Background <p>PANoptosis, a newly identified form of cell death, has been linked to both the destruction of cancer cells and the regulation of antitumor immunity. This study aimed to establish a PANoptosis-related signature associated with lung adenocarcinoma (LUAD), highlighting its role in LUAD pathogenesis.</p> Methods <p>Transcriptome data from the TCGA-LUAD dataset were analyzed to identify PANoptosis-related differentially expressed genes (PANR-DEGs). A LUAD gene signature was developed using Cox regression and LASSO analyses. The study also evaluated somatic mutations, the immune microenvironment, and immunotherapy potential across two risk groups. Additionally, prognostic gene expression was validated clinically by reverse transcription-quantitative PCR (RT-qPCR).</p> Results <p>The TCGA-LUAD dataset revealed 520 PANR-DEGs. A prognostic signature based on six key genes—CDCP1, CLIC6, FURIN, KRT6A, MFI2, and P2RY13—was constructed. Prognostic analysis indicated that pathological T and N statuses, along with the risk score, could serve as independent prognostic markers. Significant differences in the immune microenvironment were observed between the two risk groups, with TP53 showing the highest mutation frequency. Drug sensitivity assays suggested that the PANoptosis-related gene signature could serve as a predictive tool for therapy. Elevated expression levels of CDCP1, CLIC6, FURIN, KRT6A, and MFI2 were observed in tumor tissues compared to normal tissues. RT-qPCR results confirmed the findings from the bioinformatic analysis.</p> Conclusion <p>A prognostic signature composed of CDCP1, CLIC6, FURIN, KRT6A, MFI2, and P2RY13, based on PANR-DEGs, provides a theoretical framework and reference for further LUAD research.</p>