Lack of GCLC Protein Increases Cell Intake of BNCT Drugs Through Stress-Triggered Cell Drinking

GCLC deficiency enhanced boron uptake in tumor cells by depleting glutathione and triggering oxidative stress.

• A genome-wide CRISPR-Cas9 screen identified genetic factors influencing boron uptake in osteosarcoma cells.
• Loss of GCLC significantly increased the internalization of boron-containing agents in tumor cells.
• This enhancement was linked to increased oxidative stress and boosted macropinocytosis.
• GCLC deficiency resulted in a much greater uptake of boron delivery agents in tumor cells compared to normal osteoblasts.
• In U2OS xenografts, silencing GCLC led to increased boron accumulation in tumors without affecting normal tissue distribution.
• These findings suggest that targeting GCLC could improve boron delivery in BNCT for osteosarcoma treatment.

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