Single‐Cell Transcriptomics Unravels Growth Factor Erv1‐Like Mediated Ferroptosis as a Key Driver of Intestinal Epithelial Dysfunction in Ulcerative Colitis

Abstract Inflammatory bowel disease (IBD) is a group of chronic, relapsing, and idiopathic inflammatory disorders of the gastrointestinal tract, primarily including ulcerative colitis (UC) and Crohn's disease (CD). The pathogenesis of UC remains incompletely understood, particularly regarding epithelial iron homeostasis and the regulation of cell death. In recent years, the application of single‐cell RNA sequencing (scRNA‐seq) has provided a powerful tool for dissecting cell‐type‐specific molecular mechanisms in UC. In this study, a comprehensive analysis of scRNA‐seq data revealed that GFER expression is significantly downregulated in intestinal epithelial cells of UC patients, suggesting a potential role in disease development. This finding is further validated in both a DSS‐induced colitis mouse model and an LPS‐induced in vitro inflammation model of intestinal epithelial cells, where GFER overexpression markedly inhibits the expression of ferroptosis‐related markers and alleviates inflammatory damage. What's more, it is found that GFER interacts with the iron‐regulating factor PCBP1 to help maintain intracellular iron homeostasis and may also reduce lipid peroxidation by activating the PGC‐1α/PPARγ signaling pathway, thereby inhibiting ferroptosis. This study is the first to demonstrate the critical role of GFER in regulating ferroptosis in UC, providing new insights into the pathogenesis of UC and identifying a potential therapeutic target for future intervention strategies.