{
  "abstract": "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.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Di Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Ping Tao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Jinying Li"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China"
      ],
      "name": "Xingyan Zhou"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China"
      ],
      "name": "Hengdong Qu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China"
      ],
      "name": "Yaobin Li"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Haoxian Chen"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Huizhou Central People's Hospital, Huizhou, Guangdong, China"
      ],
      "name": "Hui Yuan"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Jiabin Huang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Ziyi Ji"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Pengqing Sun"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China"
      ],
      "name": "Haoting Lin"
    },
    {
      "affiliations": [
        "Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Keke Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Wei Huang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Huizhou Central People's Hospital, Huizhou, Guangdong, China"
      ],
      "name": "Huixin Chen"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China"
      ],
      "name": "Wencai Ye"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China",
        "Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Jian Hong"
    }
  ],
  "title": "Targeting PKM2-dependent glycolysis reprogrammes monocytes into Cadm1+ macrophages to promote mucosal repair and attenuate colitis progression",
  "uid": "92ee9f5e-9459-597d-8ea0-641c27553087"
}