ASS1 is a hub gene and possible therapeutic target for regulating metabolic dysfunction-associated steatotic liver disease modulated by a carbohydrate-restricted diet.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally. A low-carbohydrate diet (LCD) offers benefits to MASLD patients, albeit its exact mechanism is not fully understood. Using public liver transcriptome data from MASLD patients before/after LCD intervention, we applied differential expression analysis and machine learning to identify key genes. We initially identified 162 differentially expressed genes in the GSE107650 dataset. Secondly, employing two machine learning algorithms, we found that PRAMENP, LEAP2, LOC105379013, and argininosuccinate synthetase 1 (ASS1) are potential hub genes. Additionally, protein-protein interaction and single-cell RNA location analyses suggested that ASS1 was the most crucial hub gene. Then, L1000CDS² analysis of the gene-expression signatures was employed for drug repurposing studies. CGP71683, an appetite suppressant, was predicted to improve MASLD and may mimic the ASS1 expression pattern induced by an LCD. Molecular dynamics confirmed spontaneous, stable CGP71683-ASS1 complex formation. Overall, this work based on analysis of machine learning algorithms, essential gene identification, and drug repurposing studies suggested that ASS1 is an essential gene in MASLD and CGP71683 is a potential drug candidate for treating MASLD by targeting ASS1 and mimicking the beneficial effects of an LCD. However, due to the inherent limitations of a purely computational approach, further experimental investigation is necessary to validate the anticipated results.