ZIP8 is a recently identified membrane transporter which facilitates uptake of many substrates including both essential and toxic divalent metals (e.g. zinc, manganese, iron, cadmium) and inorganic selenium. Many ZIP8 regulated downstream signals and pathways remain to be elucidated. In this study, we investigated ZIP8 regulatory roles in downstream targets in ZIP8-gain and loss cells and in ZIP8 overexpressed lungs. Our results show that the overexpression of ZIP8 in mouse fibroblast cells (MEF) induces significant morphological change and re-organization of filament actin (F-actin), along with increased cell proliferation and migration rate. In ZIP8 knockout chronic myelogenous leukemia HAP1 cells, significant clonal morphological change with increased cell-cell adhesion was observed. In the ZIP8 overexpressed lung, F-actin was aberrantly enriched around the tracheal branch. In these ZIP8 gain and loss cell lines and ZIP8 transgenic lungs, we identified two relevant transcription factors, NF-κB and Snail2, whose activation is dependent on the ZIP8 level. They were both significantly upregulated in ZIP8 overexpressed cells and lungs. Expression of NF-κB and Snail2 targets, COL1A2 and E-cadherin, was also correspondingly elevated. Taken together, our results suggest that ZIP8 is a new regulator for cell morphology and cytoskeleton which involves NF-κB and Snail2.