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

Chujiao Hu1,2, Huading Tai3, Renguang Zhu1

  • 1State 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.

Communications Biology
|February 16, 2026
PubMed

Insights

This study identifies ATOX1 as a key gene driving cisplatin resistance in liver cancer. Targeting ATOX1 with compound 8 offers a potential new strategy to improve liver cancer treatment effectiveness.

Area of Science:

  • Hepatocellular Carcinoma Research
  • Cancer Drug Resistance Mechanisms
  • Molecular Oncology

Background:

  • Cisplatin resistance significantly limits the efficacy of liver cancer treatment.
  • Identifying novel molecular targets is crucial for overcoming therapeutic resistance in liver cancer.

Purpose of the Study:

  • To identify genes critical for cisplatin resistance in liver cancer.
  • To develop targeted inhibitors for overcoming cisplatin resistance.

Main Methods:

  • Genome-wide CRISPR-Cas9 screening to identify resistance genes.
  • In vitro and in vivo validation of gene knockdown effects.
  • Molecular dynamics simulation and virtual screening for inhibitor identification.
  • Assessment of compound 8's inhibitory activity and synergistic effects with cisplatin.

Main Results:

  • ATOX1 was identified as a critical gene for cisplatin resistance, highly expressed in liver cancer with poor prognosis.
  • ATOX1 knockdown enhanced cisplatin sensitivity in liver cancer cells.
  • Compound 8 effectively inhibited ATOX1, showing synergistic effects with cisplatin.
  • ATOX1 inhibition led to copper accumulation, NOTCH1 promoter methylation, and suppressed NOTCH1/HES1 signaling, enhancing cisplatin sensitivity.

Conclusions:

  • ATOX1 plays a crucial role in conferring cisplatin resistance in liver cancer.
  • Targeting ATOX1 with compound 8 represents a promising therapeutic strategy to overcome cisplatin resistance.
  • The mechanism involves copper accumulation and modulation of the NOTCH1/HES1 pathway.

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