Non-alcoholic fatty liver disease (NAFLD) is a hepatic metabolic syndrome resulting from lipid metabolic imbalance. Interferon regulatory factor 8 (IRF8) is well known for its roles in immune cell differentiation and tumor pathogenesis; however, its role in regulating glucose homeostasis and lipid metabolism remains unclear. This research, published in the Genes & Diseases journal by a team from Shanghai Jiao Tong University, Southern Medical University and Capital Medical University, elucidates the role of IRF8 in hepatic lipid metabolism using mouse models of gain and loss of function. The initial investigation involving multiple murine models revealed an upregulation of IRF8 expression in the liver tissues of both humans and mice with NAFLD. The research findings also demonstrated that IRF8 exacerbates hepatic lipid accumulation and metabolic disturbance under both standard and high-fat dietary conditions. Additionally, IRF8 knockdown reduced hepatic lipid accumulation and alleviated metabolic disorders induced by a high-fat diet (HFD). The researchers then employed adenovirus vectors expressing IRF8 (Ad-IRF8) or small interfering RNAs (si-IRF8) to respectively induce the overexpression or silencing of IRF8 in mouse primary hepatocytes (MPHs) and found that IRF8 positively regulates the expression of a core circadian rhythm gene, brain and muscle ARNT-like 1 (BMAL1), in hepatocytes. Furthermore, in vitro and in vivo studies collectively indicated that IRF8 modulates the expression of peroxisome proliferator-activated receptor γ (PPARγ) and related fatty acid uptake and synthesis genes mediated by BMAL1. Notably, the application of a PPARγ inhibitor (GW9662) to IRF8-overexpressing MPHs effectively suppressed the cellular lipid deposition caused by IRF8 upregulation. This finding indicates that the IRF8/BMAL1/ PPARγ axis may play an important role in liver lipid metabolism. Furthermore, adeno-associated virus-mediated IRF8 knockdown in mouse liver markedly alleviated hepatic steatosis and obesity-related metabolic syndrome. In conclusion, this study reveals a previously unknown and crucial factor modulating hepatic lipid homeostasis and the mechanism of hepatic steatosis in NAFLD models. Importantly, targeting the newly identified IRF8-BMAL1-PPARγ axis could offer promising therapeutic strategies for treating NAFLD and related metabolic disorders.