Hepatocyte TonEBP promotes metabolic stress-induced hepatic fibroinflammation involving transcriptional activation of ELR+ CXC chemokines

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by liver inflammation, fibrosis, and hepatocyte injury. Despite its clinical relevance, the molecular mechanisms linking metabolic stress to hepatic fibroinflammation remain poorly understood. In this study, we identify Tonicity-Responsive Enhancer-Binding Protein (TonEBP) as a key stress-responsive transcription factor that mediates the link between metabolic overload and liver inflammation in non-malignant hepatocytes. Using hepatocyte-specific TonEBP knockout (HKO) mice, we demonstrate that TonEBP deletion reduces liver injury, inflammation, and fibrosis in MASH and steatosis models. Mechanistically, TonEBP recruits nuclear factor-kappa B (NF-kappa B) to ELR+ CXC chemokine gene promoters, promoting neutrophil and macrophage recruitment. These findings underscore the hepatocyte-intrinsic TonEBP/NF-kappa B axis as a critical driver of immune cell infiltration and fibroinflammation in MASLD progression, revealing its pivotal role in the pathophysiology of liver disease. By highlighting this axis, we provide new insight into the molecular mechanisms that govern the transition from steatosis to steatohepatitis, emphasizing the importance of TonEBP in regulating inflammatory pathways within hepatocytes.