Slc39a8, encoding the ZIP8 metal cation transporter, is an evolutionarily conserved gene. It is ubiquitously expressed and mediates the cellular uptake of metal ions such as Mn2+, Zn2+, Fe2+, Se4+, and Co2+, playing a crucial role in maintaining metal ion homeostasis, which is essential for various biological processes [1].

Slc39a8 -/- global knockout mice are early-embryolethal [1]. Slc39a8(neo/neo) hypomorphs show severe anemia, dysregulated hematopoiesis, and other developmental defects, dying between gestational day 16.5 and postnatal day 1 [1]. Intestinal epithelial cell-specific knockout (Slc39a8-IEC KO) mice display decreased Mn levels in blood and most organs, with impaired intestinal Mn absorption, highlighting its role in intestinal Mn uptake and epithelial integrity related to inflammatory bowel disease [2]. Neuronal-specific knockout (Slc39a8-NSKO) mice have reduced brain Mn levels, leading to cerebellar morphological defects, abnormal dendritic arborization, motor dysfunction, and down-regulation of neurodevelopment-related pathways [3]. Inducible global-KO (Slc39a8 iKO) mice studies suggest SLC39A8 is required for brain Mn uptake via the blood-brain barrier [4].

In conclusion, Slc39a8 is essential for metal ion homeostasis, especially Mn homeostasis, in multiple tissues and biological processes. Mouse models with Slc39a8 gene knockout or knockdown have revealed its critical roles in various disease-related biological processes, including those associated with the immune system, cardiovascular system, and central nervous system, providing valuable insights into disease mechanisms related to metal ion dysregulation [1-4].