USP30 Inhibitors and Mitophagy, a Cellular Power Couple against Metabolic-Associated Fatty Liver Disease

Mitophagy is a selective process by which damaged or dysfunctional mitochondria are specifically targeted for degradation and removal by the cell. It prevents the accumulation of dysfunctional mitochondria, which can otherwise contribute to cellular stress and diseases such as neurodegenerative disorders and certain cancers. Ubiquitination marks proteins for degradation by the proteasome or lysosomes of the autophagy machinery. Ubiquitin-Specific Peptidase 30 (USP30) on the other hand, has been identified as a negative regulator of mitophagy. It counteracts the process of ubiquitination by removing the ubiquitin tags from proteins on the mitochondrial surface and prevents the degradation of damaged or dysfunctional mitochondria leading to cellular stress. Inhibiting USP30 activity has been shown to promote mitophagy and a potential approach to managing certain neurodegenerative diseases. Although impaired mitophagy and mitochondrial dysfunction have been linked to the pathogenesis of metabolic-associated fatty liver disease (MAFLD), research into the involvement of USP30 in the pathophysiology of MAFLD or metabolic disorders is still in its early stages. As a result, we sought to thoroughly assess the literature to determine the involvement of USP30 in the pathophysiology of MAFLD and whether modulating USP30 activity could potentially be a therapeutic strategy to manage MAFLD.