Ferritin in motion: How systemic iron balance and tumor trafficking shape glioblastoma

Iron is essential for normal biological function, and dysregulation of iron homeostasis can often be detrimental, contributing to cancer development. Maintaining iron homeostasis relies on various signaling pathways and efficient trafficking of iron and ferritin between tissues. In cancers such as glioblastoma (GBM), iron uptake is often enhanced to promote proliferation and cell survival, but may also potentially inhibit tumor progression by reducing migration and increasing ferroptosis. Of note, both iron deficiency anemia (IDA) and iron overload have been associated with several cancers and reduced overall survival outcomes. As may be expected given the complex and conflicting evidence, the role of iron trafficking pathways, systemic availability, and tumor iron dynamics in GBM remains unclear. Here, we examine iron homeostasis and transport in health and disease, with a focus on their contribution to GBM progression. While ferritin release and uptake mechanisms have been characterized under physiological conditions, their role in cancers are less defined. Thus, this review aims to summarize existing perspectives on iron metabolism in GBM and to highlight the distinction between systemic iron homeostasis and iron status within the tumor microenvironment (TME). Understanding iron's influence from this perspective may be particularly relevant to cancer therapies involving iron chelation or supplementation.