Slc39a14, also known as ZIP14, is a metal transporter gene. It functions to transport metals such as zinc, non-transferrin-bound iron (NTBI), and manganese. It is involved in multiple biological pathways related to metal homeostasis, which is crucial for normal physiological functions. Genetic animal models, like knockout (KO) murine and zebrafish models, have been instrumental in studying its function [2,3,4,6,7].

In KO mouse models, deletion of Slc39a14/Zip14 causes spontaneous intestinal permeability, low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose. It also leads to a shift in gut microbial composition, increased fungi/bacteria ratio in the gut microbiome, and altered host energy metabolism [3]. In pancreatic β-cells, absence of Slc39a14/Zip14 results in greater glucose-stimulated insulin secretion, increased energy expenditure, and a shift in energy metabolism towards fatty acid utilization [4]. In zebrafish, loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency, with associated changes in calcium homeostasis, locomotor function, and visual responses [6]. Inhibition of Slc39a14 alleviates vascular calcification by intercepting iron-overload-induced ferroptosis in vascular smooth muscle cells [1]. Also, deleting hepatic Slc39a14 expression in Trf-LKO mice reduces hepatic iron accumulation and ferroptosis-mediated liver fibrosis [5]. In human liver allografts, knockdown of SLC39A14 mitigates ischemia-reperfusion injury by preventing hepatocyte ferroptosis [8].

In conclusion, Slc39a14 plays a vital role in metal homeostasis, which impacts various biological processes such as metabolism, gut microbiome regulation, and insulin secretion. The study of Slc39a14 KO models has provided insights into its functions in diseases like vascular calcification, liver fibrosis, and metabolic disorders, contributing to a better understanding of disease mechanisms and potential therapeutic targets.