Identification of Androgen Receptor as a Molecular Docking Target for Survival and Response to Metformin-Induced Ferroptosis in Liver Cancer

Background: Hepatocellular Carcinoma (HCC) ranks among the most prevalent human cancers and stands as the third most common cause of death related to Cancer globally. Current therapies for HCC include surgical resection, local ablation, chemoembolization, liver transplantation, and molecular-targeted therapy. Only a small number of patients are detected in the early stage, and most patients are diagnosed at the time of the middle and late stages, thus losing the opportunity for surgical treatment, which is an essential reason for the high mortality of HCC patients. Initiating cytotoxicity in Cancer cells stands as a fundamental approach for tumor treatment, with the majority of research centering on Apoptosis.

Aims: Since anti-apoptotic methods often fulfill Cancer cells' ability to resist Anticancer drugs, research on new induction forms of regulative cell death, such as Ferroptosis, is of great clinical value.

Methods and results: In this study, we employed a combination of in silico molecular docking and in vitro cell validation experiments to identify three Ferroptosis suppressor genes, AR, HIF1A, and CA9, as promising components of a survival prognosis model during the metformin-induced Ferroptosis process in liver Cancer. Further, we discovered that AR could achieve efficient molecular docking with Metformin among these genes. Additionally, cell experiments revealed that Metformin could downregulate the protein expression level of AR.

Conclusion: This research has developed a prognostic model for Ferroptosis suppressor genes through the analysis of the Ferroptosis process induced by metformin in liver Cancer. It also screened and validated AR as a potential molecular docking target for metformin.