Potential Therapeutic Effects of Chrysin and Apigenin in a Diethylnitrosamine‐Induced Hepatocellular Carcinoma Rat Model

Hepatocellular carcinoma (HCC) is an aggressive cancer with poor prognosis and high mortality rates. The increasing mortality associated with HCC highlights the urgent need for alternative therapeutic approaches. Natural products and their structural analogs have shown promise as novel treatment options. This study aimed to evaluate the potential therapeutic effects of the natural flavonoids apigenin and chrysin, administered individually and in combination, in an experimental HCC model. Forty-eight rats were divided into five groups: Control, DEN, DEN + Apigenin, DEN + Chrysin, and DEN + Combination. HCC was induced by intraperitoneal administration of diethylnitrosamine (DEN, 150 mg/kg), followed by oral 2-acetylaminofluorene (2-AAF, 20 mg/kg) according to a standardized protocol. Subsequently, Apigenin and chrysin were administered orally at 50 mg/kg for 8 weeks following tumor induction. At the end of the treatment, biochemical and histopathological analyses were performed on blood and liver tissue samples. Compared to controls, DEN-induced HCC was associated with activation of tumor-promoting signaling pathways, as evidenced by increased levels of survivin, annexin-V, smoothened, sonic hedgehog, jagged1, and notch1, alongside reduced caspase-3 expression. Histological examination revealed normal liver architecture in controls, while DEN-treated rats showed varying degrees of fibrosis (62.5% moderate to severe), inflammatory lesions, regenerative nodules, and 87.5% moderate to severe inflammation. Treatment groups displayed marked reductions in fibrosis and inflammation, with the most pronounced effects observed in DEN + Apigenin and combination groups. These findings suggest that apigenin, chrysin, and their combination may exert antitumor effects in experimental HCC, with apigenin demonstrating comparatively more pronounced activity based on biochemical and histopathological findings.