Ubiquitination and ubiquitin-like modifications in metabolic dysfunction-associated steatotic liver disease: mechanisms and implications
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Metabolic dysfunction-associated steatotic liver disease(MASLD) is a complex metabolic disorder that encompasses aspectrum of conditions, from simple hepatic steatosis to metabolicassociatedsteatohepatitis (MASH). MASH is characterized byinflammation and accelerated fibrosis progression, which canultimately lead to cirrhosis and hepatocellular carcinoma. Givenits steadily increasing prevalence, MASLD has emerged as aglobal health epidemic. Significantly, MASLD represents a stagewhere liver function can still be partially restored through dietaryinterventions and physical exercise. However, the longtermsustainability of these lifestyle changes poses a significantchallenge. Furthermore, the complex and heterogeneous natureof MASH complicates the development of pharmacotherapeuticstrategies and the identification of reliable biomarkers for effectivetreatment. Therefore, it is essential to gain a comprehensiveunderstanding of the molecular mechanisms drivingMASLD and to develop targeted therapeutic interventions. Recent studies have underscored the critical role of posttranslationalmodifications (PTMs) of proteins in regulatingMASLD. PTMs, such as ubiquitination, SUMOylation, Neddylation,and UFMylation, are known to modulate proteinfunction and diverse cellular processes. Among these, ubiquitinationis particularly noteworthy for its dual role in mediatingprotein degradation through the ubiquitin-proteasome systemand in regulating cellular signaling pathways in a non-proteolyticmanner, depending on the specific linkages formed atthe seven distinct lysine residues (K6, K11, K27, K29, K33,K48, and K63) and the Met1-linked (M1) linear ubiquitin chain. Despite significant progress in this area, studies focusing onlinkage-specific ubiquitination events that regulate MASLD remain relatively limited. Thus, this review aims to provide acomprehensive summary of the role of linkage-specific ubiquitinationin regulating MASLD, as well as exploring other ubiquitinlikemodifications that may contribute to its pathophysiology.
Abstract
Metabolic dysfunction-associated steatotic liver disease(MASLD) is a complex metabolic disorder that encompasses aspectrum of conditions, from simple hepatic steatosis to metabolicassociatedsteatohepatitis (MASH). MASH is characterized byinflammation and accelerated fibrosis progression, which canultimately lead to cirrhosis and hepatocellular carcinoma. Givenits steadily increasing prevalence, MASLD has emerged as aglobal health epidemic. Significantly, MASLD represents a stagewhere liver function can still be partially restored through dietaryinterventions and physical exercise. However, the longtermsustainability of these lifestyle changes poses a significantchallenge. Furthermore, the complex and heterogeneous natureof MASH complicates the development of pharmacotherapeuticstrategies and the identification of reliable biomarkers for effectivetreatment. Therefore, it is essential to gain a comprehensiveunderstanding of the molecular mechanisms drivingMASLD and to develop targeted therapeutic interventions. Recent studies have underscored the critical role of posttranslationalmodifications (PTMs) of proteins in regulatingMASLD. PTMs, such as ubiquitination, SUMOylation, Neddylation,and UFMylation, are known to modulate proteinfunction and diverse cellular processes. Among these, ubiquitinationis particularly noteworthy for its dual role in mediatingprotein degradation through the ubiquitin-proteasome systemand in regulating cellular signaling pathways in a non-proteolyticmanner, depending on the specific linkages formed atthe seven distinct lysine residues (K6, K11, K27, K29, K33,K48, and K63) and the Met1-linked (M1) linear ubiquitin chain. Despite significant progress in this area, studies focusing onlinkage-specific ubiquitination events that regulate MASLD remain relatively limited. Thus, this review aims to provide acomprehensive summary of the role of linkage-specific ubiquitinationin regulating MASLD, as well as exploring other ubiquitinlikemodifications that may contribute to its pathophysiology.