Targeting Xanthine Oxidoreductase: A New Frontier to Overcome EGFR TKI Resistance in Intrahepatic Cholangiocarcinoma

Highlight

• Xanthine oxidoreductase (XOR) is identified as a key mediator of resistance to EGFR tyrosine kinase inhibitors (TKIs) in intrahepatic cholangiocarcinoma (iCCA).
• XOR promotes EGFR protein stability via USP8-mediated deubiquitination and upregulates MUC1, enhancing oncogenic signaling and DNA damage repair.
• Knockdown or inhibition of XOR reduces tumor proliferation, exacerbates DNA damage, and significantly increases sensitivity of iCCA cells to EGFR TKIs like gefitinib.
• Targeting XOR offers a novel therapeutic strategy to overcome TKI resistance and improve outcomes in patients with iCCA, an aggressive liver cancer with limited treatment options.

Study Background