AUTHOR=Xiong Xiang , Liu Wen , Yao Chuan 

TITLE=Development of an alkaliptosis-related lncRNA risk model and immunotherapy target analysis in lung adenocarcinoma

JOURNAL=Frontiers in Genetics

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2025.1573480

DOI=10.3389/fgene.2025.1573480

ISSN=1664-8021

ABSTRACT=BackgroundLung cancer has the highest mortality rate among all cancers worldwide. Alkaliptosis is characterized by a pH-dependent form of regulated cell death. In this study, we constructed a model related to alkaliptosis-associated long non-coding RNAs (lncRNAs) and developed a prognosis-related framework, followed by the identification of potential therapeutic drugs.MethodsThe TCGA database was utilized to obtain RNA-seq-based transcriptome profiling data, clinical information, and mutation data. We conducted multivariate Cox regression analysis to identify alkaliptosis-related lncRNAs. Subsequently, we employed the training group to construct the prognostic model and utilized the testing group to validate the model’s accuracy. Calibration curves were generated to illustrate the discrepancies between predicted and observed outcomes. Principal Component Analysis (PCA) was performed to investigate the distribution of LUAD patients across high- and low-risk groups. Additionally, Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were conducted. Immune cell infiltration and Tumor Mutational Burden (TMB) analyses were carried out using the CIBERSORT and maftools algorithms. Finally, the “oncoPredict” package was employed to predict immunotherapy sensitivity and to further forecast potential anti-tumor immune drugs. qPCR was used for experimental verification.ResultsWe identified 155 alkaliptosis-related lncRNAs and determined that 5 of these lncRNAs serve as independent prognostic factors. The progression-free survival (PFS) and overall survival (OS) rates of the low-risk group were significantly higher than those of the high-risk group. The risk signature functions as a prognostic factor that is independent of other variables. Different stages (I–II and III–IV) effectively predict the survival rates of lung adenocarcinoma (LUAD) patients, and these lncRNAs can reliably forecast these signatures. GSEA revealed that processes related to chromosome segregation and immune response activation were significantly enriched in both the high- and low-risk groups. The high-risk group exhibited a lower fraction of plasma cells and a higher proportion of activated CD4 memory T cells. Additionally, the OS of the low TMB group was significantly lower compared to the high TMB group. Furthermore, drug sensitivity was significantly greater in the high-risk group than in the low-risk group. These lncRNAs may serve as biomarkers for treating LUAD patients.ConclusionIn summary, the construction of an alkaliptosis-related lncRNA prognostic model and drug sensitivity analysis in LUAD patients provides new insights into the clinical diagnosis and treatment of advanced LUAD patients.