Role of Glucocerebrosidase in Metabolic Reprogramming and Prognosis of Hepatocellular Carcinoma: Insights from a Comprehensive Gene Expression Analysis

Introduction: Hepatocellular carcinoma (HCC) poses a substantial global public health concern, with its intricate pathogenesis remaining incompletely elucidated. Metabolic reprogramming is pivotal in liver cancer progression. This study investigates the role of the lysosomal enzyme Glucocerebrosidase (GBA) in HCC initiation. Methods: We analyzed GBA-related gene expressions in 1003 primary liver cancer samples from the GEO database and 433 liver cancer samples from the TCGA database to examine GBA expression patterns and their association with liver cancer prognosis. Additionally, we manipulated GBA and glucosylceramide synthase (UGCG) expressions in the MHCC-97H cell line to investigate their effects on lysosomal and non-lysosomal metabolic genes. Results: GBA expression was significantly elevated in liver cancer samples and closely associated with poor prognosis. Overexpression of GBA led to upregulation of related lysosomal metabolic genes (NEU1, CTSD, CTSA, GALNS, GLB1) and non-lysosomal metabolic genes (ACOT8, FDPS, PMVK, PIGC, B4GALT3). Non-lysosomal genes were involved in N-acetyl metabolism, fatty acid β-oxidation, and cholesterol synthesis. Co-upregulation of UGCG and GBA resulted in a dose-dependent increase in ACOT family gene expressions (ACOT8, ACOT4, ACOT9, ACOT11). Survival analysis indicated high expression of these genes was related to lower short-term survival rates in liver cancer patients. Conclusion: Our findings suggest GBA plays a role in the metabolic reprogramming of HCC, influencing disease progression and prognosis by modulating genes involved in N-acetyl metabolism and lysosomal complexes. Downregulating GBA expression may present a potential therapeutic strategy for managing HCC.