Loss of BATF3 impairs adipose-liver homeostasis and accelerates the transition from steatosis to fibrosis in high-fat diet-fed mice.

BATF3 is a transcription factor critical for dendritic cell differentiation and immune regulation. Although recent studies suggest that BATF3 is involved in metabolic disorders, the mechanism by which BATF3 deficiency contributes to the development of metabolic dysfunction-associated fatty liver disease (MASLD) remains unclear. Here, we examined the impact of BATF3 deficiency in mice fed a high-fat diet (HFD). We discovered that BATF3 is essential for maintaining metabolic homeostasis in adipose tissue and liver. Batf3⁻/⁻ mice developed aggravated hepatic steatosis, inflammation, and fibrosis, accompanied by enhanced adipose lipolysis, increased hepatic fatty acid uptake, and impaired insulin-AKT signaling. Our investigations into gene expression affected by BATF3 deficiency showed that angiopoietin-like protein 8 (ANGPTL8), a hepatokine abundantly expressed in the liver and adipose tissue, was specifically downregulated, identifying ANGPTL8 as a key mediator of BATF3-regulated hepatic and adipose tissue homeostasis. Importantly, we found that in addition to directly inhibiting inflammation-induced hepatic stellate cell activation, ANGPTL8 also has tissue-specific effects on lipid metabolism, alleviating hepatic lipid deposition and suppressing adipose tissue lipolysis. Collectively, our findings provide mechanistic insights into how BATF3 regulates hepatic and adipose homeostasis, contributing to fibrosis development, and highlight the BATF3-ANGPTL8 axis as a potential therapeutic target in fatty liver disease.