Targeting PKM2-dependent glycolysis reprogrammes monocytes into Cadm1 ⁺ macrophages to promote mucosal repair and attenuate colitis progression

BACKGROUND: Incomplete mucosal healing contributes to progression and relapse in ulcerative colitis (UC). Currently, therapeutic strategies that promote mucosal healing and regeneration are limited and may potentiate oncogenic transformation. OBJECTIVE: We aimed to identify whether modulating macrophage metabolism may facilitate mucosal healing without driving tumourigenesis. DESIGN: Potential therapeutic targets associated with UC disease activity and relapse were assessed in multiple omics datasets and three clinical UC studies. The function and mechanism of macrophage pyruvate kinase M2 (PKM2) in UC progression were demonstrated by macrophage-specific PKM2 knockout mice, single-cell and spatial transcriptomic profiling, and human macrophage-colonic organoid coculture models. RESULTS: T-cell infiltration. Furthermore, targeting PKM2 in intestinal macrophages attenuated colitis progression in mice. CONCLUSIONS: macrophage-mediated mucosal healing without driving tumourigenesis.