Kaempferol triggers cellular senescence via CDK1 ubiquitination in HCC cells

Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis. Cellular senescence, a state linked to cell cycle arrest, represents a potential therapeutic strategy for cancer. However, the clinical impact and regulatory mechanism of cellular senescence in HCC remains incompletely unknown. We identified HCC associated differentially expressed genes (DEGs) using bioinformatics analysis of public databases (TCGA, GEO, GEPIA, etc.). Enrichment, prognostic, risk scoring models analyses revealed cyclin-dependent kinase 1 (CDK1) as a core senescence-related gene. CDK1 expression was upregulated in HCC tissues and correlated with poor prognosis of HCC patients. In addition, CDK1 knockdown significantly increased senescence markers (the level or activity of P16, P21, and SA-β-gal), and induced cellular senescence in HepG2 cells. Molecular docking demonstrated high-affinity binding between CDK1 and kaempferol (KAE; affinity = -9.7 kcal/mol). KAE treatment similarly increased senescence markers and promoted cellular senescence in HepG2 cells. Mechanistically, KAE reduced CDK1 protein levels by promoting its ubiquitination and subsequent degradation. These findings indicated that KAE might induce cellular senescence through CDK1 ubiquitination, providing potential drugs and targets for HCC treatment.