GRIK2 functions as an ammonia-induced cell death-related prognostic marker and drives lung adenocarcinoma progression via PKA/CREB signaling

Lung adenocarcinoma (LUAD) has high incidence, mortality, and prognostic heterogeneity. Given ammonia-induced cell death (AICD)’s role in tumor procession, this study aimed to identify core genes from AICD-related prognostic signatures (AIRS) and explore their mechanisms. Gene expression profiles and clinical data of LUAD patients were retrieved from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. An AIRS based on differential expressed AICD-related genes (DEAIRGs) was constructed using Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. Further analyses were performed to evaluate the utility of this model in clinical prognostic assessment, immune regulation, gene mutation profiling, molecular subtyping, and prediction of therapeutic response. The extreme gradient boosting (XGBoost) algorithm was employed to screen for key prognostic markers. The effects of this marker on LUAD cell proliferation, clonogenic capacity, invasion, migration, and anti-apoptotic ability were assessed using Cell Counting Kit-8 (CCK-8) assays, colony formation assays, Transwell assays, and flow cytometry. Enzyme-linked immunosorbent assay (ELISA), western blotting (WB) and rescue experiments were conducted to verify the underlying mechanisms. A total of 251 DEAIRGs were identified. Consensus clustering analysis based on the TCGA cohort classified LUAD into three molecular subtypes, which exhibited significant differences in prognosis and immune characteristics. An AIRS consisting of seven genes (CAT, CAMP, SLC18A2, ACAN, PLEK2, GRIK2, and LDHA) was constructed using the TCGA cohort and validated in the GSE68465 cohort. This signature not only served as an independent risk factor for overall survival (OS) in LUAD patients but also showed excellent discriminatory performance in immune profiling, gene mutation, and therapeutic response analyses. The feature importance ranking from the XGBoost algorithm identified GRIK2 as a key prognostic marker. Knockdown of GRIK2 significantly inhibited LUAD cell proliferation and clonogenic capacity while promoting apoptosis. Knockdown of GRIK2 reduced intracellular cyclic adenosine monophosphate (cAMP) content as well as the phosphorylation levels of PKA and CREB. Subsequent rescue experiments verified that GRIK2-dependent malignant phenotypes in LUAD cells were potentially associated with regulation of the cAMP signaling cascade. This study established molecular subtypes and an AIRS, revealing the immune regulatory patterns and genetic characteristics of LUAD. The core prognostic marker GRIK2 promoted LUAD cell proliferation and enhanced anti-apoptotic capacity by activating the cAMP/PKA/CREB pathway.