PSMB8 as a Core Target Mediating the Anti-Hepatocellular Carci-Noma Activity of Lingonberry (Vaccinium vitis-idaea L.) Extract in HepG2 Cells

Hepatocellular carcinoma (HCC) is a highly malignant tumour with a poor prognosis and few effective treatment options. Development of resistance to conventional therapies and occurrence of severe side effects highlight the urgent need for novel, low-toxicity interventions. Natural products are promising candidates for HCC drug development thanks to their multi-target activity and favourable safety profiles. Previous studies reported that Lingonberry extract, a bioactive natural product, inhibits proliferation of HepG₂ cells. However, the key molecular targets and underlying anticancer mechanisms remain unclear. In this study, we analysed gene chip data from Lingonberry extract-treated HepG₂ tumour-bearing mice using bioinformatics tools, employing a cross-species, multi-level screening strategy to identify PSMB8 as the core regulatory gene. In vitro functional validations (Western blotting, RT-PCR, CCK-8 assay, colony formation assay, flow cytometry and TUNEL staining) confirmed these findings. Downregulating PSMB8 was found to effectively induce late apoptosis in HepG₂ cells, and Lingonberry extract was found to significantly reduce PSMB8 protein expression. This study identifies PSMB8 as a key mediator of the anticancer effect of Lingonberry extract in HepG₂ cells. It provides a reliable methodological reference for screening anticancer targets of natural products and supports further exploration of Lingonberry extract as a potential adjuvant/lead compound for HCC.