{
  "abstract": "Background Immune checkpoint blockade (ICB) targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has shown promise in hepatocellular carcinoma (HCC), but clinical responses are often limited in durability. Identifying novel drivers of immune evasion is crucial for improving therapeutic strategies.Methods We employed a multi-omics integrative framework to identify HCC-specific immune biomarkers. Functional roles were validated using in vitro and in vivo models, including UDP-glucuronate decarboxylase 1 (UXS1) knockout/overexpression, co-culture assays, and various mouse models. Molecular mechanisms were dissected using immunoprecipitation coupled with mass spectrometry, ubiquitination assays, chromatin immunoprecipitation, luciferase reporter assays, and single-cell RNA sequencing.Results We identified the glycosyltransferase UXS1 as a novel immune-related prognostic hub gene in HCC. UXS1 was upregulated due to copy number gain and MZF1-driven promoter hypomethylation. Functionally, UXS1 promoted HCC malignancy independently of its canonical enzymatic activity. Mechanistically, UXS1 interacted with the E3 ligase F-box and WD repeat domain-containing 7 (FBXW7) to promote histone-lysine N-methyltransferase 2D (KMT2D) ubiquitination and degradation. We further discovered that KMT2D, acting as a non-catalytic scaffold, recruited the transcriptional repressor CCAAT enhancer binding protein beta (CEBPB) to the PD-L1 promoter to maintain its repression. UXS1-mediated KMT2D degradation disrupted this complex, leading to CEBPB dissociation and consequent PD-L1 transcriptional derepression. In vivo, UXS1 suppressed CD8 + T-cell effector function. UXS1 knockout synergized with anti-PD-1 therapy, and in human HCC, high UXS1 correlated with low KMT2D, high PD-L1, and reduced CD8+ T-cell infiltration.Conclusion This study defines a novel UXS1-KMT2D-CEBPB-PD-L1 signaling axis, revealing how UXS1 drives immune evasion in HCC via epigenetic reprogramming. Targeting this axis may represent a potential strategy to overcome immune resistance, warranting further clinical investigation.",
  "authors": [
    {
      "affiliations": [
        "The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China",
        "State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China"
      ],
      "name": "Jiwei Zhang"
    },
    {
      "affiliations": [
        "The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China"
      ],
      "name": "Yuan Li"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China",
        "Department of General Surgery, Shanghai Geriatric Medical Center (Zhongshan Hospital Minhang Campus), Fudan University, Shanghai, China"
      ],
      "name": "Jiafeng Chen"
    },
    {
      "affiliations": [
        "The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China"
      ],
      "name": "Fen Ma"
    },
    {
      "affiliations": [
        "The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China"
      ],
      "name": "Ben Feng"
    },
    {
      "affiliations": [
        "The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China"
      ],
      "name": "Shiling Zhou"
    },
    {
      "affiliations": [
        "Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China"
      ],
      "name": "Yongchao Cai"
    },
    {
      "affiliations": [
        "Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China"
      ],
      "name": "Yidi Sun"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Zheng Gao"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Enfu Dong"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University, Shanghai, China",
        "Institutes of Biomedical Sciences, Fudan University, Shanghai, China"
      ],
      "name": "Jia Fan"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Xiutao Fu"
    },
    {
      "affiliations": [
        "The Center for Cancer Research, Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China"
      ],
      "name": "Zhe Li"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China",
        "Department of Liver Surgery, Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Clinical Research Center for Cancer Therapy, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China"
      ],
      "name": "Zhenbin Ding"
    }
  ],
  "title": "UDP-glucuronate decarboxylase 1 promotes tumor immune evasion by accelerating KMT2D loss in hepatocellular carcinoma",
  "uid": "10c732ab-426a-5e42-b388-7e478eb1c6e0"
}