Integrated Proteomic and scRNA‐Seq Analysis Reveals Pyroptosis‐Related Subtypes in Lung Adenocarcinoma

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Abstract
Background: Pyroptosis is a recently identified form of programmed cell death that plays an important role in cancer initiation and progression. However, the function of pyroptosis in lung adenocarcinoma (LUAD) remains unclear. The study integrated proteomic and single‐cell RNA sequence (scRNA‐seq) data to investigate the potential role of pyroptosis‐related proteins (PRPs) in the tumor microenvironment (TME) and their associations with tumor immunity, prognosis, and therapeutic response. Methods: A comprehensive proteomic analysis was conducted on 103 lung adenocarcinoma patients. We integrated scRNA‐seq data with bioinformatics analyses to evaluate prognostic and immunological characteristics. Unsupervised clustering based on the PRP expression identified three subtypes. We then used gene set enrichment analysis (GSEA) to assess biological functions. We applied TME and CIBERSORT algorithms to analyze immune cell infiltration. Next, we performed functional enrichment, immune infiltration, and cell–cell communication analyses using scRNA‐seq data grouped according to the proteomic subtypes. We constructed a PRP‐related prognostic signature using least absolute shrinkage and selection operator (LASSO)‐Cox regression analysis. Finally, we validated the expression and functional significance of selected proteins by immunohistochemistry, Western blotting, quantitative PCR, and in vitro loss‐of‐function assays. Results: We identified multiple PRPs that correlated with clinicopathologic characteristics, patient prognosis, and immune infiltration patterns in the TME. We further identified three distinct molecular subtypes, including lipid metabolism, signaling transduction, and immune activation. Among these subtypes, the lipid metabolism subtype showed the best prognosis. ScRNA‐seq analysis further supported the immune characteristics of three subtypes and revealed distinct cellular interaction networks and ligand‐receptor pairs. We also established and validated a PRP‐related prognostic score that effectively predicted overall survival in patients with LUAD. In addition, the PRP score was significantly associated with tumor immune status and sensitivity to chemotherapeutic agents. Conclusion: Our integrated analysis of proteomic and scRNA‐seq data demonstrated that PRPs are closely associated with the tumor‐immune‐stromal microenvironment, clinicopathological features, and prognosis in LUAD. These findings improve our understanding of the biological roles of PRPs in LUAD and may provide new strategies for prognostic evaluation and immunotherapy development.
Funding Information
  • National Natural Science Foundation of China (82570107)
  • National Natural Science Foundation of China (82130001)
  • National Natural Science Foundation of China (82500110)
  • National Natural Science Foundation of China (82203517)
  • National Natural Science Foundation of China (82200089)
  • National Natural Science Foundation of China (82400103)
  • Zhongshan Hospital (ZY2024‐001)
  • Zhongshan Hospital (ZSLCYJ202319)
  • China Postdoctoral Science Foundation (2024M750545)
  • China Postdoctoral Science Foundation (2024T170162)

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