{
  "abstract": "Background Metabolic dysfunction-associated steatohepatitis (MASH) has become a major global health burden yet effective pharmacological treatments remain scarce. Lipotoxicity is one of the central drivers of MASH, but the molecular regulators that control lipid metabolism homeostasis in MASH remain incompletely defined.Objective To discover and characterise key regulators of hepatic lipotoxicity that drive MASH progression and to delineate their mechanistic and therapeutic relevance.Design We integrated multiple RNA-seq datasets from murine and human MASH to identify candidate genes linked to disease-associated metabolic signatures. Functional and mechanistic studies were performed using primary hepatocytes, hepatocyte-specific transgenic and knockout mice and an AAV8-based post-onset knockdown model. Protein interactions and subcellular dynamics were evaluated using co-immunoprecipitation-mass spectrometry, structural modelling and colocalisation analysis. The small molecule of monooxygenase DBH like 1 (MOXD1) inhibitor candidates was screened by the artificial intelligence (AI) model, and their anti-MASH capacity was evaluated in vitro and in vivo.Results We identified MOXD1 as a previously unrecognised gene tightly associated with MASH transcriptional programmes. Hepatocyte MOXD1 significantly exacerbated MASH phenotypes. Mechanistically, MOXD1 directly interacted with the ACOX1–PEX5 translocation complex, promoting ACOX1 trafficking to peroxisomes to block lipolysis, lipophagy. We further identified four key MOXD1 residues required for ACOX1 binding and resultant pro-MASH capacity. Importantly, based on the AI model and interacting details of MOXD1–ACOX1, we identified a small molecule rM15 that directly binds to MOXD1 and blocks its interaction with ACOX1. Notably, rM15 robustly protected against hepatocyte lipid accumulation and suppressed diet-induced MASH progression in vivo.Conclusion This study identifies MOXD1 as a previously unrecognised regulator of hepatic fatty-acid homeostasis and a key driver of MASH pathogenesis. Targeting the MOXD1–ACOX1 axis offers a promising therapeutic strategy for MASH.",
  "authors": [
    {
      "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",
        "Signature Research Program in Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore"
      ],
      "name": "Mei Li"
    },
    {
      "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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China",
        "TargetHunter PharmaTech (Jiangxi) Co Ltd, Ganzhou, China"
      ],
      "name": "Jinquan 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",
        "Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China"
      ],
      "name": "Yunfan Yang"
    },
    {
      "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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China",
        "TargetHunter PharmaTech (Jiangxi) Co Ltd, Ganzhou, China"
      ],
      "name": "Xu Cheng"
    },
    {
      "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": "Qidan Li"
    },
    {
      "affiliations": [
        "Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China"
      ],
      "name": "Penglong Li"
    },
    {
      "affiliations": [
        "Department of Colorectal and Anal Surgery (Clinical Center for Pelvic Floor Surgery), Zhongnan Hospital of Wuhan University, Wuhan, China"
      ],
      "name": "Siyi Zhou"
    },
    {
      "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": "Hong Shen"
    },
    {
      "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": "Zixuan Liu"
    },
    {
      "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": "Yichao Mao"
    },
    {
      "affiliations": [
        "TargetHunter PharmaTech (Jiangxi) Co Ltd, Ganzhou, China"
      ],
      "name": "Dianyu Liu"
    },
    {
      "affiliations": [
        "TargetHunter PharmaTech (Jiangxi) Co Ltd, Ganzhou, China"
      ],
      "name": "Yang Hu"
    },
    {
      "affiliations": [
        "TargetHunter PharmaTech (Jiangxi) Co Ltd, Ganzhou, China"
      ],
      "name": "Li Zhang"
    },
    {
      "affiliations": [
        "TargetHunter PharmaTech (Jiangxi) Co Ltd, Ganzhou, China"
      ],
      "name": "Jianyou Zeng"
    },
    {
      "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": "Jun 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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Juan Wan"
    },
    {
      "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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Junjie Zhou"
    },
    {
      "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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Jiajun Fu"
    },
    {
      "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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Manli 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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Hailong Yang"
    },
    {
      "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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Lan Bai"
    },
    {
      "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",
        "Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital, Gannan Medical University, Ganzhou, China"
      ],
      "name": "Xin 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": "Jingjing Cai"
    },
    {
      "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",
        "Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China"
      ],
      "name": "Zhi-Gang She"
    },
    {
      "affiliations": [
        "Signature Research Program in Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore"
      ],
      "name": "Yibin Wang"
    },
    {
      "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": "Hongliang Li"
    },
    {
      "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": "Xiao-Jing Zhang"
    }
  ],
  "title": "Blocking MOXD1-derived ACOX1 peroxisome trafficking suppresses metabolic dysfunction-associated steatohepatitis",
  "uid": "90b14e8f-d4e9-5926-aa5e-6f599717e6de"
}