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Hepatic Iron Overload and Hepatocellular Carcinoma: New Insights into Pathophysiological Mechanisms and Therapeutic Approaches
by
, , , , , and
Elena Chatzikalil
1,2
,
Konstantinos Arvanitakis
3,4
,
Georgios Kalopitas
3,4,
Matilda Florentin
5,
Georgios Germanidis
3,4,
Theocharis Koufakis
6,* and
Elena E. Solomou
7,* 1
Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece
2
“Aghia Sofia” Children’s Hospital ERN-PeadCan Center, 11527 Athens, Greece
3
Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece
4
Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
5
Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
6
Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
7
Department of Internal Medicine, University of Patras Medical School, 26500 Rion, Greece
*
Authors to whom correspondence should be addressed.
Cancers 2025, 17(3), 392; https://doi.org/10.3390/cancers17030392
Submission received: 18 December 2024
/
Revised: 19 January 2025
/
Accepted: 22 January 2025
/
Published: 24 January 2025
(This article belongs to the Special Issue Advanced Research in Oncology in 2024)
Simple Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers globally, posing a substantial health burden. Ongoing research on primary HCC risk factors has revealed an epidemiological shift, with the focus moving from viral hepatitis to metabolic dysfunction-associated steatotic liver disease (MASLD). Recent studies on MASLD-related HCC risk factors have identified only a limited number of risk stratification tools and novel therapeutic options. Interestingly, iron metabolism appears to be dysregulated in both MASLD and HCC, with iron overload emerging as a sensitive diagnostic and prognostic marker for HCC. Therefore, the development of iron-oriented therapeutic strategies could play a critical role in HCC monitoring and treatment, contributing to global efforts that aim to improve overall survival of patients with HCC.
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions.
Keywords:
hepatocellular carcinoma; MASLD; iron overload; HFE mutations; chelation therapy
