Metabolic rate-limiting enzyme-associated genes as novel biomarkers for prognosis and treatment response in lung adenocarcinoma

Metabolic rate-limiting enzymes serve as crucial mediators of tumor metabolic reprogramming and are pivotal in the initiation, progression, and metastasis of malignancies. Nevertheless, the prognostic value of metabolic rate-limiting enzyme-related genes remains unexplored in lung adenocarcinoma (LUAD). Herein, transcriptomic data of LUAD acquired from TCGA and GEO databases were utilized to screen differentially expressed metabolic rate-limiting enzyme-related genes. A risk model of nine genes was established via Cox regression analysis. ROC curve validated the moderate predictive performance of this model with AUC values exceeding 0.66. In Kaplan-Meier survival analysis, patients in the high-risk subgroup exhibited markedly inferior overall survival outcomes. A nomogram integrating clinical characteristics and risk scores was constructed, followed by comprehensive analyses of immune infiltration patterns, immunotherapeutic responsiveness, somatic mutation profiles, and drug sensitivity. Disparities in immune cell infiltration and immune-associated biological functions were identified between the two subgroups. Patients in the low-risk group presented elevated IPS scores and reduced TIDE scores, implying a higher potential sensitivity to immunotherapy. The overall mutation rate of model-related genes in the high-risk group reached 11.02%, which was higher than the 6.61% in the low-risk group, accompanied by more sophisticated mutational landscape characteristics. Drug sensitivity analysis identified multiple promising candidate agents (Linsitinib, Momelotinib, and GDC-0152). In vitro experiments demonstrated that F2 knockdown or GDC-0152 treatment effectively suppressed cell proliferation and facilitated cellular apoptosis. Collectively, metabolic rate-limiting enzyme-related genes can be promising LUAS prognostic biomarkers. The risk model is expected to provide reliable references for LUAD prognostic assessment and individualized treatment.