Comprehensive characterization of pyroptosis reveals novel molecular typing of biliary atresia as well as contributes to precise treatment

Abstract

Abstract Background: Biliary Atresia (BA) is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. Current research has found a variety of causes for BA, with inflammation and fibrosis is more studied. However, these etiological mechanisms are not present in all patients. Pyroptosis has been increasingly appreciated as a programmed cell death process but is less studied in BA. We have re-classified BA by integrating gene microarray data and scRNA-seq data to support individualized clinical treatment and mechanistic studies. Methods: The BA microarray dataset GSE122340 was downloaded from the Gene Expression Omnibus (GEO) database. GSE46960 and GSE15235 and sequencing data of identical twins as validation cohorts. Through retrospective analysis, 17 differential pyroptosis genes (DEPRGs) were used for typing research. An effective method for identifying BA typing through machine learning algorithms. Subsequently, we performed drug prediction for the pyroptosis subtype to enable individualized treatment. Pyroptosis-score was constructed and combined with scRNA-seq datasets to reveal immune cells and pathways activated during pyroptosis. Results: Two novel subtypes of pyroptosis were identified. The C1 subtype shows activation of pyroptosis, enhanced inflammatory response, and increased infiltration of monocytes and neutrophils. The C2 subtype exhibits cell cycle activation, low pyroptosis, and a milder inflammatory response. Macrophage pyroptosis may promote the infiltration of more immune cells and the release of inflammatory factors, further aggravating the occurrence of hepatic pyroptosis, which in turn leads to a poorer prognosis in inflammatory BA. Conclusion: In summary, we have defined two novel subtypes of pyroptosis and offered the possibility of identifying them and individualizing treatment. The role of macrophages, neutrophils, and plasma cells in the pyroptosis process of BA is worthy of further study.