Loss of Xanthine Oxidoreductase Potentiates Propagation of Hepatocellular Carcinoma Stem Cells

Background and Aims Liver cancer stem cells (CSCs) exist in the tumor environment and are critically involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of self‐renewal and maintenance of liver CSCs remain poorly understood. Approach and Results We identified that xanthine oxidoreductase (XOR), which was expressed at low levels in human HCC samples and liver CSCs, restrained HCC formation and chemoresistance by attenuating liver CSC propagation. Mechanistically, XOR physically interacts with ubiquitin‐specific peptidase 15 (USP15), thereby promoting deubiquitination of Kelch‐like ECH associated protein 1 (KEAP1) to stabilize its expression, which leads to degradation of Nrf2 (nuclear factor erythroid 2–related factor 2) through ubiquitination and subsequently reactive oxygen species accumulation in liver CSCs. Finally, our data reveal that XOR promotes USP15‐mediated Nrf2‐KEAP1 signaling to block liver CSCs and tumor propagation. Conclusion We identified that XOR may represent a potential therapeutic target for clinical intervention in HCC driven by liver CSCs.