Abstract
Background: The prognosis and clinical treatment of hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors, remains significantly challenging, underscoring the urgent need for novel biomarkers and therapeutic strategies to improve patient outcomes. Our study investigated the clinical significance and biological functions of glucosylceramidase beta 3 (GBA3) in HCC progression. Methods: GBA3 expression was analyzed in 39 paired HCC and adjacent non-tumor tissues, validated in The Cancer Genome Atlas (TCGA) dataset, and further confirmed via immunohistochemistry (IHC) in 90 additional paired specimens. The connection between GBA3 expression and clinical outcomes was analyzed through use of TCGA data and Kaplan-Meier survival analysis. The functional roles of GBA3 were examined through knockdown experiments in HCC cells, with proliferation, migration, and invasion being evaluated. Mechanistic studies were conducted to clarify the link between GBA3 downregulation and ceramide metabolism via ceramide synthase 3 (CerS3). Results: The expression of GBA3 messenger RNA (mRNA) and protein were significantly downregulated in HCC tissues as compared to non-tumor tissues. Low GBA3 expression correlated with advanced HCC and shorter patient survival. Functional assays demonstrated that GBA3 knockdown enhanced HCC cell proliferation, migration, and invasion. Mechanistically, GBA3 downregulation reduced CerS3 expression, disrupting ceramide metabolism and promoting HCC progression. Conclusions: GBA3 downregulation in HCC is related to the aggressive behavior and poor prognosis, indicating its potential as a sphingolipid metabolism-related prognostic biomarker and therapeutic target for HCC.