{
  "abstract": "Background Liver cancer stem/progenitor cells drive tumor initiation, malignant progression, and therapeutic response in hepatocellular carcinoma (HCC). CD133/Prom1 marks a stem-like HCC population characterized by dedifferentiation toward an embryonic-like state and enhanced epithelial–mesenchymal transition (EMT). However, the molecular mechanisms that maintain liver cancer stemness remain incompletely understood.Methods CD133/Prom1 + lineage tracing and ablation mouse models were integrated with single-cell RNA sequencing (scRNA-seq) to reveal the necessity of Myelin Expression Factor 2 (MYEF2) in HCC stemness maintenance and the underlying molecular programs governing stemness. Clinical HCC specimens from internal and public cohorts were analyzed to assess correlations among MYEF2 expression, patient survival, and stemness markers. The roles of MYEF2 in HCC proliferation, stemness, and migration were assessed using gain- and loss-of-function assays in vitro and in vivo. RNA-seq and scRNA-seq identified signaling pathways regulated by MYEF2. RIP-seq identified MYEF2-bound mRNAs, while RIP-qPCR, mRNA stability assays, and RNA pull-down assays characterized MYEF2–MAP2K6/MKK6 mRNA interactions. Dual-luciferase reporter assays, ChIP-qPCR, and mIF colocalization assays demonstrated that E2F6 acts as an upstream transcription factor of MYEF2. The therapeutic effects of AAV8-mediated MYEF2 silencing, alone or in combination with sorafenib, were evaluated in an immunocompetent HCC mouse model.Results MYEF2 was identified as a key regulator of CD133 + liver cancer stem/progenitor cells. MYEF2 depletion in CD133-lineage HCC cells induced differentiation, indicating its essential role in maintaining stemness. Clinically, elevated MYEF2 expression correlates with stemness markers, poor differentiation, and reduced survival. Functionally, MYEF2 overexpression promotes tumorigenesis, self-renewal, metastasis, and sorafenib resistance. Mechanistically, we find that MYEF2 upregulates the mRNA stability of MAP2K6/MKK6 via direct binding. The subsequent activation of p38/MAPK signaling, along with enhanced SREBP activity and cholesterol biosynthesis, contributes to the enhancement of HCC stemness. Importantly, in an immunocompetent mouse model, delivery of rAAV8-shMyef2 reduces cholesterol accumulation, decreases the CD133+ stem/progenitor population, and sensitizes tumors to sorafenib.Conclusions MYEF2 is a liver cancer stem/progenitor–specific regulator that sustains stemness by stabilizing MAP2K6/MKK6 mRNA, thereby activating MAPK signaling and maintaining cholesterol homeostasis. Targeting MYEF2 represents a promising strategy to suppress HCC progression and overcome sorafenib resistance.",
  "authors": [
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Jingru Li"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Hailing Yang"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Xinyue Zhang"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Shiyu Wu"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Shujie Peng"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Jihui Huo"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Lefan Zhu"
    },
    {
      "affiliations": [
        "School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong"
      ],
      "name": "Toni Ki-Fong Man"
    },
    {
      "affiliations": [
        "Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Yanqin Wu"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Shiyan Wang"
    },
    {
      "affiliations": [
        "Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Lixia Xu"
    },
    {
      "affiliations": [
        "Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong"
      ],
      "name": "Terence Kin-Wah Lee"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Xiaoxing Li"
    },
    {
      "affiliations": [
        "Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, China"
      ],
      "name": "Zhao Zhang"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Lei Zhou"
    }
  ],
  "title": "IDDF2026-ABS-0433 MYEF2 stabilizes MAP2K6 mRNA to drive cholesterol-dependent cancer stemness in hepatocellular carcinoma",
  "uid": "cae7064c-bf6e-5bbe-8db6-82bf4e0725a9"
}