Donafenib and GSK-J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Donafenib is a multi-receptor tyrosine kinase inhibitor approved for the treatment of patients with advanced HCC, but its clinical effect is very limited. Here, through integrated screening of a small-molecule inhibitor library and a druggable CRISPR library, that GSK-J4 is synthetically lethal with donafenib in liver cancer is shown. This synergistic lethality is validated in multiple HCC models, including xenograft, orthotopically induced HCC, patient-derived xenograft, and organoid models. Furthermore, co-treatment with donafenib and GSK-J4 resulted in cell death mainly via ferroptosis. Mechanistically, through integrated RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with high throughpu

SUBMITTER: Zheng C 

PROVIDER: S-EPMC10401117 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature