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 Glycolysis was markedly upregulated in intestinal macrophages within damaged regions in UC patients, whereas PKM2 expression was associated with increased disease severity and a greater incidence of relapse. PKM2 depletion in macrophages enhanced intestinal barrier function and ameliorated colitis progression in mice. Mechanistically, PKM2 deficiency promoted monocyte differentiation into reparative Cadm1 + macrophages and enhanced Lgr5 + stem cell self-renewal via the PGE2/EP4 axis. Cross-species analysis revealed that human STAB1 + macrophages, which exhibit transcriptomic and metabolic similarities to mouse Cadm1 + macrophages, were positively associated with UC remission and spatial distribution of CD8 + T cells in colorectal cancer. Interestingly, macrophage PKM2 deletion greatly suppressed tumourigenesis in mice, accompanied by an increased abundance of Cadm1 + macrophages and enhanced CD8 + T-cell infiltration. Furthermore, targeting PKM2 in intestinal macrophages attenuated colitis progression in mice. Conclusions Therapeutic targeting of PKM2-dependent glycolysis in macrophages enhanced Cadm1 + macrophage-mediated mucosal healing without driving tumourigenesis.