Hepcidin: A multifaceted hormone in iron homeostasis and tumor biology

Iron is an essential trace element that plays a crucial role in various biological processes, including oxygen transport, DNA synthesis and cell proliferation. Iron homeostasis is a critical biological equilibrium that involves the balance of iron absorption, utilization, storage and excretion. Iron is intricately linked to the pathophysiology of cancer. Its dual role as a vital nutrient and a potential carcinogen highlights the complexity of iron's influence on tumorigenesis. Iron balance is finely tuned through a complex interplay of molecular components and regulatory mechanisms. Hepcidin, a liver-derived peptide hormone, is the principal regulator of systemic iron availability. 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. In human cancers, the expression of hepcidin is significantly altered, leading to increased iron absorption and retention. Hepcidin has emerged as a significant player in cancer biology due to its potential as both a tumor suppressor and a promoter. Understanding the context-dependent role of hepcidin in cancer opens avenues for novel therapeutic strategies. Modulating hepcidin levels or its activity could be a potential approach to treat cancer, either by starving tumors of iron or by normalizing the iron-rich microenvironment to enhance the efficacy of existing cancer treatments. In this review, we provide a comprehensive overview of the critical functions of hepcidin in iron metabolism, summarize the upstream regulatory factors that control the expression of hepcidin, and delve deeply into the downstream signaling pathways and molecular mechanisms by which hepcidin regulates the tumorigenesis, as well as elucidate the promising potential of hepcidin as a novel therapeutic target in the treatment of cancer, underscoring the significance of understanding and harnessing the complex interplay between hepcidin, iron metabolism and cancer biology.