Lung cancer remains a leading cause of cancer-related death globally, with high malignancy and poor prognosis. PANoptosis, a novel programmed cell death pathway combining apoptosis, pyroptosis, and necroptosis, has been increasingly implicated in disease pathogenesis, yet its role in lung cancer is poorly understood. This study integrated bulk and single-cell RNA-seq data from TCGA and GEO databases to identify and validate PANoptosis-related genes in lung cancer. We identified eight key genes (DAPK2, CAV1, PDK4, IL3RA, NOTCH1, CHMP4B, IRAK1, and SFN) that are significantly dysregulated in tumors and correlated with prognosis. Functional enrichment analysis implicated these genes in cell adhesion, cytokine signaling, necrotic pathways, and cell cycle regulation. Furthermore, immune infiltration analysis suggested roles for CHMP4B and IRAK1 in modulating the tumor immune microenvironment. Experimental validation via qPCR and IHC confirmed differential expression of these genes in cell lines and clinical samples. Drug sensitivity analysis also linked CHMP4B and PDK4 to response to targeted agents like Gefitinib. In conclusion, our results reveal the significance of PANoptosis-related genes in lung cancer pathogenesis and highlight their potential as prognostic biomarkers and therapeutic targets. Lung cancer is among the leading causes of cancer-related morbidity and mortality worldwide, characterized by high aggressiveness, early metastasis, and poor prognosis. PANoptosis, a recently recognized form of programmed cell death that integrates apoptosis, pyroptosis, and necroptosis, has been implicated in various diseases. However, comprehensive studies investigating PANoptosis-related genes in lung cancer remain limited, and their functional roles in tumorigenesis and progression are not fully understood. In this study, we integrated transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases with single-cell RNA sequencing analysis to identify PANoptosis-related genes involved in lung cancer. A combination of differential gene expression analysis, functional enrichment analysis, immune infiltration profiling, and drug sensitivity prediction was performed to explore the biological significance and therapeutic potential of these genes. Furthermore, we validated the expression patterns of key genes using quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) in lung cancer cell lines and tissue specimens. Eight PANoptosis-related genes (DAPK2, CAV1, PDK4, IL3RA, NOTCH1, CHMP4B, IRAK1, and SFN) were identified as being significantly associated with lung cancer. Their expression levels were notably altered in tumor tissues compared to normal controls and were significantly correlated with patient prognosis. Functional enrichment analysis revealed these genes were mainly involved in cell adhesion, cytokine signaling, necrosis-related pathways, and cell cycle regulation. Notably, CHMP4B and IRAK1 showed distinct expression patterns in different immune cell populations, indicating their potential roles in shaping the tumor immune microenvironment. Importantly, qPCR and IHC analyses confirmed the differential expression of these genes across lung cancer cell lines and clinical specimens. Drug sensitivity analysis further suggested that genes such as CHMP4B and PDK4 were associated with the response to targeted therapies including Gefitinib. This study provides a comprehensive landscape of PANoptosis-related gene dysregulation in lung cancer and highlights their potential as prognostic biomarkers and therapeutic targets. The integrated bioinformatics analysis combined with experimental validation supports their functional relevance in lung cancer development and treatment.
Shuang Han (Sat,) studied this question.