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

Rationale: 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. Methods: 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 (Nrf1^M-KO ) mice were developed to investigate the role and underlying mechanisms of macrophage Nrf1 in vivo and in vitro. Results: 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 Nrf1^M-KO mice exhibited enhanced M1 polarization and mitochondrial dysfunction. Mechanistically, Nrf1 directly binds to Foxo1 and inhibits its transcriptional activity. The target gene KLF16, regulated by the Nrf1-Foxo1 complex, is crucial for modulating mitochondrial function and immune response. Conclusions: Our study highlights the functional properties of macrophage Nrf1-Foxo1 axis in controlling mitochondrial reprogramming and liver fibrosis progression.