KEY POINTS
- A genome-wide CRISPR–Cas9 screen used 77,441 guide RNAs targeting 19,114 genes to identify regulators of oxidative-stress resistance in hepatocellular carcinoma.
- DCAF4 was upregulated in tumour tissue, including a cohort of 98 resected hepatocellular carcinomas, and higher expression was associated with adverse pathological features and poorer overall survival.
- DCAF4 promoted KEAP1 ubiquitination and degradation within stress granules, releasing NRF2 and increasing antioxidant genes including HO-1 and NQO1.
- DCAF4 depletion increased reactive oxygen species and sensitized hepatocellular carcinoma cells to iodine-125 seed irradiation.
- Virtual screening identified Rebaudioside M, which bound DCAF4 with an approximate dissociation constant of 11 µM and enhanced brachytherapy response in preclinical tumour models.
CLINICAL TAKEAWAY
The DCAF4–KEAP1–NRF2 axis is a plausible mechanism of resistance to oxidative injury from iodine-125 brachytherapy and a potential radiosensitization target. Rebaudioside M and its liposomal formulation remain experimental compounds, with no evidence yet concerning human dosing, safety or clinical efficacy.