Aucan targets CDK2 to suppress glioblastoma progression by inhibiting PI3K/AKT pathway-mediated proliferation and inducing apoptosis

Abstract Background Glioblastoma is the most aggressive form of primary brain tumor, characterized by uncontrolled proliferation and anti-apoptotic properties of tumor cells. Despite therapeutic advances, treatment options remain limited, highlighting the need for novel drugs. This study investigated the therapeutic potential of Aucan (C₁₈H₁₇NO₆), a dibenzofuran analog from Natural herbal plant, Usnea, against glioblastoma, focusing on its mechanisms of action. Methods This study investigates the role of Aucan in glioma cells through in vitro and in vivo experiments, and combines network pharmacology, Mendelian randomisation, and single-cell sequencing to analyse the targets and potential mechanisms of Aucan's action on glioma. The effects of Aucan on glioma cell proliferation were assessed using the CCK-8 assay and plate cloning experiments, while changes in glioma cell invasion were detected using the Transwell assay. Subcutaneous tumour and orthotopic tumour model models were established in nude mice to evaluate the therapeutic efficacy of Aucan in vivo, and histopathological changes in major organs were detected using haematoxylin and HE staining. Network pharmacology combined with Mendelian randomisation identified CDK2 as a key gene in glioma, and single-cell sequencing analysis revealed its high expression in astrocytic cells undergoing carcinogenesis. Finally, functional recovery experiments demonstrated that Aucan targets CDK2 to modulate the PI3K/AKT pathway, thereby exerting its anti-glioblastoma effects. Results In vitro, Aucan inhibited glioma cell proliferation, migration, and invasion while inducing apoptosis. In vivo, It suppressed tumor growth in both subcutaneous and intracranial models and prolonged survival without major organ toxicity. Network pharmacology and Mendelian randomization identified CDK2 as a critical target, with single-cell RNA-seq confirming its overexpression in tumor astrocytes. Aucan downregulated CDK2, leading to reduced PI3K/AKT pathway activity, decreased proliferation, and increased apoptosis. CDK2 knockdown replicated these effects. Conclusions Aucan exerts anti-glioma effects by targeting CDK2, thereby inhibiting PI3K/AKT-mediated proliferation and promoting apoptosis. These results position Aucan as a promising therapeutic candidate for glioblastoma.