APOL4-mediated intracellular cholesterol trafficking is essential for glioblastoma cell growth
Background Dysregulated fatty acid metabolism is a key contributor to poor prognosis in glioma, and targeting cholesterol metabolism represents a promising therapeutic strategy. Apolipoprotein L4 (APOL4), a member of the Apolipoprotein L family, has been implicated in lipid metabolism, but its role in glioma remains unclear. Methods RNA-sequencing were performed to analysis gene expression under exogenous cholesterol treatment. Comprehensive bioinformatics analyses were performed using CGGA datasets to evaluate APOL4 expression, clinical correlations, and prognostic significance in GBM. In vitro experiments, including CRISPR-Cas9 mediated APOL4 knockdown, MTT assays, wound healing assays and immunofluorescence were performed to validate the oncogenic role of APOL4. Xenograft mouse models were employed to validate tumor growth in vivo. Results RNA-sequencing showed that exogenous cholesterol upregulated the expression of APOL4 in U-87 cells. Clinical database analysis revealed that APOL4 was significantly upregulated in human glioblastoma. Genetic depletion of APOL4 markedly suppressed glioblastoma cell proliferation in vitro and impaired xenograft tumor growth in vivo. Furthermore, APOL4 localized to late endosomes and lysosomes, where it likely facilitated the cytoplasmic transport of exogenous cholesterol, supporting tumor cell growth. Conclusions Our study identifies APOL4 as a novel regulator of cholesterol trafficking in glioma cells, promoting glioblastoma progression. These findings highlight APOL4 as a potential therapeutic target for glioma treatment.
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