Identification of a novel lactylation-related gene signature to predict immune infiltration and prognosis for lung adenocarcinoma

Lactylation, a recently identified post-translational modification, has been linked to tumor progression, angiogenesis, metastasis, and immune modulation. Nevertheless, the lactylation-related genes and mechanisms of metabolic-immune interactions in lung cancer remain unclear. We performed comprehensive analyses of transcriptomic profiles, immune landscapes, functional pathways, and drug sensitivity for lung adenocarcinoma (LUAD). Lactylation-related genes were identified by weighted gene co-expression network analysis (WGCNA) and single-cell RNA sequencing (scRNA-seq) analysis. A prognostic risk model was identified by univariate COX and least absolute and selection operator (LASSO) regression. The patients were divided into high-lactylation score and low-lactylation score groups based on median risk scores in TCGA and GEO cohorts. The associations between the lactylation-related gene risk and immune cell infiltration, biological functions, mutation landscapes, and drug sensitivity were compared. Finally, we verified the prognostic model and CD74 gene using multiple public datasets. Seven lactylation-related prognostic genes with prognostic value for LUAD patients were selected, including CD74, HLA-DMA, PTGDS, CD5, CLEC7A, IGSF6, and ICAM3. The immune cell function, signaling pathways, TMB, and anticancer drug sensitivity were compared between the high-lactylation riskscore and the low-lactylation riskscore patients. A high riskscore indicated a poor prognosis. Besides, a prognostic nomogram integrating the model and clinical features showed moderate accuracy in predicting the prognosis for LUAD patients. Additionally, we systematically validated the prognostic lactylation-related signatures using the GEO, TISCH, and scRNA-seq databases. Finally, we found that high expression of CD74 was positively correlated with longer survival time of lung cancer patients and the immune infiltration score. The lactylation-related prognostic model could predict the prognosis for LUAD patients. CD74 was expected to become a novel target for LUAD.