In silico and in vitro study of the proapoptotic, autophagic and antitumor effects of cirsimaritin and humulene in hepatocellular carcinoma.

The effects of natural compounds in cancer chemoprevention are being extensively studied. This study assesses the cytotoxic, apoptotic and autophagic effects of cirsimaritin and humulene in hepatoma cells. Antioxidant activity in normal kidney epithelial cell line (VERO) and cytotoxicity tests in HepG2 cells were investigated. Their effects on P53, c-myclocus (C-Myc), apoptotic, and autophagic proteins in HepG2 cells along with flow cytometric analysis of cell cycle and apoptosis were determined. Molecular docking to some proteins was studied. The in vitro results indicated an enhanced antioxidant activity in VERO cells by cirsimaritin and humulene, with low cytotoxic effects in HepG2 cells (half maximal inhibitory concentrations (IC(50)) were 363 and 378 µg/ml respectively) and no cytotoxicity in normal cells at high concentration. They reduced C-Myc expression and induced P53 activity, G1-cell cycle arrest, and proapoptotic and autophagic cascades in HepG2 cells. Flow cytometric analysis of cell cycle and apoptotic cells and the in silico study confirmed the biochemical results of cirsimaritin against P53, proapoptotic, and autophagic proteins. Collectively, cirsimaritin could markedly inhibit HepG2 cell progression through induction of P53, apoptotic, and autophagic cascades in tested hepatocellular carcinoma cells over humulene's effects. Its protective antioxidant effects in normal cells and anticancer effect make it a promising candidate for preventing the progression of HCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-026-00963-3.