Lipid metabolism-related gene expression predicts prognostic outcomes in lung adenocarcinoma

Aberrant lipid metabolism is closely associated with tumorigenesis and progression; however, its specific roles and molecular mechanisms in lung adenocarcinoma (LUAD) remain to be fully elucidated. This study aims to develop a prognostic signature based on lipid metabolism-related genes and to investigate the functional role of the key gene MBTPS2 in LUAD.

Transcriptomic profiles and clinical data pertaining to LUAD were retrieved from the Gene Expression Omnibus (GEO) (training set) and The Cancer Genome Atlas (TCGA) (external test set) repository. A lipid metabolism-related gene set was obtained from the Gene Set Enrichment Analysis (GSEA) online portal. Prognostic lipid metabolism-related genes were identified through univariate Cox, followed by Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate Cox regression analyses to construct a prognostic signature. The predictive accuracy of this model was assessed using Kaplan-Meier survival analysis and time-dependent receiver operating characteristic (ROC) curves. Functional enrichment analysis was performed to investigate the potential biological processes associated with differentially expressed genes (DEGs) between the high- and low-risk groups. The expression levels of the 12 signature genes in LUAD cell lines were quantified by quantitative real-time polymerase chain reaction (qRT-PCR). The oncogenic functions of MBTPS2 were examined using a series of in vitro assays, including Cell Counting Kit-8 (CCK-8), wound healing and apoptosis.

A prognostic signature comprising 12 lipid metabolism-related genes (HILPDA, ACHE, PPARD, ETNK1, ST3GAL2, NCOA2, HACD1, MBTPS2, UGT8, LPIN2, SPHK2, and AKR1C4) was successfully established. Based on this signature, LUAD patients were stratified into high- and low-risk subgroups. Patients in the high-risk group exhibited a significantly shorter overall survival in both the training and validation cohorts. The robust predictive capacity of the signature was confirmed by ROC curve analysis. Additionally, the risk score served as an independent prognostic factor for LUAD after adjustment for other clinical variables. MBTPS2 was found to be significantly overexpressed in LUAD tissues and cell lines at both the messenger RNA (mRNA) and protein levels. Functional assays revealed that knockdown of MBTPS2 in H1975 cells inhibited proliferative and migratory capacities and induced apoptosis, whereas its overexpression in A549 cells promoted these oncogenic phenotypes. MBTPS2 expression was also positively correlated with key lipid metabolism regulators, including SREBP1, FASN, and SCD1.

This study developed and validated a novel lipid metabolism-related prognostic signature that functions as an independent indicator for LUAD patient. Furthermore, MBTPS2 was identified as an unfavorable prognostic factor that promotes proliferation, and lipid metabolism, while suppressing apoptosis in LUAD.