Nootkatone Orchestrates Mitochondrial Redox Homeostasis via Nrf2 to Attenuate Sleep Deprivation-Induced Gut Barrier Disruption

Several clinical studies have shown that sleep deprivation is strongly associated with intestinal barrier dysfunction. Nootkatone (NKT), a principal bioactive sesquiterpenoid from grapefruit, has shown therapeutic potential for sleep and gastrointestinal disorders, although its mechanisms remain unclear. This study investigated the protective effects of NKT on SD-induced colonic injury. NKT significantly ameliorated SD-induced intestinal barrier dysfunction by upregulating key epithelial proteins and inducing mucin production. NKT also suppressed the expression of proinflammatory cytokines. Transcriptomic analysis revealed that NKT modulated pathways associated with mitochondrial function, oxidative stress, and intestinal inflammation. Importantly, NKT treatment also restored the gut microbial composition, increased the abundance of beneficial bacteria, and improved microbiota–metabolite interactions. Mechanistically, NKT activated the nuclear factor erythroid 2-related factor 2(Nrf2) pathway, leading to reduced reactive oxygen species accumulation and improved mitochondrial function in colonic tissues. These results highlight the potential of NKT as a plant-derived therapeutic agent for sleep-related gastrointestinal disorders.