Prognostic and immunological implications of paraptosis‐related genes in lung adenocarcinoma: Comprehensive analysis and functional verification of hub gene

Abstract Background Lung adenocarcinoma (LUAD) poses significant clinical challenges due to its inherent heterogeneity and variable response to treatment. Recent research has specifically focused on elucidating the role of Paraptosis‐related genes (PRGs) in the progression of cancer and the prognosis of patients. Methods We conducted a comprehensive analysis of the differential expression of PRGs in LUAD. Additionally, univariate Cox regression analysis was utilized to determine the prognostic significance of these genes. Furthermore, consensus clustering was employed to differentiate molecular subtypes within LUAD, while immune heterogeneity was assessed. To evaluate treatment outcomes, the expression of immune checkpoint inhibitors was examined, and the sensitivity of LUAD patients to chemotherapy drugs was assessed. Moreover, machine learning algorithms were employed to construct a Paraptosis‐related risk score with prognostic and immunological indicators. Finally, to validate the findings, in vitro experiments were performed to verify the regulatory effect of key PRGs on Paraptosis. Results Our analysis identified 24 PRGs that exhibited differential expression, with CDKN3, TP53, and PHB emerging as the most prominently upregulated genes in tumor tissues. Among these genes, seven were identified as prognostic markers, with HSPB8 being the sole protective factor. Notably, our analysis also revealed the existence of two distinct molecular subtypes within LUAD, each characterized by unique prognoses and immune responses. Specifically, Subtype B displayed a poorer prognosis but demonstrated increased sensitivity to both chemotherapy and immunotherapy. In addition, our development of a Paraptosis‐Associated Risk Score yielded a significant prognostic value in predicting patient outcomes. Furthermore, we found regulatory effect of CDKN3 on Paraptosis in two cell lines. Conclusions Our study highlights the importance of PRGs in LUAD, particularly in prognosis and treatment response. The identified molecular subtypes and Paraptosis‐Associated Risk Score offer valuable insights for personalized treatment strategies.