Role of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Signaling in Liver and Metabolic Diseases.

MAP4K4 is a serine/threonine protein kinase belonging to the germinal center kinase subgroup of sterile 20 protein family of kinases. MAP4K4 has been involved in regulating multiple biologic processes and a plethora of pathologies, including systemic inflammation, cardiovascular diseases, cancers, and metabolic and hepatic diseases. Recently, multiple reports have indicated the upregulation of MAP4K4 expression and signaling in hyperglycemia and liver diseases. This review provides an overview of our current knowledge of MAP4K4 structure and expression, as well as its regulation and signaling, specifically in metabolic and hepatic diseases. Reviewing these promising studies will enrich our understanding of MAP4K4 signaling pathways and, in the future, will help us design innovative therapeutic interventions against metabolic and liver diseases using MAP4K4 as a target. SIGNIFICANCE STATEMENT: Although most studies on the involvement of MAP4K4 in human pathologies are related to cancers, only recently its role in liver and other metabolic diseases is beginning to unravel. This mini review discusses recent advancements in MAP4K4 biology within the context of metabolic dysfunction and comprehensively characterizes MAP4K4 as a clinically relevant therapeutic target against liver and metabolic diseases.