The key findings include: (1) Nrf1 expression in macrophages is decreased and negatively correlates with histological damage observed in liver fibrosis; (2) myeloid Nrf1 deficiency aggravates M1 polarization, enhances inflammatory response and facilitates liver fibrosis; (3) Nrf1 directly binds to Foxo1 in the nucleus and inhibits downstream KLF16 transcription; (4) KLF16 is critical for Nrf1/Foxo1-regulated mitochondrial energy metabolism, macrophage polarization and inflammatory response in fibrotic livers. The gene discussed is KLF16; the disease is Hepatic fibrosis.