{
  "abstract": "Objective Metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma (MASLD-HCC) is an emerging malignancy with limited therapeutic options. The identity and function of cancer stem cells (CSCs) in MASLD-HCC remain poorly understood. In this study, we characterised CSCs in MASLD-HCC and investigated their contribution to MASLD-HCC tumourigenesis and therapy response.Design We performed expression profiling in human MASLD-HCC samples (n=29 pairs of tumour and adjacent normal tissues). Advanced in vivo genetic lineage tracing coupled with single-cell RNA sequencing was used to characterise CD133+ CSCs in preclinical models. To establish causality, we developed a hepatocyte-specific CD133-overexpressing mouse model of MASLD-HCC. We identified CD133 protein interactors by mass spectrometry. A novel strategy combining CD133-targeted small interfering RNA (siRNA) nanoparticles with first-line therapy was assessed in clinically relevant MASLD-HCC models.Results CD133 + CSCs were significantly enriched in human MASLD-HCC tumours and positively correlated with established markers of malignancy. In vivo genetic lineage tracing in mice revealed that CD133+ cells exhibit hallmark CSC properties, including self-renewal, tumour-initiating capacity and multipotent differentiation, as compared with CD133− counterparts. Hepatocyte-specific CD133 overexpression in mice accelerated MASLD-HCC tumourigenesis. Mechanistically, CD133 interacts with myosin heavy chain 9 (MYH9) to stabilise active β-catenin, thereby propagating Wnt/β-catenin signalling that drives CSC phenotypes and tumourigenic potential. Therapeutically, genetic ablation of CD133+ cells or systemic delivery of CD133-siRNA nanoparticles potently sensitised MASLD-HCC to sorafenib and lenvatinib, significantly improving outcomes in MASLD-HCC.Conclusion This study established CD133 + CSCs as critical mediators through the CD133-MYH9/β-catenin axis in MASLD-HCC. Targeting CD133 enhances multikinase inhibitor efficacy, offering a promising therapeutic strategy for MASLD-HCC.",
  "authors": [
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Yasi Pan"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Xiang Zhang"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Chi Chun Wong"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China",
        "Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Huarong Chen"
    },
    {
      "affiliations": [
        "School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Stephanie Ma"
    },
    {
      "affiliations": [
        "Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China"
      ],
      "name": "Terence Kin-Wah Lee"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Kai Yuan"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Cong Liang"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Xingyu Zhou"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Harry Cheuk Hay Lau"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Pingmei Huang"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Danyu Chen"
    },
    {
      "affiliations": [
        "Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Lina Wang"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Yanqiang Ding"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Qinyao Wei"
    },
    {
      "affiliations": [
        "Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Alvin Ho Kwan Cheung"
    },
    {
      "affiliations": [
        "Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Ka Fai To"
    },
    {
      "affiliations": [
        "Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"
      ],
      "name": "Jun Yu"
    }
  ],
  "title": "Targeting cancer stem cells enhances multikinase inhibitor therapy in metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma",
  "uid": "418a6e34-0095-5350-851d-46f15861f510"
}