Zfp697/ZNF697 is an RNA-binding protein that modulates TGF-β1 signaling and hepatic inflammation in liver disease.

Liver diseases driven by metabolic dysfunction, inflammation, and fibrosis such as metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injury represent a growing global health burden. The zinc finger protein Zfp697 (ZNF697 in humans) is a newly identified regulator of inflammation and regeneration in skeletal muscle. Here, we characterize the role of liver Zfp697 and show that its expression is increased in multiple animal models of liver disease. Indeed, Zfp697/ZNF697 transcript levels show a strong positive correlation with several markers of liver inflammation and fibrosis. In line with that, in human and mouse hepatocytes TGF-β1 increases Zfp697 expression, which in turn regulates genes involved in TGF-β1 signaling, chemokine secretion, and immune cell recruitment. In mice, hepatocyte-specific Zfp697 deletion improves glucose tolerance and is associated with the absence of MASH-induced lean mass loss but does not confer uniform hepatoprotection. Biochemical purification of Zfp697 protein interactors and enhanced crosslinking and immunoprecipitation (eCLIP) analyses reveal that Zfp697 interacts with other RNA-binding proteins and associates with over 1,000 RNAs in mouse liver. Zfp697-associated RNAs include several transcript types, with a large representation of mRNAs which group in pathways related to transcriptional regulation, PI3K/AKT signaling, and cell differentiation. These findings identify Zfp697 as a novel RNA-interacting protein and modulator of TGF-β signaling in the liver and provide a basis for further investigation of its role in liver disease.