The RNA-binding protein Zfp697 regulates hepatic inflammation response

Liver diseases such as MASLD, MASH, and acute liver injury represent a growing global health burden, driven by inflammation, metabolic dysfunction, and fibrosis. The zinc finger protein Zfp697 (ZNF697 in humans), a newly identified regulator of inflammation and regeneration in skeletal muscle, has not been studied in the liver. Here, we characterize Zfp697 in the liver for the first time and show it is induced in multiple models of liver disease. Human and mouse Zfp697 is induced by TGF-ß1 and regulates genes involved in immune cell recruitment and chemokine secretion and modulates TGF-ß1 signaling. Hepatocyte-specific Zfp697 deletion improves glucose intolerance and mitigates body weight and lean mass loss in MASH. Proteomic and eCLIP analyses reveal Zfp697 interacts with RNA-binding proteins and binds multiple RNAs in a liver-specific manner. These findings identify Zfp697 as a novel RNA-binding protein involved in liver disease and highlight its potential as a therapeutic target. Overall design: FLAG-Zfp697 eCLIP and corresponding input samples were obtained from the livers of 10 weeks old male C57BL/6J mice (n = 3), one week following Ad-FLAG-Zfp697 injection.