Nur77通过抑制上皮-间质转化抗肝纤维化的机制OA

Objective To explore the mechanism of the orphan nuclear receptor Nur77 targeting epithelial-mesenchymal transition to combat liver fibrosis.Methods Forty C57/BL6 mice were randomly divided into four groups:negative control(NC),hepatic fibrosis model(NM),Nur77 overexpression control(OEC),and Nur77 overexpression model(OEM),with 10 mice per group.Hepatic fibrosis was induced in mice via intraperitoneal injection of carbon tetrachloride in olive oil.The OEC group received an intravenous injection of 200 μL of Nur77 overexpression virus,while the NC and NM groups received an intravenous injection of 200 μL of a negative control virus.Following the intervention,hepatic function and pathological alterations were assessed.Protein levels of α-SMA,E-cadherin,Nur77,and PI3K were detected using Western blotting and immunofluorescence.For cellular experiments,human hepatic stellate cells(LX-2)were activated and cultured with PDGF-BB.Results ① After 8 weeks of model induction,the body weight of the NM group was significantly lower than that of the NC and OEM groups(both P<0.05).② Compared to the NM group,the levels of ALT and AST in the OEM group were significantly reduced(both P<0.05).HE staining revealed that,compared with the NM group,the OEM group exhibited reduced severity of pathological injury and decreased collagen fiber distribution.③ Western blotting and immunofluorescence assays demonstrated that α-SMA protein expression was significantly elevated in the NM group compared to the NC group(P<0.05),and α-SMA expression was markedly reduced in the OEM group relative to the NM group(P<0.05).④ Immunohistochemical staining indicated that the number and expression level of E-cadherin positive cells were significantly decreased in the NM group compared to the NC group;the yellow positive staining area was notably increased in the OEM group compared to the NM group(P<0.05).⑤ Nur77 protein expression was significantly reduced in the NM group compared to the NC group;Nur77 protein expression was markedly increased in the OEM group relative to the NM group.⑥ RNA-seq analysis revealed significant enrichment of the PI3K/Akt signaling pathway;Western blotting analysis showed that p-Akt/Akt and p-PI3K/PI3K were significantly elevated in the NM group compared to the NC group(P<0.05);in contrast to the NM group,the OEM group exhibited a significant decrease in p-PI3K/PI3K and p-Akt/Akt(P<0.05).Conclusions Nur77 inhibits epithelial-mesenchymal transition in a mouse model of liver fibrosis.Its mechanism involves the regulation of the PI3K/Akt signaling axis,offering novel strategies and intervention targets for the precise treatment of liver fibrosis.