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.