Targeting E3 ubiquitin ligases and their adaptors as a therapeutic strategy for metabolic diseases

Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process targets a large number of cellular proteins, affecting all biological pathways involved in the cell cycle, development, growth, and differentiation. Thus, aberrant regulation of ubiquitination is likely associated with several diseases, including various types of metabolic diseases. Among the ubiquitin enzymes, E3 ubiquitin ligases are regarded as the most influential ubiquitin enzymes due to their ability to selectively bind and recruit target substrates for ubiquitination. Continued research on the regulatory mechanisms of E3 ligases and their adaptors in metabolic diseases will further stimulate the discovery of new targets and accelerate the development of therapeutic options for metabolic diseases. In this review, based on recent discoveries, we summarize new insights into the roles of E3 ubiquitin ligases and their adaptors in the pathogenesis of metabolic diseases by highlighting recent evidence obtained in both human and animal model studies. This review highlights the crucial role of E3 ubiquitin ligases and their adaptors in regulating metabolic diseases, such as obesity, diabetes, and nonalcoholic fatty liver disease. The authors discuss the mechanisms controlling E3 ubiquitin ligases and their adaptors, as well as the potential of targeting specific E3 ubiquitin ligases or adaptors for therapeutic interventions. By developing therapeutic approaches that target these proteins, it may be possible to stabilize target proteins without affecting the expression of others, resulting in more effective treatments for metabolic diseases with fewer adverse effects. Further understanding of the complex biochemistry underlying the physiological functions regulated by E3 ubiquitin ligases and their adaptors is necessary to identify their potential roles as metabolic regulators and therapeutic targets.