PIK3C2B drives lung cancer progression through coordinating metabolic reprogramming and EMT-mediated metastasis.

Lung cancer is the leading cause of cancer-related mortality worldwide, is driven by metastatic dissemination and metabolic adaptation. However, the underlying mechanisms remain poorly understood. This study identifies PIK3C2B, an understudied isoform of PI3K, as a key regulator of these processes. Integrative transcriptomics analysis of eight GEO datasets revealed 336 consistently dysregulated genes, with PIK3C2B emerging as a candidate associated with metastasis. Elevated expression of PIK3C2B was correlated with reduced overall survival (log-rank p < 0.05) and shorter disease-free survival (p < 0.05) in lung adenocarcinoma patients. Immunohistochemistry confirmed PIK3C2B overexpression in patient tumors. Functional validation showed that silencing PIK3C2B impaired proliferation and migration, while its overexpression enhanced these phenotypes. Mechanistically, PIK3C2B expression was correlated with epithelial-to-mesenchymal transition (EMT) regulators, suggesting its role in mesenchymal transition. Metabolic profiling using Seahorse analysis revealed that PIK3C2B enhanced mitochondrial oxidative phosphorylation (increased basal OCR and ATP production) and glycolytic flux (and fatty acid metabolism). Our findings establish PIK3C2B as a dual-function oncoprotein that promotes lung cancer progression through EMT activation and bioenergetic reprogramming. Its prognostic significance and role in metabolic adaptability highlight PIK3C2B as a promising therapeutic target for disrupting metastasis and enhancing tumor resilience.