Cell death & diseaseJul 14, 2026

CRISPR screen finds DCAF4 helps liver cancer resist radiation by activating cell stress defense

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

Updated Jul 15, 2026

Abstract

DDB1 and CUL4-associated factor 4 (DCAF4) is identified as a crucial regulator of oxidative stress resistance in hepatocellular carcinoma (HCC).

DCAF4 promotes the breakdown of KEAP1, which is involved in managing oxidative stress.
The interaction between DCAF4 and KEAP1 is facilitated by stress granules that form under oxidative stress.
Activation of NRF2 and the subsequent increase in antioxidant genes occur as a result of KEAP1 degradation.
XBP1 is found to enhance the expression of DCAF4.
A small-molecule inhibitor targeting the DCAF4-KEAP1 interaction shows potential in increasing sensitivity to brachytherapy and reducing tumor growth in HCC models.

Simplified

Hepatocellular carcinoma (HCC) cells sustain viability and radioresistance by actively countering oxidative stress. Understanding the mechanisms regulating reactive oxygen species (ROS) homeostasis is therefore crucial for developing novel therapies. Using integrated genome-wide CRISPR-Cas9 screening coupled with transcriptomic and metabolomic profiling, we identified DDB1 and CUL4-associated factor 4 (DCAF4) as an essential regulator of oxidative stress resistance in HCC. Mechanistically, DCAF4 functions as a CRL4 E3 ligase adapter that promotes KEAP1 ubiquitination and degradation. Notably, under oxidative stress, cytoplasmic stress granules (SGs) form a localized platform that facilitates the DCAF4-KEAP1 interaction, accelerating KEAP1 degradation and leading to NRF2 activation and upregulation of antioxidant genes. We further identified that the transcription factor XBP1 enhances DCAF4 expression. Targeting this axis, we performed computational screening to identify a small-molecule inhibitor that disrupts the DCAF4-KEAP1 interaction. This compound effectively enhanced brachytherapy (BT) sensitivity and inhibited tumor growth in preclinical HCC models.

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

0%of authors

0 of 16

authors report competing interests

16 report none

PubMed

CRISPR screen finds DCAF4 helps liver cancer resist radiation by activating cell stress defense

Abstract

Full Text

Funding

Competing interests

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