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. Abstract Figure. Pum2 deficiency aggravates colitis via macrophage-epithelial crosstalk driving inflammation and necroptosis. Left: Pum2 loss promotes macrophage-driven inflammation, with increased chemokine expression, macrophage infiltration, and a pro-inflammatory phenotype characterized by TNFα secretion. Right: Macrophage-epithelial crosstalk triggers epithelial necroptosis. Proinflammatory signals from Pum2-deficient macrophages sensitize epithelial cells to TNFα-induced death. Simultaneously, epithelial Pum2 loss elevates ROS, facilitating RIPK1, RIPK3, and MLKL phosphorylation. This synergistic cascade amplifies necroptosis and establishes a self-perpetuating loop of barrier disruption and inflammation.