Targeting BUB1B-Driven Cancer stemness in lung adenocarcinoma: a novel therapeutic strategy via PI3K/AKT pathway modulation

Tumor stemness is a key driver of therapeutic resistance and malignant progression in lung adenocarcinoma (LUAD), but its molecular basis and clinical significance remain unclear. This study explores the tumor stemness index (mRNAsi) and its role in LUAD to identify potential therapeutic targets. Transcriptomic data from TCGA and PCBC datasets were analyzed to evaluate mRNAsi in LUAD. Weighted gene co-expression network analysis (WGCNA) was applied to identify stemness-related genes, and the tumor immune microenvironment (TIME) was characterized. Core regulatory genes were prioritized using least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forest with Boruta (RFB), followed by validation in independent datasets. Elevated mRNAsi was significantly associated with aggressive clinicopathological features and the immune-cold subtype (Immune_L), among the two identified immune subtypes (Immune_H and Immune_L). Budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) was identified as a central regulator of LUAD stemness, showing significant correlations with enhanced proliferation, migration, invasion, and stemness markers (all p < 0.01). Mechanistic analyses demonstrated that BUB1B significantly activated the Ca2+/PI3K/AKT signaling axis (p = 0.002), thereby promoting tumor progression and maintaining stemness phenotypes. BUB1B serves as a pivotal regulator of LUAD stemness and malignancy, linking mRNAsi with clinical features, immune context, and genomic alterations. These findings support BUB1B as a promising diagnostic, prognostic, and therapeutic biomarker, though multicenter validation is needed.