{
  "abstract": "Background Cholangiocarcinoma (CCA) is a highly lethal malignant tumour with increasing incidence. Current therapies exhibit limited benefits, which urgently demand the identification of novel therapeutic targets.Objective We aimed to identify potential therapeutic targets for CCA and broaden current therapies.Design Potential therapeutic targets for CCA were identified by sgRNA library screening and validated in preclinical models. Multi-omics sequencing and various experimental approaches were performed to validate the mechanism by which Aurora kinase B (AURKB) regulates CCA progression and the immune microenvironment, supported by clinical samples from public data sets and Tongji Hospital cohorts. The translational therapy was comprehensively validated in CCA organoid, patient-derived xenograft and preclinical murine models.Results AURKB was identified as a highly expressed and targetable kinase in CCA. Knockout of AURKB significantly inhibited CCA progression, reduced CD8 + T cell exhaustion and enhanced antitumour response. Mechanistically, AURKB promoted the generation of histone H3 lysine 9 tri-methylation (H3K9me3)/serine 10 phosphorylation, leading to a decrease in the enrichment of H3K9me3 at the neutral cholesterol ester hydrolase 1 (NCEH1) promoter, thereby increasing NCEH1 expression and cholesterol levels in tumours. High AURKB expression in clinical samples predicted poorer outcomes in patients with CCA undergoing neoadjuvant chemoimmunotherapy and was associated with cholesterol accumulation within tumours. AURKB inhibitor or simvastatin can suppress CCA progression and significantly enhance sensitivity to chemoimmunotherapy.Conclusions AURKB regulates cholesterol levels and immune microenvironment in tumours, highlighting that targeting AURKB or adopting cholesterol-reducing strategy holds promise for CCA treatment, especially in conjunction with first-line chemoimmunotherapy.",
  "authors": [
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Furong Liu"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Wei Chen"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Ze Zhang"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Weifeng Zeng"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Haofan Hu"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Shangwu Ning"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Zhibin Liao"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Yachong Liu"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Hongwei Zhang"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Qinggang Fu"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Bixiang Zhang"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Xiaoping Chen"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Wanguang Zhang"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China",
        "Key Laboratory of Organ Transplantation, Ministry of Education",
        "NHC Key Laboratory of Organ Transplantation",
        "Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China"
      ],
      "name": "Zhanguo Zhang"
    }
  ],
  "title": "Targeting Aurora kinase B regulates cholesterol metabolism and enhances chemoimmunotherapy in cholangiocarcinoma",
  "uid": "2f2c8265-d48e-53a7-a1f5-2accea315a7e"
}