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JAK/STAT signaling and cellular iron metabolism in hepatocellular carcinoma: therapeutic implications

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Abstract

Iron metabolism plays a crucial role in the development and progression of hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Iron is an essential micronutrient that is involved in many physiological processes, including oxygen transport, DNA synthesis, and cellular growth and differentiation. However, excessive iron accumulation in the liver has been linked to oxidative stress, inflammation, and DNA damage, which can increase the risk of HCC. Studies have shown that iron overload is common in patients with HCC and that it is associated with a poor prognosis and reduced survival rates. Various iron metabolism-related proteins and signaling pathways such as the JAK/STAT pathway are dysregulated in HCC. Moreover, reduced hepcidin expression was reported to promote HCC in a JAK/STAT pathway-dependent manner. Therefore, it is important to understand the crosstalk between iron metabolism and the JAK/STAT pathway to prevent or treat iron overload in HCC. Iron chelators can bind to iron and remove it from the body, but its effect on JAK/STAT pathway is unclear. Also, HCC can be targeted by using the JAK/STAT pathway inhibitors, but their effect on hepatic iron metabolism is not known. In this review, for the first time, we focus on the role of the JAK/STAT signaling pathway in regulating cellular iron metabolism and its association with the development of HCC. We also discuss novel pharmacological agents and their therapeutic potential in manipulating iron metabolism and JAK/STAT signaling in HCC.

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Funding

JSM is funded by King Hussein Cancer Foundation, Jordan (2022-KHA-001), and the Research Institute for Medical and Health Sciences, University of Sharjah (Project No. 22010901118).

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Authors and Affiliations

  1. Iron Biology Group, Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah, United Arab Emirates

    Bilal Rah, Nada Mazen Farhat, Mawieh Hamad & Jibran Sualeh Muhammad

  2. Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates

    Mawieh Hamad

  3. Department of Basic Medical Sciences, College of Medicine, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates

    Jibran Sualeh Muhammad

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Conceptualization was contributed by JSM, and BR; methodology was contributed by BR; formal analysis was contributed by BR; investigation was contributed by BR, and NMF; data curation was contributed by BR; writing—original draft preparation, was contributed by BR; writing—review and editing, was contributed by JSM, MH, and BR; supervision was contributed by JSM and MH. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Mawieh Hamad or Jibran Sualeh Muhammad.

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Rah, B., Farhat, N.M., Hamad, M. et al. JAK/STAT signaling and cellular iron metabolism in hepatocellular carcinoma: therapeutic implications. Clin Exp Med 23, 3147–3157 (2023). https://doi.org/10.1007/s10238-023-01047-8

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