{
  "abstract": "Metabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial metabolic liver disease that occurs in the context of obesity, insulin resistance and cardiometabolic comorbidities. Monotherapy targeting single pathways often provides only partial improvements in histological liver fibrosis and systemic metabolic parameters, prompting growing interest in multitargeted combination therapies. Multitargeted and combination strategies for MASH can modulate multiple and complementary pathogenic processes, potentially improving efficacy, promoting liver fibrosis regression, optimising systemic metabolic outcomes and reducing treatment-related adverse effects. Liver-directed combination therapies, such as thyroid hormone receptor-beta (THR-β) agonists along with acetyl-CoA carboxylase (ACC) inhibitors or peroxisome proliferator-activated receptor agonists, aim to improve histological features of MASH. Regimens combining systemic metabolic and liver-specific agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists with fibroblast growth factor-21 analogues or THR-β agonists, aim to optimise metabolic outcomes, including body weight, insulin resistance and plasma lipids. Thoughtfully designed drug pairings, such as diacylglycerol O-acyltransferase 2 inhibitors combined with ACC inhibitors or GLP-1 and glucagon receptor dual agonists, could improve safety and tolerability by leveraging complementary mechanisms that may mitigate adverse effects. These therapeutic strategies aim to achieve more comprehensive and durable improvements in both liver pathology and systemic health than single-agent therapy alone. This review integrates current knowledge on multitargeted and combination therapies for MASH, examines mechanistic rationales and emerging clinical evidence and addresses practical considerations for patient-centred implementation. Therefore, we aim to provide clinicians and researchers with a comprehensive framework to optimise individualised management and improve both hepatic and systemic outcomes in individuals living with MASH.",
  "authors": [
    {
      "affiliations": [
        "MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China",
        "Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China"
      ],
      "name": "Xiao-Dong Zhou"
    },
    {
      "affiliations": [
        "MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China",
        "Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China"
      ],
      "name": "Qiong-Yue Fan"
    },
    {
      "affiliations": [
        "Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, and University of Southampton, Southampton General Hospital, Southampton, UK"
      ],
      "name": "Christopher D Byrne"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Verona, Verona, Italy",
        "Metabolic Diseases Research Unit, IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy"
      ],
      "name": "Giovanni Targher"
    },
    {
      "affiliations": [
        "Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore",
        "Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore"
      ],
      "name": "Mark D Muthiah"
    },
    {
      "affiliations": [
        "Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore",
        "Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore"
      ],
      "name": "Daniel Q Huang"
    },
    {
      "affiliations": [
        "Medical Care Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China",
        "Institute of Aging, Wenzhou Medical University, Wenzhou, China"
      ],
      "name": "Qin-Fen Chen"
    },
    {
      "affiliations": [
        "Houston Methodist Hospital, Houston, TX, USA",
        "Houston Research Institute, Houston, TX, USA"
      ],
      "name": "Mazen Noureddin"
    },
    {
      "affiliations": [
        "Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, UK"
      ],
      "name": "Wenhao Li"
    },
    {
      "affiliations": [
        "Sorbonne Université, Institute for Cardiometabolism and Nutrition, Hospital Pitié Salpêtrière, Paris, France"
      ],
      "name": "Vlad Ratziu"
    },
    {
      "affiliations": [
        "MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA"
      ],
      "name": "Rohit Loomba"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium"
      ],
      "name": "Sven M Francque"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA"
      ],
      "name": "Arun J Sanyal"
    },
    {
      "affiliations": [
        "MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China",
        "Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China"
      ],
      "name": "Ming-Hua Zheng"
    }
  ],
  "title": "Combination therapies for metabolic dysfunction-associated steatohepatitis: challenges and opportunities",
  "uid": "a06c4be1-abff-51a8-82cc-e5d05273486b"
}