Estrogen Receptor β Alleviates Colitis by Inhibiting Ferroptosis in Intestinal Epithelial Cells.

BACKGROUND: Ulcerative colitis (UC), a major type of inflammatory bowel disease, is characterized by chronic inflammation of the colonic mucosa and submucosa. Estrogen receptor β (ERβ) predominates in the colon and exerts anti-inflammatory effects. Ferroptosis, a recently discovered form of iron-dependent programmed cell death, is implicated in the pathogenesis of several diseases, including UC. However, the link between ferroptosis and the anti-inflammatory actions of ERβ in UC remains to be elucidated. METHODS: We analyzed colonic mucosal samples from inflammatory and non-inflammatory regions of UC patients to assess ferroptosis levels. Experimental colitis was induced in wild-type C57BL/6 mice and intestinal epithelial cell-specific ERβ knockout (ERβ(-/-)) mice using dextran sulfate sodium (DSS). We measured body weight, colon length, disease activity index (DAI), and histopathological scores. RNA sequencing was performed to identify differentially expressed genes and related signaling pathways, with additional ferroptosis assessment in vivo and in vitro through biochemical markers and cellular assays. RESULTS: In UC patients, ferroptosis was significantly elevated in inflammatory mucosal regions compared to non-inflammatory areas. Compared to the wild-type counterparts, ERβ(-/-) mice exacerbated DSS-induced experimental colitis, including reduced body weight, shortened colon length, and higher DAI scores. RNA sequencing showed enrichment of inflammatory and immune response pathways, with significant activation of JAK/STAT, NF-κB, and TNF signaling in ERβ(-/-) mice. ERβ deficiency induced ferroptosis in both in vitro and in vivo models. Ferroptosis indicators such as PTGS2 were upregulated, GPX4 expression was downregulated, and there were increases in malondialdehyde, iron content, reactive oxygen species, and mitochondrial damage. CONCLUSION: Our findings demonstrate that ERβ deficiency exacerbates colitis and enhances ferroptosis in IECs. ERβ positively regulates GPX4 transcription, thereby inhibiting ferroptosis and alleviating colitis. These insights suggest that modulation of ERβ and its regulation of ferroptosis may represent a novel therapeutic strategy for UC.