A palmitoylation-related prognostic risk scoring model and tumor microenvironment characterization in lung adenocarcinoma, using single-cell RNA sequencing data.

Lung adenocarcinoma (LUAD) is the predominant pathological subtype of non-small cell lung cancer. Its considerable tumor heterogeneity and drug resistance present major clinical obstacles, resulting in unfavorable patient outcomes. Protein palmitoylation is known to be a key factor in tumorigenesis; however, its cell-specific expression patterns and prognostic value in LUAD remain incompletely characterized. Using two independent datasets, TCGA-LUAD and GSE68465, and scRNA-seq data from 10 LUAD samples, we analyzed the expression of palmitoylation-related genes. Through single-cell clustering, CNV analysis, and palmitoylation activity scoring, malignant epithelial cells were identified. 10 machine learning algorithms were applied to construct prognostic models based on differentially expressed genes. RT-qPCR was used to detect mRNA expression of prognostic marker genes in clinical samples. In vitro experiments validated SEC61G's role in regulating drug sensitivity. A subset of malignant epithelial cells with high palmitoylation activity was identified. A 5-gene signature (UBE2S, SEC61G, CCT6A, GAPDH, HLA-DRA) was established by the integrated CoxBoost+SuperPC method, showing robust predictive efficacy in both GSE68465 and TCGA-LUAD. High-risk samples carried higher mutation burden, greater genomic heterogeneity, and a stronger tumor immunosuppressive microenvironment than the low-risk group. Clinical sample testing revealed upregulation of UBE2S, SEC61G, CCT6A, and GAPDH in LUAD patients and downregulation of HLA-DRA. SEC61G expression inversely correlated with AZD3759 sensitivity. In vitro, SEC61G knockdown or AZD3759 alone suppressed LUAD proliferation and induced apoptosis; no synergy was observed with combination therapy, indicating that SEC61G modulates AZD3759 sensitivity in LUAD cells. Our study comprehensively reveals the cellular heterogeneity of palmitoylation, establishes a robust palmitoylation-related prognostic model, and identifies SEC61G as a promising therapeutic target in LUAD, offering a novel perspective for LUAD precision stratification and treatment studies.