SLC39A8 encodes ZIP8, an electroneutral divalent metal cation:bicarbonate symporter that mediates cellular uptake of zinc, manganese, iron, cobalt, selenium, and cadmium 1. The transporter functions at the plasma membrane as well as intracellularly at lysosomal membranes, transporting metal-bicarbonate complexes or metal-selenite anions 1. SLC39A8 is ubiquitously expressed across all cell types and plays critical roles in development, tissue homeostasis, and immunity 1. Zinc uptake via SLC39A8 indirectly regulates the transcription factor MTF1 and metalloproteases involved in cartilage and heart development, while also controlling innate immune function and inflammatory responses 1. In intestinal epithelium, SLC39A8 mediates manganese absorption at the apical membrane and maintains epithelial integrity through sphingolipid metabolism pathways 2. In lung alveolar progenitor cells, ZIP8 regulates cell renewal through SIRT1-dependent mechanisms; deficiency impairs regeneration and promotes idiopathic pulmonary fibrosis 3. SLC39A8 variants associate with congenital disorder of glycosylation type 2N and exhibit striking pleiotropy, linked to developmental disorders, cardiovascular disease, schizophrenia, inflammatory bowel disease, Parkinson disease, and multi-organ fibrosis 145. Pathogenic variants disrupt protein localization, expression, or metal uptake capacity, with differential effects across metal substrates 6.