Loss of Pum2 exacerbates colitis by disrupting macrophage–epithelial crosstalk and promoting epithelial necroptosis

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder characterized by persistent mucosal immune activation and compromised epithelial barrier function. In this study, we identify the RNA-binding protein PUMILIO2 (Pum2) as a previously unrecognized regulator of intestinal inflammation. Analysis of colonic tissues from UC patients revealed reduced Pum2 expression, which inversely correlated with disease activity. In dextran sulfate sodium (DSS)-induced colitis models, Pum2 deficiency exacerbated mucosal injury, accompanied by heightened macrophage inflammation. Mechanistically, Pum2 loss during colitis drives macrophage hyperactivation and TNFα-dependent epithelial necroptosis, which together intensify pathogenic macrophage–epithelial interactions and barrier breakdown. The dynamic downregulation of Pum2 in active inflammation underscores its potential as a therapeutic target for modulating macrophage–epithelial interactions and restoring intestinal barrier integrity in the context of colitis.