Abstract
Fatty acid metabolism is critically involved in glioblastoma (GBM) pathogenesis; however, its regulatory mechanisms remain incompletely understood. In this study, we identified biliverdin reductase A (BLVRA) as a novel metabolic driver and prognostic biomarker in GBM by integrating bulk and single-cell RNA sequencing with in vitro functional validation. Using ten machine learning algorithms, we developed a fatty acid metabolism-related gene prognostic index (FAMRGPI), which demonstrated strong prognostic value and highlighted the importance of metabolic reprogramming and immune modulation in GBM. Among FAMRGPI components, BLVRA emerged as an independent prognostic factor, with elevated expression associated with poor clinical outcomes. Single-cell transcriptomic analysis revealed that BLVRA expression correlated with tumor heterogeneity and differentiation potential. Experimental validation confirmed that BLVRA was markedly upregulated in GBM tissues and cell lines. Functional assays showed that BLVRA knockdown suppressed GBM cell proliferation and colony formation, disrupted lipid homeostasis (decreased carnitine and triglyceride levels, increased CPT1A and coenzyme A), and induced oxidative stress and DNA damage. Mechanistically, BLVRA depletion increased ROS accumulation, upregulated γ-H2AX, p53, and cleaved caspase-3 expression, and led to downregulation of key cell cycle regulators including CDK2, CDK4, CDK6, Cyclin D1, and c-MYC, thereby promoting cell cycle arrest and apoptosis. This study is the first to establish BLVRA as a critical regulator of fatty acid metabolism in GBM, revealing its dual role in maintaining metabolic homeostasis and supporting tumor growth. These findings uncover a novel metabolic vulnerability in GBM and suggest that BLVRA may serve as a potential therapeutic target for metabolic intervention.