Estrogen receptor β alleviates colitis in intestinal epithelial cells and activates HIF-1a and ATG-9a-mediated autophagy

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.