A disulfidptosis- and glycolysis-related gene signature for prognostic stratification and characterization of the tumor microenvironment in lung adenocarcinoma

Lung adenocarcinoma (LUAD) exhibits profound metabolic plasticity and immune heterogeneity, contributing to poor outcomes. Disulfidptosis, a newly characterized disulfide stress-induced cell death, is closely linked to redox balance, while glycolysis constitutes a central metabolic program driving tumor progression. However, the prognostic relevance and immunological implications of genes associated with both processes in LUAD remain incompletely understood. Genes implicated in disulfidptosis and glycolysis were integrated to construct a prognostic risk model. Survival-associated genes were identified to establish a multigene signature, whose performance was subsequently validated using internal and external independent cohorts. The tumor microenvironment, immune infiltration patterns, and tumor mutation burden (TMB) were comprehensively evaluated. Drug sensitivity prediction and exploratory molecular docking analyses were conducted to explore therapeutic implications. Expression of key genes was validated through in vitro experiments and public proteomic resources. A four-gene prognostic signature comprising RPE , TXN , PPP2R1A , and HMMR was established, effectively stratifying LUAD patients into high- and low-risk groups with distinct survival outcomes. High-risk tumors showed enrichment of cell cycle and DNA replication pathways, whereas low-risk tumors exhibited pronounced immune-related signatures. High-risk tumors displayed reduced immune components accompanied by a potentially immunosuppressive immune microenvironment. Furthermore, drug sensitivity profiling identified that the high-risk group was theoretically more sensitive to specific agents, such as ABT737 and axitinib. Patients with low-risk scores and high TMB had the most favorable prognosis. Experimental validation confirmed upregulated expression of model genes in LUAD cell lines and tissues. This study establishes an exploratory disulfidptosis- and glycolysis-related gene signature that captures the interplay among metabolic reprogramming, immune suppression, and clinical outcomes in LUAD, providing a framework for prognostic stratification and metabolism-oriented therapeutic strategies.