Contribution of classification based on ferroptosis-related genes to the heterogeneity of MAFLD

Abstract

Abstract Background Metabolic dysfunction-associated fatty liver disease (MAFLD) is a highly heterogeneous disease and its heterogeneity might be associated with ferroptosis because ferroptosis plays an important role in the development of MAFLD. We aimed to perform integrative analysis of ferroptosis related genes and MAFLD subtypes using bioinformatics. Methods A differential expression analysis was performed to identify key ferroptosis-related genes associated with the clinical characteristics of MAFLD. Furthermore, consensus k clustering was utilized to distinguish ferroptosis-related clinical subtypes of MAFLD and assess the association of ferroptosis-related gene expression and clinical features between patients with different subtypes of MAFLD. Moreover, the variation in the immune status and regulatory relationship of ferroptosis-related genes in individuals with MAFLD was also explored using single sample gene set enrichment analysis, weighted gene coexpression network analysis and enrichment analyses. Results Eight ferroptosis-related genes were identified as closely associated with both the hepatic steatosis grade and non-alcoholic fatty liver disease activity score. Two subtypes of MAFLD based on ferroptosis-related genes were identified by consensus clustering. They exhibited significantly different clinical features, immune statuses, biological processes and outcomes. The progression of the two subtypes was associated with immunity. Conclusions Two highly heterogeneous subtypes of MAFLD with significantly distinct clinical features, biological processes and immune statuses were identified based on ferroptosis-associated genes, which strongly supports the hypothesis that ferroptosis plays an important role in the development of MAFLD.