ZIP14 Deletion Disrupts Divalent Metal Homeostasis in Mouse Cerebrospinal Fluid

ABSTRACTZIP14 is a member of the SLC39A (ZIP) family of metal transporters, primarily facilitating the cellular influx of divalent metals including manganese (Mn), zinc (Zn), and iron (Fe). Previous studies have demonstrated that Zip14 knockout (Zip14‐/‐) mice exhibit significant increases in whole blood and brain Mn levels. However, the impact of ZIP14 deletion on metal homeostasis within the cerebrospinal fluid (CSF) remained unexplored. In this study, we comprehensively assessed Mn, Zn, Fe, sodium (Na), potassium (K), and calcium (Ca) levels in whole blood, serum, and CSF of male and female Zip14‐/‐ mice to elucidate both systemic and central nervous system (CNS)‐specific alterations in metal homeostasis. Our findings reveal that Zip14‐/‐ mice exhibit pronounced Mn accumulation, with CSF Mn levels increasing by approximately 15‐fold in males and 46‐fold in females compared to wild‐type controls. Correspondingly, blood Mn levels rose 23‐fold in males and 17‐fold in females, while serum Mn levels increased 10‐fold and 15‐fold, respectively. In contrast, Zn and Fe levels in whole blood and serum remained comparable between Zip14‐/‐ and wild‐type mice. However, significant elevation