The Impact of Silencing Hepatic AATF on Transcriptomic and Metabolomic Signatures in Experimental MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 30% of the global population and has emerged as a significant public health concern. It is a multifactorial pathological condition driven by various molecular influencers. Thus, identifying and understanding the molecular drivers of MASLD pathogenesis is essential for developing targeted therapeutic strategies. Here, we elucidate the role of apoptosis antagonizing transcription factor (AATF) as a molecular driver in the pathogenesis of MASLD. Liver-specific silencing of AATF reduced body weight, liver weight, and insulin resistance in WD mice compared to WD controls. Biochemical, histological, and molecular analyses showed reduced liver injury, and steatosis. Transcriptomics analysis showed reduced cellular stress response, inflammation and fibrosis in WDsiAATF. Furthermore, untargeted metabolomics revealed increased biosynthesis of glycerophospholipids and promoted fatty acid oxidation while reducing the triglyceride accumulation. These findings show a molecular link between AATF and hepatic lipid metabolism, implying that AATF could be a promising therapeutic target for MASLD.