Slc39a8, encoding the ZIP8 metal cation transporter, is an evolutionarily conserved gene. It is ubiquitously expressed and mediates the uptake of cations like Mn2+, Zn2+, Fe2+, Se4+, and Co2+ into cells, playing a crucial role in metal ion homeostasis [1]. Mouse genetic models, including Slc39a8 -overexpressing, Slc39a8(neo/neo) knockdown, cell type-specific conditional knockout (CKO), and Slc39a8(-/-) global knockout (KO) mouse lines, have been instrumental in studying its function [1].

Slc39a8(neo/neo) hypomorphs exhibit severe anemia, dysregulated hematopoiesis, and other developmental defects, dying between gestational day 16.5 and postnatal day 1 [1]. Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice show decreased blood and organ Mn levels, impaired intestinal Mn absorption, highlighting its role in maintaining Mn homeostasis and epithelial integrity relevant to inflammatory bowel disease (IBD) [2]. Neuronal Slc39a8-specific knockout (Slc39a8-NSKO) mice have reduced brain Mn levels, cerebellar morphological and functional defects, and motor dysfunction, indicating its importance in brain Mn uptake and cerebellum development [3]. In addition, Slc39a8-inducible global-KO (Slc39a8 iKO) mice show decreased brain Mn accumulation, suggesting SLC39A8 mediates brain Mn uptake via the blood-brain barrier [4].

In conclusion, Slc39a8 is essential for metal ion homeostasis, especially for Mn. Model-based research, particularly KO and CKO mouse models, has revealed its critical roles in various biological processes, including hematopoiesis, intestinal Mn absorption, brain development, and Mn uptake in the brain. These findings have implications for understanding diseases such as IBD, neurological disorders, and those related to Mn dyshomeostasis [1,2,3,4].