Hinokitiol identified from Phyllanthus fraternus leaves a potential therapeutic solution for hepatocellular...

Phyllanthus fraternus G.L. Webster is an important medicinal plant known for its hepatoprotective activity since ancient times. Our previous study resulted in the identification of hepatoprotective lead compounds through in-silico approach from the aqueous extract of P. fraternus leaves. This finding instigated us to know the potential of identified lead compounds against the fatal liver disease hepatocellular carcinoma (HCC). In the present study, hinokitiol identified from Phyllanthus fraternus has been subjected to a network pharmacology-based study to know the possible targets of HCC and elucidate their mechanism of action. The protein-protein interaction analysis of the target genes of HCC and hinokitiol resulted in the identification of the five hub genes AKT1, EGFR, CASP3, TNF and SRC. These genes exhibited the best docking scores with hinokitiol, demonstrating strong binding affinities: AKT1 (- 6.3), EGFR (- 6.8), CASP3 (- 4.5), TNF (- 4.4), and SRC (- 6.0), which were further validated by molecular dynamics simulations that provided insights into the stability and flexibility of the protein-ligand complexes. The hub genes analysis predicts the involvement of two genes, AKT1, and EGFR, in HCC through MAPK, PI3K-Akt, and calcium signaling pathways. Although three other hub genes CASP3, TNF and SRC could also play a role in developing HCC by prognosis of Hepatitis B, and C and apoptosis. This finding was further validated by the Gepia2 and human protein atlas, confirming the usefulness of hinokitiol against HCC.

The online version contains supplementary material available at 10.1007/s40203-026-00698-1.