Zinc-Transporting Protein ZIP4 Promotes Aggressive Growth in Brain Tumors, Study Finds

In a recent study published in the Proceedings of the National Academy of Sciences, researchers from the University of Oklahoma have uncovered a key factor behind the aggressive nature of glioblastoma, one of the deadliest types of brain tumors. The research centers on ZIP4, a protein responsible for transporting zinc throughout the body. Under normal conditions, ZIP4 plays a vital role in maintaining proper zinc levels, essential for various physiological functions. However, in glioblastoma, ZIP4 becomes overexpressed, leading to several detrimental effects that facilitate tumor progression.

The study reveals that glioblastoma cells absorb approximately ten times more zinc than healthy brain tissue. This excessive zinc uptake triggers the release of extracellular vesicles (EVs)—tiny bubble-like particles carrying the protein TREM1. While TREM1 typically boosts immune responses, in the context of glioblastoma, it paradoxically reprograms nearby microglia, immune cells in the brain, turning them into allies that support tumor growth. These reprogrammed microglia release chemicals that promote tumor expansion, significantly contributing to the malignancy.

"Everything begins with the overexpression of ZIP4 in glioblastoma," explained senior author Dr. Min Li. The cascade initiated by ZIP4 overabundance underscores its central role in tumor aggressiveness. Furthermore, the team tested a small-molecule inhibitor targeting both ZIP4 and TREM1. This inhibitor effectively blocked their actions, resulting in slowed tumor growth, which highlights the potential of ZIP4 and TREM1 as therapeutic targets.

Neurosurgeon and co-author Dr. Ian Dunn emphasized the significance of these findings, noting that they bring hope for future treatment approaches. Given the difficulty of surgically removing glioblastoma and its high recurrence rate, new strategies targeting molecular pathways like ZIP4 could improve patient outcomes.

Dr. Li's previous research on ZIP4 in pancreatic cancer revealed that overexpression of this protein also confers resistance to chemotherapy and fosters tumor metastasis. His findings suggest that ZIP4 plays a critical role in various cancers by promoting resistance and aiding tumor spread, making it an exciting target for cancer therapy.

Overall, this groundbreaking research sheds light on the molecular mechanisms driving glioblastoma progression and opens pathways for the development of novel targeted treatments that could significantly alter the prognosis of this formidable disease.

For more details, see Liyang Zhang et al, "A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity," Proceedings of the National Academy of Sciences (2025).