Exploration of mechanism of Bufalin and Bufalin derivatives in hepatocellular carcinoma

Bufalin, a promising candidate for the treatment of hepatocellular carcinoma (HCC), has garnered interest from researchers in exploring its pharmacological mechanisms. The traditional single-target research method makes it difficult to elucidate the molecular mechanism systematically, and there are still limitations.

To explore the synergistic mechanisms of Bufalin and its derivatives in the treatment of HCC through quantitative and integrated analysis of big data, this study provides a reference for clinical screening of anti-liver cancer drugs and accelerates the research and development of new drugs.

The literature on the anti-liver cancer activity of Bufalin was searched, the research trends and hotspots were analyzed, and the hot targets were identified. Potential targets and signaling pathways were predicted and compared with established targets. To evaluate the affinity of Bufalin and its derivatives with key targets and validate the results of network pharmacology. The structure-activity relationships and pathways were reviewed, and key pharmacophore and potential pathways were identified.

Analysis of 302 literatures showed that Na⁺/K⁺-ATPase was a hot target in the anti-liver cancer mechanism of Bufalin. 76 potential targets are primarily associated with pathways such as PI3K/AKT/mTOR, Hedgehog, and AMPK/mTOR, which play roles in regulating key targets like phosphoinositide 3-kinase (PIK3), adenosine monophosphate-activated protein kinase (AMPK), and epidermal growth factor receptor (EGFR). Bufalin derivatives have a higher affinity with key targets. The cdocker interaction energy (CIE) of BF211, compound 1, and compound 2 with PI3K were -48.0722 kcal/mol, -50.8791 kcal/mol, and -59.7326 kcal/mol, respectively, which were significantly lower than Bufalin (-26.0859 kcal/mol).

Bufalin and its derivatives have significant anti-HCC activity and show good potential for drug development. Their mechanism of action involves a complex network of AMPK targets and PI3K/AKT/mTOR signaling pathways. In the future, specific inhibitors should be developed against these targets and pathways as a new therapeutic strategy for HCC. Among them, compounds 2, 7, and 8 have a higher affinity for potential targets than Bufalin and its other derivatives and have higher research value. In addition, α-pyrone is the key pharmacophore of Bufalin, and structural modification of the C3 position can significantly regulate its cytotoxicity and solubility. Therefore, optimization of the structure of the C3 position is expected to reduce the toxicity and improve the water solubility of Bufalin, overcoming the limitations of its clinical application and providing a safer and more effective solution for the treatment of HCC.