Propionate metabolism-related molecular subtypes and prognostic signature in lung adenocarcinoma

Propionate exerts antiproliferative and immunomodulatory effects in tumors, but its role in the metabolism of lung adenocarcinoma (LUAD) remains underexplored. This study aimed to characterize molecular subtypes based on propionate metabolism-related genes (PMRGs) and assess their prognostic and immunological relevance in LUAD. Using transcriptomic data from The Cancer Genome Atlas (TCGA)-LUAD and validation from GSE30219, consensus clustering was performed to identify subtypes associated with propionate metabolism. Immune infiltration and tumor microenvironment characteristics were analyzed through established algorithms. Differentially expressed genes (DEGs) were identified, and a prognostic model was constructed using Cox and least absolute shrinkage and selection operator (LASSO) regression. Three molecular subtypes (low, medium, and high propionate metabolism) were identified, demonstrating significant differences in overall survival and immune microenvironment features. The high-propionate subtype was characterized by elevated immune and stromal scores, as well as increased M2 macrophage infiltration. A 7-gene prognostic signature was developed, with risk stratification revealing significant survival and drug sensitivity differences between high- and low-risk groups. Key prognostic genes, including SLC2A1, SLC16A1, IL1A, AHSG, and ALOX15, were validated through RT-qPCR. This study highlights the molecular heterogeneity of propionate metabolism in LUAD and proposes a prognostic signature that could inform immunotherapeutic stratification.