2. Academic Validation
  3. CRISPR-Cas9 screening identifies ATOX1-driven cisplatin resistance mechanisms in liver cancer and evaluates targeted inhibitor efficacy

CRISPR-Cas9 screening identifies ATOX1-driven cisplatin resistance mechanisms in liver cancer and evaluates targeted inhibitor efficacy

  • Commun Biol. 2026 Feb 16;9(1):439. doi: 10.1038/s42003-026-09722-8.
Chujiao Hu # 1 2,  Huading Tai # 3,  Renguang Zhu # 1,  Zhengyu Shu 1,  Guanghao Guo 4,  Dan Ma 5,  Shi Zuo 6 7,  Lei Tang 8,  Zhirui Zeng 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, Guizhou Medical University, Guiyang, China.
  • 2 Key Laboratory for Cancer Prevention and treatment of Guizhou Province, Guizhou Medical University, Guiyang, China.
  • 3 Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China.
  • 4 Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
  • 5 Department of hematology, Affiliated hospital of Guizhou Medical University, Guiyang, China. readying100@163.com.
  • 6 Key Laboratory for Cancer Prevention and treatment of Guizhou Province, Guizhou Medical University, Guiyang, China. drzuoshi@gmc.edu.cn.
  • 7 Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China. drzuoshi@gmc.edu.cn.
  • 8 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, Guizhou Medical University, Guiyang, China. tlei1974@gmc.edu.cn.
  • 9 Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China. zengzhirui@gmc.edu.cn.
  • # Contributed equally.
PMID: 41699288 DOI: 10.1038/s42003-026-09722-8
Abstract

Liver Cancer treatment with cisplatin is often hindered by drug resistance. This study aimed to identify key genes associated with cisplatin resistance in liver Cancer and develop targeted inhibitors. Using genome-wide CRISPR-Cas9 screening, ATOX1 was identified as a critical gene for cisplatin resistance. ATOX1 was highly expressed in liver Cancer tissues and associated with poor prognosis. Knockdown of ATOX1 in liver Cancer cells enhanced cisplatin sensitivity in vitro and in vivo. Molecular dynamics simulation and virtual screening identified compound 8 as a potent ATOX1 inhibitor with high affinity (Kd = 12.5 μM) and exhibited synergistic effects with cisplatin on liver Cancer cell growth. Mechanistically, compound 8 inhibits the activity of ATOX1, leading to intracellular copper accumulation. The elevated copper levels subsequently promote increased DNA methylation at the NOTCH1 promoter, resulting in suppression of the NOTCH1/HES1 signaling pathway and enhancing the sensitivity of liver Cancer cells to cisplatin. In conclusion, ATOX1 is crucial for cisplatin resistance in liver Cancer and linked to poor prognosis. Targeting ATOX1 with compound 8 may be a novel therapeutic strategy for overcoming cisplatin resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-181975
    ATOX1抑制剂
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