{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T16:32:56Z","timestamp":1757608376551,"version":"3.44.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Non-Alcoholic Steatohepatitis (NASH) rates are progressively accelerating due to lifestyle changes, which contribute to increased Hepatocellular carcinoma (HCC) incidence. HCC accounts for 90% of liver cancer cases, which ranks as the sixth prevalent, and the third leading cause of cancer-related deaths globally. NASH-HCC outweighs the decline in viral hepatitis-HCC, leaving a gap in the available therapies. The limited overall survival in the current treatments invokes the necessity of exploring novel therapeutic strategies to improve the poor prognosis of HCC. The pH gradient is a hallmark of cancer and is associated with increased intracellular sodium. Elevating this accumulation of intracellular sodium with sodium ionophores, such as Monensin, leads to selective death of murine HCC cancer cells without affecting the functionality of vital organs and proliferating activity of normal and transformed tissues. This study synthesizes the status of HCC risk and management, its molecular landscape, and sheds light on exploiting the elevated accumulation of intracellular sodium as a novel therapeutic strategy against HCC.<\/jats:p>","DOI":"10.3389\/fphar.2025.1671001","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T04:14:11Z","timestamp":1756872851000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["NASH-related Hepatocellular carcinoma: current therapeutic approaches and the emerging role of sodium homeostasis as a novel targeting strategy"],"prefix":"10.3389","volume":"16","author":[{"given":"Abdulsalam","family":"Ashkar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Fiorilla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Tasso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Carini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1002\/hep.22249","article-title":"Adenosine-dependent activation of hypoxia-inducible factor-1 induces late preconditioning in liver cells","volume":"48","author":"Alchera","year":"2008","journal-title":"Hepatology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"742149","DOI":"10.1155\/2013\/742149","article-title":"Structure and antimicrobial properties of monensin A and its derivatives: summary of the achievements","volume":"2013","author":"Aowicki","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"B3","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.ejrad.2018.01.025","article-title":"Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines","volume":"101","author":"Ayuso","year":"2018","journal-title":"Eur. J. Radiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1097\/RLI.0000000000000470","article-title":"Quantification of total and intracellular sodium concentration in primary prostate cancer and adjacent normal prostate tissue with magnetic resonance imaging","volume":"53","author":"Barrett","year":"2018","journal-title":"Invest. Radiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1080\/13651820410024049","article-title":"Diagnosis of hepatocellular carcinoma","volume":"7","author":"Bialecki","year":"2005","journal-title":"HPB"},{"key":"B7","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1007\/s13181-017-0616-6","article-title":"Survival after severe rhabdomyolysis following monensin ingestion","volume":"13","author":"Blain","year":"2017","journal-title":"J. Med. Toxicol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1002\/hep.1840210431","article-title":"Alteration of Na+ homeostasis as a critical step in the development of irreversible hepatocyte injury after adenosine triphosphate depletion","volume":"21","author":"Carini","year":"1995","journal-title":"Hepatology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1006\/excr.1999.4408","article-title":"Alterations of cell volume regulation in the development of hepatocyte necrosis","volume":"248","author":"Carini","year":"1999","journal-title":"Exp. Cell Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1002\/hep.510310125","article-title":"Ischemic preconditioning reduces Na(+) accumulation and cell killing in isolated rat hepatocytes exposed to hypoxia","volume":"31","author":"Carini","year":"2000","journal-title":"Hepatology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S1470-2045(08)70285-7","article-title":"Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial","volume":"10","author":"Cheng","year":"2009","journal-title":"Lancet Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1038\/s42003-023-04946-4","article-title":"Boosting intracellular sodium selectively kills hepatocarcinoma cells and induces hepatocellular carcinoma tumor shrinkage in mice","volume":"6","author":"Clemente","year":"2023","journal-title":"Commun. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"17523","DOI":"10.1038\/srep17523","article-title":"Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells","volume":"5","author":"Deng","year":"2015","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1111\/1440-1681.12385","article-title":"Targeting Na+\/K+ -translocating adenosine triphosphatase in cancer treatment","volume":"42","author":"Durlacher","year":"2015","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3390\/cells14030185","article-title":"Monensin inhibits triple-negative breast cancer in mice by a Na+-dependent cytotoxic action unrelated to cytostatic effects","volume":"14","author":"Fiorilla","year":"2025","journal-title":"Cells"},{"key":"B20","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1007\/s00424-023-02902-z","article-title":"Acid-sensing ion channels and downstream signalling in cancer cells: is there a mechanistic link?","volume":"476","author":"Gr\u00fcnder","year":"2024","journal-title":"Pflugers Arch."},{"key":"B22","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1111\/febs.13840","article-title":"ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters","volume":"284","author":"Hanukoglu","year":"2017","journal-title":"FEBS J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/s41575-020-00381-6","article-title":"Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention","volume":"18","author":"Huang","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1177\/153303460400300603","article-title":"Multiparametric and multinuclear magnetic resonance imaging of human breast cancer: current applications","volume":"3","author":"Jacobs","year":"2004","journal-title":"Technol. Cancer Res. Treat."