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

Tumor stemness contributes to therapeutic resistance and malignant progression in lung adenocarcinoma (LUAD), yet its molecular basis remains unclear. This study investigated the tumor stemness index (mRNAsi) to identify key regulators and potential therapeutic targets in LUAD. Transcriptomic data from TCGA and PCBC datasets were analyzed to evaluate mRNAsi in LUAD. Weighted gene co-expression network analysis was used to identify stemness-related genes, and the tumor immune microenvironment was characterized. Core regulatory genes were screened using machine learning analyses and validated using independent datasets and experimental approaches. Higher mRNAsi was associated with aggressive clinicopathological features and an immune-cold subtype. Budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) was identified as a key regulator of LUAD stemness and was significantly correlated with enhanced proliferation, migration, invasion, and stemness marker expression. Mechanistic analyses indicated that BUB1B promotes LUAD progression by activating the Ca²⁺/PI3K/AKT signaling pathway. BUB1B is a pivotal regulator linking tumor stemness with malignant progression and immune context in LUAD, highlighting its potential as a diagnostic, prognostic, and therapeutic biomarker.