Iron is an essential trace element required for numerous biological processes, including oxygen transport, cellular respiration, and DNA synthesis (Coffey and Ganz, 2017, Galy et al., 2024). However, due to its potential to catalyze the formation of reactive oxygen species (ROS), iron must be tightly regulated to prevent oxidative damage and maintain cellular function (Dixon & Stockwell, 2014). Iron homeostasis is a delicate balance orchestrated by absorption, transport, storage and regulatory proteins (Galy et al., 2024, Ganz, 2013, Roemhild et al., 2021, Vogt et al., 2021). The regulation of iron homeostasis is crucial for maintaining overall health and preventing human diseases related to iron imbalance (Koleini et al., 2021). Understanding the intricate mechanisms that control iron levels has significant implications for the development of treatments for various disorders, including anemia, iron overload syndromes, neurodegenerative diseases and cancer (Crielaard, Lammers, & Rivella, 2017).

Iron metabolism is often dysregulated in cancer cells, which require iron for their rapid growth and proliferation (Brown et al., 2020, Salnikow, 2021). Iron influences the occurrence and development of cancer through a multifaceted interplay with various cellular and molecular processes (Dixon and Stockwell, 2014, Torti and Torti, 2013, Zhang et al., 2024). Initially, iron overload, which can result from genetic predisposition, dietary intake or chronic diseases, creates a pro-tumorigenic environment by promoting oxidative stress. ROS generated through the Fenton reaction directly damage cellular DNA, leading to mutations and genomic instability, which are hallmarks of cancer initiation. As tumors evolve, cancer cells develop strategies to increase their iron uptake, such as overexpressing iron transporters like transferrin receptor 1 (TfR1) and downregulating hepcidin, the master regulator of systemic iron homeostasis (Brown et al., 2020, Guo et al., 2021, Morales and Xue, 2021). Moreover, iron is essential for the function of mitochondria, the organelles responsible for ATP production, thereby supporting the energy-intensive processes of tumor growth (Gao, Zhou, Wu, & Chen, 2021). Iron also plays a role in cancer cell invasion and metastasis by modulating the expression of matrix metalloproteinases and other proteases (Chen, Fan, Yang, & Gu, 2019). Additionally, the iron storage protein ferritin may protect cancer cells from ROS-induced damage, thereby contributing to their survival and resistance to therapies (Alkhateeb and Connor, 2013, Kotla, Dutta, Parimi, & Das, 2022). Therefore, the intricate relationship between iron and cancer encompasses a range of biological processes, from initial DNA damage and uncontrolled proliferation to angiogenesis, invasion and metastasis, highlighting iron as a critical factor in the pathogenesis of cancer and a potential target for therapeutic intervention.

Hepcidin, a small peptide hormone primarily produced in the liver, plays a critical role in the regulation of iron homeostasis and has emerged as a significant player in the pathogenesis of cancer (Joachim and Mehta, 2022, Lin et al., 2023, Vela and Vela-Gaxha, 2018). The impact of hepcidin on tumor development and progression is multifaceted, involving the modulation of iron availability to cancer cells and its interplay with various cellular processes (Joachim and Mehta, 2022, Lin et al., 2023, Schwartz et al., 2021, Vela and Vela-Gaxha, 2018). Hepcidin exerts its effects by binding to the iron export protein ferroportin (FPN1), leading to its internalization and degradation, which in turn reduces the release of iron from macrophages and the intestinal absorption of dietary iron (Atanasiu et al., 2007, Nemeth et al., 2004). Elevated levels of hepcidin, as observed in some cancer types, can limit the supply of iron to tumor cells, potentially inhibiting their growth and proliferation. Iron deprivation leads to cell cycle arrest and apoptosis in cancer cells that are highly dependent on iron for their metabolic needs. Conversely, reduced hepcidin levels, as seen in certain cancers, result in iron overload within the tumor microenvironment. This excess iron generates ROS, thus causing DNA damage and genomic instability, and promoting carcinogenesis. Understanding the role of hepcidin in cancer leads to novel therapeutic strategies. Manipulating hepcidin levels or targeting its interaction with FPN1 could be a means to modulate iron metabolism in cancer cells, either to starve them of iron or to induce iron-mediated cell death, such as ferroptosis (Ginzburg, 2019, Guo et al., 2015, Zhang et al., 2014). In summary, the effect of hepcidin on cancer development and progression is complex, with its dysregulation potentially contributing to both tumor growth and suppression. Elucidating the mechanisms behind hepcidin’s effects on iron metabolism in cancer may provide valuable insights for the development of targeted therapies (Rochette et al., 2015).