{
  "abstract": "Background Metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC), enabling rapid tumour growth and immune evasion. Protein post-translational modification (PTM) crosstalk is a critical regulator of cellular processes; however, its contribution to metabolic reprogramming in HCC remains unclear.Objective To elucidate the function of the deubiquitinase JOSD1 in modulating PTM crosstalk and its impact on tumour glycolysis, progression and immunotherapy response in HCC.Design We combined multi-omics analyses with functional and mechanistic studies in cell lines, animal models and patient samples to characterise JOSD1 and its downstream pathways in HCC.Results JOSD1 was identified as a gene associated with glycolysis and correlated with a poor prognosis. Its over-expression promoted malignant phenotypes and enhanced glycolytic flux. Mechanistically, the JOSD1-AARS1 axis cooperatively regulates the ubiquitination-lactylation crosstalk at the K251 residue of PGAM1, thereby stabilising PGAM1, enhancing its enzymatic activity and promoting lactate accumulation. This metabolic shift impaired CD8 + T cell infiltration and function, promoting immune suppression. Therapeutically, liver-targeted inhibition of JOSD1 effectively suppressed tumour progression and synergised with anti-PD-1 therapy, leading to prolonged survival.Conclusion The JOSD1-AARS1 axis regulates the ubiquitination-lactylation crosstalk on PGAM1, with JOSD1 acting as the critical upstream molecular switch that drives metabolic reprogramming and immune evasion in HCC. Targeting JOSD1 represents a promising therapeutic strategy to modulate tumour metabolism and improve immunotherapy efficacy.",
  "authors": [
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Qing Li"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Kai Yu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Suiqing Zhou"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Chunyao Fang"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Liren Zhang"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Feiyu Jin"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Xiangyu Hou"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Feifan Yao"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Yuhong Tang"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China"
      ],
      "name": "Jiali Xu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Ruizhi Zhang"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Hao Peng"
    },
    {
      "affiliations": [
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute",
        "School of Pharmacy",
        "First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Song Tian"
    },
    {
      "affiliations": [
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute",
        "School of Pharmacy",
        "First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Yang Hu"
    },
    {
      "affiliations": [
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute",
        "School of Pharmacy",
        "First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Dianyu Liu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Xiaofeng Tie"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Xiaoyu Liu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Pancreatic Spleen Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China"
      ],
      "name": "Shu Chen"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China"
      ],
      "name": "Guandou Yuan"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China"
      ],
      "name": "Wen-li Xu"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China"
      ],
      "name": "Mingbei Zhong"
    },
    {
      "affiliations": [
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute",
        "School of Pharmacy",
        "First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Lirong Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute",
        "School of Pharmacy",
        "First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Jiaxing Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute",
        "School of Pharmacy",
        "First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Yufeng Hu"
    },
    {
      "affiliations": [
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute",
        "School of Pharmacy",
        "First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Zhi- Gang She"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu Province, China"
      ],
      "name": "Jingjing Dai"
    },
    {
      "affiliations": [
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute",
        "School of Pharmacy",
        "First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Xu Cheng"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China"
      ],
      "name": "Songqing He"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing Medical University, Nanjing, Jiangsu Province, China",
        "Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China",
        "Jiangsu Provincial Key Laboratory of Chronic Digestive Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China"
      ],
      "name": "Xuehao Wang"
    }
  ],
  "title": "JOSD1 drives hepatocellular carcinoma malignancy by modulating the ubiquitination-lactylation switch on PGAM1",
  "uid": "3bc52566-418d-56cc-b96d-98710cab84a5"
}