential mechanisms of these Optimal feature genes were inferred through pseudotime analysis and gene pathway activity analysis, followed by experimental validation. Cell-cell communication and metabolic assessments were employed to explore the reasons for elevated lactylation levels in IPF, and relevant findings were verified through in vitro cellular experiments. Both single-cell sequencing and bulk RNA sequencing consistently demonstrated elevated lactylation levels in the IPF patients. High lactylation levels were associated with worse lung function and poorer prognosis. Through the integration of five machine learning algorithms, Cox regression analysis and Mendelian randomization, two optimal feature genes IGFBP7 and CCT2 were identified. These optimal feature genes were found to be significantly highly expressed in vascular endothelial cells, and this conclusion was experimentally validated. Pseudotime analysis results combined with RNA interference (RNAi) and wound healing assays demonstrated that both optimal feature genes promoted endothelial-mesenchymal transition (EndMT) in endothelial cells. Through cell-cell communication analysis, we discovered that TGF-β can promote metabolic reprogramming in endothelial cells, leading to increased lactate production and ultimately elevated expression of the optimal feature genes. Lactylation levels are significantly increased in IPF patients. TGF-β can induce metabolic reprogramming in endothelial cells, leading to high expression of IGFBP7 and CCT2, thereby promoting EndMT.