ZNF469 is a transcriptional regulator of fibrosis in MASLD

Metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD), is a silent disease with little to no symptoms but is common in individuals who are overweight, diabetic, or genetically predisposed. The onset of fibrosis in MASH represents a critical inflection point in disease severity that progresses to portal hypertension, cirrhosis, liver failure and hepatocellular carcinoma. Liver transplantation remains the only treatment for cirrhosis. Liver fibrosis is the result of several integrated signaling networks that regulate the deposition of extracellular matrix, primarily collagens and fibronectin. The cascade of responses in hepatic stellate cells (HSCs) drives the activation and transition or normally quiescent HSCs into a myofibroblast-like phenotype that is contractile, proliferative and fibrogenic. In an effort to define the transcriptional networks underlying HSC activation in humans we applied genomescale enhancer mapping (CUT&RUN) and bulk RNA- sequencing to an existing repository of >250 human NAFLD liver tissues with pathology ranging from normal to advanced fibrosis. This analysis nominated 125 candidate transcription factors (TFs) as potential regulators of collagen production. We employed a CRISPR screen in HSCs to test whether these TFs regulate collagen production using high content imaging readouts. We identified ZNF469 (Zfp469 in mice) as a modulator of collagen production in human HSCs. Our central hypothesis is that ZNF469 functions as a TF that positively regulates fibrosis through direct gene regulation of collagen in hepatic stellate cells. To test this hypothesis we will pursue two subaims: 1) establish how ZFP469 regulates the initiation of fibrosis in diet-induced MASH models; and 2) determine how ZFP469 regulates the maintenance and regression of established liver fibrosis in MASH. This project has the potential to establish ZNF469 as a novel transcriptional regulator of liver fibrosis with potential for therapeutic translation.