Communications biologyFeb 16, 2026

CRISPR screen finds how ATOX1 causes cisplatin resistance in liver cancer and tests drugs targeting it

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

ATOX1 may drive cisplatin resistance in liver cancer, and compound 8 may restore sensitivity by disrupting copper-linked NOTCH1/HES1 signaling.

Evidence

A preclinical liver cancer study combined genome-wide CRISPR-Cas9 screening, tumor expression and prognosis analyses, cell and in vivo knockdown experiments, and virtual screening of an ATOX1 inhibitor with Kd = 12.5 μM.

Caveat

Compound 8 efficacy and the proposed copper-DNA methylation-NOTCH1 mechanism were tested preclinically, not in a human therapeutic trial.

Simplified

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.

Full Text

Full text is available at the source.

View Full Text ↗

Featured in

CRISPR Gene EditingIssue #25

Gene editing in mouse brains fixes autism-like behaviors caused by genetic mutations

↗

CRISPR screen finds how ATOX1 causes cisplatin resistance in liver cancer and tests drugs targeting it

Abstract

Full Text

Featured in

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the crispr gene editing brief