{
  "abstract": "Background Hepatocellular carcinoma (HCC), one of the most prevalent cancers worldwide, has a high mortality owing to diagnostic challenges and therapeutic resistance. Lactate metabolism and protein lactylation play key roles in HCC progression; nevertheless, their regulatory mechanisms remain poorly understood.Objective This study aims to elucidate how lactate metabolism and protein lactylation contribute to HCC malignant progression by integrating multi-omics data, identifying key regulatory factors and exploring therapeutic strategies targeting this pathway.Design Integrated multi-omics analysis identified AARS2–AP-2γ as a key axis in HCC. Through mechanistic studies and virtual screening, we developed kukoamine A—a targeted inhibitor delivered via nanocarriers—demonstrating significant therapeutic potential.Results AARS2 was identified as a key regulator linking lactate metabolism to HCC progression through lactylation modification. It catalyses AP-2γ lactylation at K444, enhancing TRIM28 binding to promote K63-linked ubiquitination and nuclear translocation, thereby facilitating tumour progression. The inhibitor kukoamine A disrupts AARS2–AP-2γ interaction and, when delivered via zeolitic imidazolate framework-8 nanocarriers, demonstrates improved liver targeting, potent antitumour activity and synergy with PD-1 blockade, offering new strategic avenues for HCC precision therapy.Conclusion AARS2 links lactate metabolism to HCC progression via lactylation. Kukoamine A nanotherapy targeting this axis shows synergistic efficacy with immunotherapy, advancing the prospects of precision oncology.",
  "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": "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": "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": "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": "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": "Xiaoyu 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": "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": [
        "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": [
        "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": "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 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": "Chaowen Zheng"
    },
    {
      "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, Nanjing Medical University, Nanjing, Jiangsu, 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": "Landscape screening identifies the lactate-modifying enzyme AARS2 as a master regulator and therapeutic target in hepatocellular carcinoma",
  "uid": "67ffa19b-2f18-5b83-aa47-1571b4c94a92"
}