Ubiquitin-like posttranslational modifications in NAFLD progression and treatment

Nonalcoholic fatty liver disease(NAFLD)is a long-lasting condition that affects the liver,destroying its function.Liver injury can cause steatosis and inflammation,and further activation of hepatic stellate cells(HSCs)often leads to the development of nonalcoholic liver fibrosis.The patient with NAFLD is at risk of developing advanced liver disease and complications,such as liver failure,hepatocellular carcinoma(HCC),and portal hypertension.Although our understanding of the cellular and molecular mechanisms of NAFLD has greatly improved in recent years,treatment remains limited.Analysis and characterization of protein posttranslational modifications(PTMs)could improve our understanding of NAFLD pathology and leading to the development of new and more effective treatments.In recent years,a number of studies have described how ubiquitin-like(Ubl)-PTMs change during NAFLD and how treatments targeting specific enzymes mediating these Ubl-PTMs can improve various liver diseases,particularly in relation to NAFLD and nonalcoholic liver fibrosis.New strategies for evaluating modified proteomes could provide novel insights into the roles of Ubl-PTMs in NAFLD progression and the therapeutic value of targeting the proteins involved in these Ubl-PTMs.

MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression

Liver fibrosis is a significant health burden,marked by the consistent deposition of collagen.Unfortunately,the currently available treatment approaches for this condition are far from optimal.Lysyl oxidase-like protein 2(LOXL2)secreted by hepatic stellate cells(HSCs)is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver fibrosis.Mesenchymal stem cell-derived small extracellular vesicles(MSC-sEVs)have been proposed as a potential treatment option for chronic liver disorders.Previous studies have found that MSC-sEV can be used for microRNA delivery into target cells or tissues.It is currently unclear whether microRNA-4465(miR-4465)can target LOXL2 and inhibit HSC activation.Additionally,it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver fibrosis.This study explored the effect of miR-4465-modified MSC-sEV(MSC-sEVmiR-4465)on LOXL2 expression and liver fibrosis development.The results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in HSC.Moreover,MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in vitro.MSC-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse model.MSC-sEVmiR-4465 mediating via LOXL2 also hindered the migration and invasion of HepG2 cells.In conclusion,we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2,which might provide a promising therapeutic strategy for liver diseases.