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

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

  • Adv Sci (Weinh). 2023 Jun 17;e2206798. doi: 10.1002/advs.202206798.
Chenyang Zheng 1 2 3,  Bo Zhang 2 3 4,  Yunyun Li 1 2 3,  Kejia Liu 5,  Wei Wei 1 2 3,  Shuhang Liang 2 3 4,  Hongrui Guo 1 2 3,  Kun Ma 6,  Yao Liu 1 2 3,  Jiabei Wang 1 2 3,  Lianxin Liu 1 2 3
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
  • 2 Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China.
  • 3 Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China.
  • 4 Department of Gastrointestinal Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
  • 5 Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, CAS Centre for Excellence in Molecular Cell Science, University of Science and Technology of China, Hefei, Anhui, 230001, China.
  • 6 Department of Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150007, China.
PMID: 37330650 DOI: 10.1002/advs.202206798
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 throughput sequencing (ATAC-seq) analyses, that donafenib and GSK-J4 synergistically promoted the expression of HMOX1 and increased the intracellular Fe2+ level is found, eventually leading to Ferroptosis. Additionally, through cleavage under targets & tagmentation followed by sequencing (CUT&Tag-seq), it is found that the enhancer regions upstream of HMOX1 promoter significantly increased under donafenib and GSK-J4 co-treatment. A chromosome conformation capture assay confirmed that the increased expression of HMOX1 is caused by the significantly enhanced interaction between the promoter and upstream enhancer under dual-drug combination. Taken together, this study elucidates a new synergistic lethal interaction in liver Cancer.

Keywords

donafenib; ferroptosis; gsk-j4; hmox1; synthetic lethal.

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