Estrogen receptor β deficiency increases the susceptibility to ulcerative colitis by inducing mitochondrial fission and consequently accelerating senescence of colonic epithelial cells

作者：Yilei Guo, Yue He, Yanrong Zhu, Wenjie Zhang, Haochang Lin, Mianjiang Zhao, Jiafeng Zhang, Yawen Bai, Zhifeng Wei, Yufeng Xia, Yue Dai · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103919 · 被引用次数：5 · 研究领域：interferon and immune responses、NF-κB Signaling Pathways、Inflammatory Bowel Disease

The incidence of ulcerative colitis (UC) is significantly higher among individuals with colonic estrogen receptor β (ER β ) deficiency, such as postmenopausal women, but the involvement of ER β deficiency in UC pathogenesis remains obscure. Here, we showed that colonic ER β expression level in UC patients was negatively correlated with disease severity. In mice, ER β knockout induced spontaneous colitis-like symptoms and increased susceptibility to dextran sulfate sodium-induced colitis, with earlier onset and aggravated severity, whereas ER β overexpression reduced colitis susceptibility. Transcriptomic analysis and subsequent validation in UC patient samples revealed that ER β deficiency in colonic epithelial cells accelerated cellular senescence, which concurrently causing disruption of epithelial barrier and release of proinflammatory cytokines, ultimately increasing susceptibility to colitis. Mechanistically, ER β deficiency induced mitochondrial fission, resulting in mitochondrial DNA leakage and cGAS-STING pathway activation, thereby accelerating colonic epithelial cell senescence. Consistently, pre-administration of the phytoestrogens genistein and arctigenin attenuated mitochondrial fission-induced colonic epithelial cell senescence of mice through upregulating ER β expression, thereby markedly reducing susceptibility to colitis. In summary, our findings identify ER β as a susceptibility gene and therapeutic target for UC, unveil mitochondrial fission induced-colonic...