Clusterin deficiency aggravates colitis-associated oxidative injury by disrupting mitochondrial function and intestinal barrier integrity.

BACKGROUND: Oxidative stress and disrupted redox signaling contribute to the pathogenesis of ulcerative colitis (UC). The specific role of CLU in intestinal oxidative stress, however, remains poorly characterized. This study investigated the role of CLU in UC and its underlying mechanisms. METHODS: Mucosal CLU expression was evaluated in patients with UC and analyzed in relation to disease activity. CLU knockout mice with dextran sulfate sodium-induced colitis were used to assess intestinal injury, oxidative stress, and barrier integrity. In vitro, CLU knockdown and overexpression were established in NCM460 cells exposed to H₂O₂. Mitochondrial structure and function, antioxidant responses, barrier integrity, and Akt-Keap1-Nrf2 signaling were evaluated. RESULTS: Mucosal CLU expression was inversely associated with Mayo score in UC patients. CLU deficiency aggravated DSS-induced colitis, oxidative injury, and intestinal barrier disruption. In H₂O₂-treated IECs, CLU knockdown increased mitochondrial ROS accumulation, reduced antioxidant capacity, impaired mitochondrial membrane potential, and decreased barrier protein expression, whereas CLU overexpression attenuated these changes. In CLU-knockdown cells, AKTi-1/2 improved mitochondrial ultrastructure and ATP production and partially restored Keap1-Nrf2 antioxidant signaling. CONCLUSIONS: CLU deficiency aggravates colitis-associated oxidative injury and mitochondrial dysfunction, while CLU contributes to the maintenance of epithelial redox homeostasis. These effects are associated with AKT-dependent modulation of Keap1-Nrf2 antioxidant signaling.