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

TL;DR

This study identifies the androgen receptor (AR) as a key target for metformin-induced ferroptosis in liver cancer, offering a new approach to improve survival and treatment response.

Contribution

Novel identification of AR as a metformin docking target and a prognostic model for ferroptosis suppressor genes in liver cancer.

Findings

AR, HIF1A, and CA9 were identified as ferroptosis suppressor genes in metformin-induced liver cancer cell death.

Metformin efficiently docks with AR and downregulates its protein expression in vitro.

A survival prognosis model based on ferroptosis suppressor genes was developed and validated.

Abstract

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.

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.

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.

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.

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