Targeting CCDC90B restores intestinal stem cell function under hyperuricemic stress

Hyperuricemia (HUA) affects diverse biological processes and signaling pathways across multiple organ systems; however, its impact on the intestine remains poorly understood. Here, we show that HUA disrupts intestinal barrier function primarily by impairing intestinal stem cell (ISC) function, which is essential for epithelial renewal. Mechanistically, elevated uric acid (UA) directly binds to the mitochondrial protein CCDC90B, leading to excessive mitochondrial ROS accumulation, activation of the NLRP3 inflammasome, and subsequent initiation of downstream pyroptotic signaling. The resulting exhaustion of the intestinal stem cell pool impairs epithelial regeneration and further weakens intestinal barrier integrity. Collectively, these findings reveal a previously unrecognized mechanism linking UA to ISC dysfunction and highlight CCDC90B as a potential therapeutic target for HUA-associated intestinal dysfunction.