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Cholesterol’s new tricks propel MASH-HCC: impact in immunotherapy
  1. Carmen Garcia-Ruiz1,2,3,
  2. Sandra Torres1,2,3,
  3. Jose C Fernandez-Checa1,2,3,4
  1. 1 Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
  2. 2 Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  3. 3 Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
  4. 4 Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  1. Correspondence to Dr Jose C Fernandez-Checa, Institute of Biomedical Research of Barcelona, Barcelona, Catalunya, Spain; checa229{at}yahoo.com

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Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the end-stage of chronic liver diseases, including metabolic-associated steatohepatitis (MASH), an advanced form of metabolic dysfunction-associated steatotic liver disease. The incidence of MASH-driven HCC is expected to continue rising throughout the world due to its association with the obesity and type 2 diabetes epidemic.1 HCC has a poor prognosis with frequent recurrence and intrahepatic metastasis and effective treatment options, such as local ablative therapies, resection or transplantation are mainly limited to early disease stages.1 Unfortunately, the therapeutic armamentarium for HCC is limited, ineffective and subject to secondary or acquired chemoresistance indicating the urgent need to understand the molecular mechanisms leading to MASH-HCC that will allow the identification of new therapeutic targets for the treatment of MASH-HCC development. Although targeting programmed death-ligand 1/programmed cell death protein-1 (PD-1) in the tumour immune microenvironment (TIME) with immune checkpoint inhibitors has shown promising results in different cancer types, the impact of this approach in HCC is somewhat less effective, particularly in MASH-driven HCC tumours which harbour a unique TIME with an accumulation of an exhausted T-cell subsets (CD8+ PD-1+) contributing to the refractory response to anti-PD-1 therapy.2

Since the description that the type rather than the amount of fat drives the transition from steatosis to MASH,3 cholesterol has emerged as a crucial player in MASH pathogenesis and MASH-driven HCC development in part through the generation of bile acids (BAs) via the alternative pathway in which mitochondrial cholesterol is metabolised to the oxysterol 27-hydroxycholesterol to fuel BAs synthesis.4 Previous studies demonstrated that de novo cholesterol synthesis in the mevalonate pathway propels MASH progression5 with a crucial role of squalene epoxidase (SLQE) in MASH-HCC development whose expression is associated with poor outcome in patients with MASH-HCC. …

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Footnotes

  • Contributors Conceptualisation: CG-R, JCF-C. Discussion: CG-R, ST, JCF-C. Writing: CG-R, ST, JCF-C. Figure design: ST, JCF-C.

  • Funding We would like to acknowledge support from PID2020-115055RB-I00, PID2022-142956OB-100, PID2022-140169OB-C22, 2023AEP068 and 2024AEP053 from Plan Nacional de I+D funded by the Agencia Estatal de Investigación (AEI), 2021 SGR 00491 from AGAUR and the European Horizons research and innovation programme HORIZON-HLTH-2022-STAYHLTH-02 under agreement No 101095679.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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