SLC39A11 mediates intracellular manganese partitioning and adaptive iron transport

Zrt/Irt-like protein (ZIP) family members typically mediate zinc transport into the cytoplasm. Here, we characterize SLC39A11(ZIP11)-an evolutionarily conserved ZIP homologous to Escherichia coli metal ZupT-revealing its context-dependent role in metal homeostasis. ZIP11 could remove Fe²⁺ from the endoplasmic reticulum (ER)/Golgi to the cytosol when ER/Golgi Fe²⁺ rises. This is relevant to fibrosis, where ZIP13 upregulation supports collagen synthesis and ZIP11 mitigates iron overload. Significantly, AAV8-mediated ZIP11 expression drastically suppresses CCl₄-induced liver fibrosis in mice, highlighting therapeutic potential. However, ZIP11 normally regulates Mn²⁺ partitioning between ER/Golgi and cytosol: its loss reduces ER/Golgi Mn²⁺, increases cytosolic Mn²⁺, and enhances manganese toxicity. ZIP11 and Mn²⁺ transporter TMEM165 double deficiency exacerbates Mn²⁺ sensitivity, indicating synergy between them. We therefore establish ZIP11 as an ER/Golgi Mn²⁺ transporter with Fe²⁺ transport plasticity and as an ER/Golgi-to-cytosol iron transporter that acts oppositely to ZIP13 to maintain optimal ER/Golgi iron levels.