Inflammatory bowel disease (IBD) is a formidable disease due to its complex pathogenesis. Macrophages, as a major immune cell population in IBD, are crucial for gut homeostasis. However, it is still unveiled how macrophages modulate IBD. Here, we found that LIM domain only 7 (LMO7) was downregulated in pro-inflammatory macrophages, and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) through K48-mediated ubiquitination in macrophages. As an enzyme that regulates glycolysis, PFKFB3 degradation led to the glycolytic process inhibition in macrophages, which in turn inhibited macrophage activation and ultimately attenuated murine colitis. Moreover, we demonstrated that PFKFB3 was required for histone demethylase Jumonji domain-containing protein 3 (JMJD3) expression, thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27 (H3K27me3). Overall, our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis. Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.

炎症性肠病（IBD）因其复杂的发病机制而成为一种可怕的疾病。巨噬细胞作为 IBD 的主要免疫细胞群，对于肠道稳态至关重要。然而，巨噬细胞如何调节 IBD 仍不清楚。在这里，我们发现促炎巨噬细胞中仅 LIM 结构域 7 (LMO7) 下调，并且 LMO7 通过 K48 介导的泛素化直接降解 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3 (PFKFB3)巨噬细胞。作为一种调节糖酵解的酶，PFKFB3 的降解导致巨噬细胞中的糖酵解过程受到抑制，进而抑制巨噬细胞的活化，最终减轻小鼠结肠炎。此外，我们证明PFKFB3是组蛋白去甲基化酶Jumonji结构域蛋白3（JMJD3）表达所必需的，从而抑制组蛋白H3赖氨酸27（H3K27me3）三甲基化的蛋白水平。总的来说，我们的结果表明 LMO7/PFKFB3/JMJD3 轴对于调节巨噬细胞功能和 IBD 发病机制至关重要。靶向 LMO7 或巨噬细胞代谢可能是治疗炎症性疾病的有效策略。