},{"key":"B26","doi-asserted-by":"publisher","first-page":"4309","DOI":"10.1007\/s13277-015-3070-6","article-title":"Involvement of acid-sensing ion channel 1\u03b1 in hepatic carcinoma cell migration and invasion","volume":"36","author":"Jin","year":"2015","journal-title":"Tumour Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"102406","DOI":"10.1016\/j.jceh.2024.102406","article-title":"Evolving global etiology of hepatocellular carcinoma (HCC): insights and trends for 2024","volume":"15","author":"Koshy","year":"2025","journal-title":"J. Clin. Exp. Hepatol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"188304","DOI":"10.1016\/j.bbcan.2019.07.001","article-title":"Sodium homeostasis in the tumour microenvironment","volume":"1872","author":"Leslie","year":"2019","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"B30","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/j.jhep.2024.05.037","article-title":"Immunotherapy for hepatocellular carcinoma: the next evolution in expanding access to liver transplantation","volume":"81","author":"Li","year":"2024","journal-title":"J. Hepatol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.3390\/cancers12071914","article-title":"Locoregional therapy approaches for hepatocellular carcinoma: recent advances and management strategies","volume":"12","author":"Makary","year":"2020","journal-title":"Cancers"},{"volume-title":"Hepatocellular carcinoma (HCC): practice essentials, anatomy, pathophysiology","year":"2024","key":"B33"},{"key":"B34","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1111\/jon.12823","article-title":"MRI detection of changes in tissue sodium concentration in brain metastases after stereotactic radiosurgery: a feasibility study","volume":"31","author":"Mohamed","year":"2021","journal-title":"J. Neuroimaging Off. J. Am. Soc. Neuroimaging"},{"key":"B35","doi-asserted-by":"publisher","first-page":"719896","DOI":"10.3389\/fonc.2021.719896","article-title":"Advances of targeted therapy for hepatocellular carcinoma","volume":"11","author":"Niu","year":"2021","journal-title":"Front. Oncol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1148\/radiol.2272020483","article-title":"Tissue sodium concentration in human brain tumors as measured with 23Na MR imaging","volume":"227","author":"Ouwerkerk","year":"2003","journal-title":"Radiology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/nrc3579","article-title":"Disrupting proton dynamics and energy metabolism for cancer therapy","volume":"13","author":"Parks","year":"2013","journal-title":"Nat. Rev. Cancer"},{"volume-title":"Monensin sodium","year":"2025","key":"B38"},{"key":"B39","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/j.jhep.2021.11.018","article-title":"BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update","volume":"76","author":"Reig","year":"2022","journal-title":"J. Hepatol."},{"key":"B40","unstructured":"Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia\n          \n          \n            \n              Roncalli\n              M.\n            \n          \n          \n          2009"},{"key":"B41","doi-asserted-by":"publisher","first-page":"7468","DOI":"10.1002\/anie.201713318","article-title":"Evidence for the role of intracellular water lifetime as a tumour biomarker obtained by in vivo field-cycling relaxometry","volume":"57","author":"Ruggiero","year":"2018","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global burden of primary liver cancer in 2020 and predictions to 2040","volume":"77","author":"Rumgay","year":"2022","journal-title":"J. Hepatol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1111\/cts.13593","article-title":"Investigation of the anticancer mechanism of monensin via apoptosis-related factors in SH-SY5Y neuroblastoma cells","volume":"16","author":"Serter Kocoglu","year":"2023","journal-title":"Clin. Transl. Sci."},{"key":"B45","unstructured":"A randomized, double-blind, placebo-controlled phase III trial of TSU-68 in combination with transcatheter arterial chemoembolization in patients with unresectable hepatocellular carcinoma. Clinicaltrials.gov\n          \n          \n          2019"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.2527\/jas1984.5861512x","article-title":"Comparative toxicology of monensin sodium in laboratory animals","volume":"58","author":"Todd","year":"1984","journal-title":"J. Anim. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"17914","DOI":"10.1038\/s41598-018-36214-5","article-title":"Monensin inhibits cell proliferation and tumor growth of chemo-resistant pancreatic cancer cells by targeting the EGFR signaling pathway","volume":"8","author":"Wang","year":"2018","journal-title":"Sci. Rep."},{"key":"B57","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1007\/s10555-023-10084-4","article-title":"Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers","volume":"42","author":"Wang","year":"2023","journal-title":"Cancer Metastasis Rev."},{"key":"B48","doi-asserted-by":"publisher","first-page":"113835","DOI":"10.1016\/j.biopha.2022.113835","article-title":"Acid-sensing ion channel 1: potential therapeutic target for tumor","volume":"155","author":"Wang","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B49","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nrc3110","article-title":"Dysregulated pH: a perfect storm for cancer progression","volume":"11","author":"Webb","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"B50","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1002\/cld.1006","article-title":"Molecular mechanisms linking nonalcoholic steatohepatitis to cancer","volume":"17","author":"Wegermann","year":"2021","journal-title":"Clin. Liver Dis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.3892\/etm.2021.10826","article-title":"Monensin suppresses cell proliferation and invasion in ovarian cancer by enhancing MEK1 SUMOylation","volume":"22","author":"Yao","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1177\/0748233720974128","article-title":"Rhabdomyolysis and hepatotoxicity following accidental monensin ingestion: a report of two cases","volume":"37","author":"Zhang","year":"2021","journal-title":"Toxicol. Ind. Health"},{"key":"B54","doi-asserted-by":"publisher","first-page":"121943","DOI":"10.1016\/j.lfs.2023.121943","article-title":"The emerging significance of mitochondrial targeted strategies in NAFLD treatment","volume":"329","author":"Zhang","year":"2023","journal-title":"Life Sci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1080\/07853890.2023.2166980","article-title":"Effect of antibiotic monensin on cell proliferation and IGF1R signaling pathway in human colorectal cancer cells","volume":"55","author":"Zhou","year":"2023","journal-title":"Ann. Med."},{"key":"B56","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/S1470-2045(18)30937-9","article-title":"Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased \u03b1-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"20","author":"Zhu","year":"2019","journal-title":"Lancet Oncol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1671001\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T04:14:14Z","timestamp":1756872854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1671001\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":47,"alternative-id":["10.3389\/fphar.2025.1671001"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1671001","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2025,9,3]]},"article-number":"1671001"}}