Mechanistic study of quercetin in the treatment of hepatocellular carcinoma with diabetes via MEK/ERK pathway

Hepatocellular carcinoma (HCC) is a complex disease, further exacerbated by coexisting diabetes. With the rising incidence of HCC-diabetes cases, alternative treatment strategies are urgently needed. Traditional Chinese Medicine (TCM) offers promising options, and quercetin, a bioactive flavonoid, has shown significant antitumor and antidiabetic effects. This study aimed to investigate the efficacy of quercetin in treating HCC with diabetes using bioinformatics and network pharmacology. We constructed a prognostic model for HCC-diabetes using multivariate Cox proportional hazards regression and identified potential targets for quercetin by intersecting quercetin target genes with HCC-diabetes genes. Molecular docking and molecular dynamics simulations screened these potential targets, and in vitro experiments verified quercetin's targets and pathways. The results revealed a prediction model with four essential genes that effectively predict HCC prognosis in diabetic patients. IL6 and MMP9 were identified as potential targets of quercetin through molecular docking and dynamics simulations. In vitro experiments revealed that quercetin promotes apoptosis, inhibits cell proliferation, and suppresses epithelial-mesenchymal transition (EMT) in HepG2 cells under high-glucose conditions by reducing IL6 expression and inhibiting the MEK/ERK pathway. In summary, quercetin may delay the progression of HCC-diabetes by modulating IL6 to inhibit the MEK/ERK signaling pathway, thereby promoting apoptosis and inhibiting the proliferation and EMT of HepG2 cells.