Non-Targeted Metabolomics Reveal Apomorphine’s Therapeutic Effects and Lysophospholipid Alterations in Steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH), characterized by progressive inflammation and fibrosis, evolves from metabolic dysfunction-associated steatotic liver disease and significantly heightens the risk of cirrhosis and hepatocellular carcinoma. Understanding metabolic pathways that influence MASH progression is crucial for developing targeted therapies. Non-targeted metabolomics offer a comprehensive view of metabolic alterations, enabling identification of novel biomarkers and pathways without preconceived ideas. Conversely, targeted metabolomics deliver precise and reproducible measurements, focusing on predefined metabolites to accurately quantify established pathways. This study utilized hepatocyte-specific PTEN knockout mice as a model to explore metabolic shifts associated with MASH. By integrating non-targeted metabolomics and targeted metabolomics, we analyzed liver samples from three groups: normal, pathological (MASH-affected), and MASH-affected, but treated with apomorphine, an antioxidant and recently reported ferroptosis inhibitor with potential therapeutic effects. Metabolic profiling identified lysophospholipids (LPLs) as significantly altered metabolites, with elevated levels in the MASH model and a notable reduction after apomorphine treatment. This suggests that LPLs are central to the etiology of MASH and may serve as targets for therapeutic intervention. Our findings underscore the effectiveness of apomorphine in modulating disease-specific metabolic disruptions, offering insights into its potential as a treatment for human MASH.