The Proteomics of MASLD Progression: Insights From Functional Analysis to Drive the Development of New Therapeutic Solutions

ABSTRACT Background Metabolic dysfunction–associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide, with alarming prevalence reaching epidemic proportions. Aims and Methods The objective of this study is to provide a comprehensive review of the latest blood proteomics studies on MASLD and metabolic dysfunction–associated steatohepatitis (MASH), with emphasis on fibrosis. Furthermore, our objective is to conduct an analysis of protein pathways and interactions by integrating proteomics data using functional enrichment analysis of the deregulated proteins. Results Notwithstanding the considerable discrepancies in the methodology and the number of proteins examined in the circulation, the analysis reveals a consistent pattern among the list of proteins that are decreased or increased in the blood of the affected patients. The relevant biological processes (BP) associated with down‐ and upregulated proteins are high‐density lipoprotein remodelling and complement activation, respectively. The protein families identified include not only those expected to be involved in the immune system and cell adhesion and migration but also ligands of glycoproteins expressed in cells that have been subjected to stress and proteins containing the Sushi domain. Conclusions The application of cutting‐edge methodologies to investigate the blood proteome in MASH is yielding insights that facilitate the elucidation of disease mechanisms and the identification of optimal noninvasive biomarkers. However, several challenges remain to be addressed in future research, including the generalisation of results on a global scale, the optimisation of analytical technologies and the implementation of large longitudinal studies to gain insights into the molecular mechanisms that underpin the development of advanced disease.