BAG6 is a novel player in controlling nonalcoholic steatohepatitis: result from a comprehensive in-silico study

Nonalcoholic steatohepatitis, or NASH, is a multifactorial disease characterized by hepatic lipid accumulation, inflammation, cell death, and fibrosis, and an efficacious pharmaceutical intervention for this is yet to be discovered. The present study aims to identify potential targets capable of reversing the disease-specific molecular alterations and elucidate their possible action mechanism. Our study uses combinations of different methods, such as genome-scale metabolic modelling, directional protein-protein interaction network, connectivity map, and network controllability, to identify potential targets in NASH. Our approach yielded three promising targets, BAG6, CASP3, and CYCS, and captured their effects on inflammation, fibrosis, steatosis, and apoptosis. The association of CASP3 and CYCS with NASH are already reported in the literature. So BAG6 was selected as a novel target. In the Huh-7 cell-line, its ablation reduced fatty acid accumulation and decreased levels of NASH-signature transcripts, supporting our hypothesis on BAG6 as a potential NASH target. ### Competing Interest Statement The authors have declared no competing interest. * BAG6 : BCL2 Associated Athanogene 6 NAFLD : Nonalcoholic fatty liver disease NASH : Nonalcoholic steatohepatitis NAFL : Nonalcoholic fatty liver PPI : Protein-protein interaction GSMM : Genome-scale metabolic model CMap : Connectivity Map database DEG : Differentially expressed genes GSEA : Gene set enrichment analysis. NES : Normalized enrichment scores MOMA : Minimization of metabolic adjustment TS : Transformation score MTA : Metabolic transformation algorithm MCG : Metabolic candidate genes CP : Candidate proteins DPN : Directional PPI network ICP : Indispensable candidate protein FFA : Free Fatty Acid