Macrophage Nrf1/NFE2L1-Foxo1 axis controls liver fibrosis by modulation of mitochondrial reprogramming

<b>Rationale:</b> Nuclear factor erythroid 2-like 1 (Nrf1/NFE2L1) is a crucial redox-sensitive factor essential for mitochondrial homeostasis. However, its function in controlling macrophage-associated liver inflammation and fibrosis remains to be fully understood. Herein, this study was conducted to elucidate the roles of macrophage Nrf1 in regulating liver fibrosis. <b>Methods:</b> Expression levels were analyzed in human liver tissues collected from individuals diagnosed with or without liver fibrosis. High-fat diet feeding, carbon tetrachloride injection or bile duct ligation was performed respectively to established three mouse models of liver fibrosis. Myeloid-specific Nrf1-knockout (<i>Nrf1^M-KO</i> ) mice were developed to investigate the role and underlying mechanisms of macrophage Nrf1 <i>in vivo</i> and <i>in vitro</i>. <b>Results:</b> Macrophage Nrf1 expression was markedly reduced in liver samples from both humans and mice with liver fibrosis. The deletion of myeloid Nrf1 remarkably accelerated liver inflammation and fibrosis. Macrophages from <i>Nrf1^M-KO</i> mice exhibited enhanced M1 polarization and mitochondrial dysfunction. Mechanistically, Nrf1 directly binds to Foxo1 and inhibits its transcriptional activity. The target gene <i>KLF16</i>, regulated by the Nrf1-Foxo1 complex, is crucial for modulating mitochondrial function and immune response. <b>Conclusions:</b> Our study highlights the functional properties of macrophage Nrf1-Foxo1 axis in controlling mitochondrial reprogramming and liver fibrosis progression.