Li Junrong, Chen Yidong, Yu Qi, Li Shuang, Zhang Xiaopeng, Cheng Yiyu, Fu Xiaoyu, Li Jiamin, Zhu Liangru
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Division of Gastroenterology, Chongqing Hospital Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Chongqing, China.
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Exp Cell Res. 2025 Apr 15;447(2):114520. doi: 10.1016/j.yexcr.2025.114520. Epub 2025 Mar 17.
Estrogen receptor β (ERβ) plays a pivotal role in regulating intestinal epithelial function and inflammation. Its involvement in inflammatory bowel diseases (IBD), particularly in ulcerative colitis (UC), remains poorly understood, despite emerging evidence pointing to its anti-inflammatory properties. This study investigated ERβ expression in UC patients using quantitative PCR, Western blot, and immunofluorescence. To investigate the functional role of ERβ, a DSS-induced colitis mouse model and LPS-treated HT-29 cells were used. Autophagy activity was evaluated through Western blot, transmission electron microscopy (TEM), and autophagy inhibitors. Co-immunoprecipitation (Co-IP) and dual luciferase reporter assays were employed to explore the interaction between ERβ and hypoxia-inducible factor-1α (HIF-1α), as well as the regulation of ATG-9a expression. The results demonstrated that ERβ expression was significantly downregulated in the inflammatory colons of UC patients. In vivo, ERβ activation by ERB041 alleviated DSS-induced colitis in mice, reducing weight loss, histopathological damage, and inflammatory cytokine levels. In vitro, ERB041 enhanced autophagy in LPS-treated HT-29 cells, accompanied by a reduction in pro-inflammatory cytokines. Furthermore, ERβ activation promoted the expression of tight junction proteins and preserved epithelial barrier integrity. Co-IP and dual luciferase assays revealed that ERβ interacted with HIF-1α and modulated ATG-9a-mediated autophagy. These results indicate that ERβ alleviates intestinal inflammation and activates HIF-1a and ATG-9a-mediated autophagy, providing new insights into the therapeutic potential of targeting ERβ in UC and highlighting its role in maintaining intestinal homeostasis.
雌激素受体β（ERβ）在调节肠道上皮功能和炎症中起关键作用。尽管越来越多的证据表明其具有抗炎特性，但其在炎症性肠病（IBD），特别是溃疡性结肠炎（UC）中的作用仍知之甚少。本研究使用定量PCR、蛋白质免疫印迹法和免疫荧光法检测了UC患者中ERβ的表达。为了研究ERβ的功能作用，使用了葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型和经脂多糖（LPS）处理的HT-29细胞。通过蛋白质免疫印迹法、透射电子显微镜（TEM）和自噬抑制剂评估自噬活性。采用免疫共沉淀（Co-IP）和双荧光素酶报告基因检测法探讨ERβ与缺氧诱导因子-1α（HIF-1α）之间的相互作用，以及对自噬相关蛋白9a（ATG-9a）表达的调控。结果表明，UC患者炎症结肠中ERβ表达显著下调。在体内，ERB041激活ERβ可减轻DSS诱导的小鼠结肠炎，减少体重减轻、组织病理学损伤和炎症细胞因子水平。在体外，ERB041增强LPS处理的HT-29细胞中的自噬，同时促炎细胞因子减少。此外，ERβ激活促进紧密连接蛋白的表达并维持上皮屏障完整性。免疫共沉淀和双荧光素酶检测显示，ERβ与HIF-1α相互作用并调节ATG-9a介导的自噬。这些结果表明，ERβ可减轻肠道炎症并激活HIF-1α和ATG-9a介导的自噬，为靶向ERβ治疗UC的潜力提供了新的见解，并突出了其在维持肠道稳态中的作用。
