{
  "abstract": "Background The JAK/STAT pathway plays a pivotal role in hepatic ischaemia/reperfusion (I/R) injury, a serious perioperative complication. Although signal transducers and activators of transcription 1 (STAT1) activation is known to drive I/R-induced injury, the specific post-translational modifications (PTMs) governing its activity in hepatic I/R remain poorly understood.Objective This study identifies SMYD2, SET and MYND domain Containing 2 (SMYD2) as a critical regulator of STAT1 and investigates the mechanistic basis of SMYD2-mediated PTMs in modulating STAT1 function during hepatic I/R.Design Using an integrated transcriptomic-proteomic approach and functional screening, we identified SMYD2 as a critical regulator of STAT1 activation in hepatic I/R injury. Clinical correlations linked SMYD2 expression to postoperative liver function, while loss-of-function and gain-of-function studies in vitro and in vivo validated its mechanistic role.Results Our findings demonstrate that SMYD2 modulates hepatic I/R injury through the JAK-STAT1 pathway. Clinically, elevated SMYD2 expression correlated with improved liver function and better surgical outcomes following hepatectomy. Mechanistic studies revealed that SMYD2 physically interacts with STAT1 and mediates its methylation at lysine 175 (K175), thereby inhibiting STAT1 phosphorylation and nuclear translocation. Both in vitro and in vivo studies demonstrated that SMYD2 overexpression alleviated hepatic I/R injury, whereas its genetic depletion or pharmacological inhibition exacerbated the damage.Conclusion This study establishes SMYD2 as a novel negative regulator of STAT1 activity through K175 methylation, providing new insights into the epigenetic control of STAT1 during hepatic I/R injury. Our findings reveal a previously unrecognised mechanism for fine-tuning STAT1 signalling in hepatic I/R injury, and targeting the SMYD2-STAT1 axis may present a promising therapeutic strategy for mitigating I/R-associated liver damage.",
  "authors": [
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Zhiyong Yang"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Yufeng Hu"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Chunyong Yang"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Yujie Li"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Xueyuan Zhong"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Zhenfu Wu"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Yingjie Zuo"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Shanyu Gan"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Lin Chen"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China"
      ],
      "name": "Ziyang Zeng"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Guiheng Qi"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Yuanbao Chen"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Junjie Zhou"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Xiao-Jing Zhang"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Hongliang Li"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing",
        "State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Bin Yi"
    }
  ],
  "title": "SMYD2-mediated methylation of STAT1 protects against hepatic ischaemia/reperfusion injury by blocking JAK-STAT1 signalling pathways",
  "uid": "0031b39e-543b-51f4-b4b1-bb096e62439c"
}