Identification of pyroptosis-related gene signature in nonalcoholic steatohepatitis

Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the major causes of liver-related morbidity and mortality globally. It ranges fromsimple steatosis to non-alcoholic steatohepatitis (NASH) characterized by ballooning and hepatic inflammation. In the past few years, pyroptosis has been shown as a type of programmed cell death that triggers inflammation and plays a role in the development of NASH. However, the roles of pyroptosis-related genes (PRGs) in NASH remained unclear. Methods: : In this study, we studied the expression level of pyroptosis-related genes (PRGs) in NASH and healthy controls, developed a diagnostic model of NASH based on PRGs and explored the pathological mechanisms associated with pyroptosis. We further compared immune status between NASH and healthy controls, analyzed immune status in different subtypes of NASH. Results: : We identified altogether twentyPRGs that were differentially expressed between NASH and normal liver tissues. Then, a novel diagnostic model consisting of seven PRGs including CASP3, ELANE, GZMA, CASP4 , CASP9 , IL6 and TP63 for NASH was constructed with an area under the ROC curve (AUC) of 0.978(CI 0.965-0.99). Obvious variations in immune status between healthy controls and NASH cases were detected. Subsequently, the consensus clustering method based on differentially expressed PRGs was constructed to divide all NASH cases into two distinct pyroptosis subtypes with different immune and biological characteristics. Further combined with screening drug targets by using DGIdb database, we explored possible drugs targets of NASH including Oltipraz, Metaproterenol, Fingolimod. Conclusion: Pyroptosis-related genes may play an important role in NASH and can provide new insights into the diagnosis and underlying mechanisms of NASH.