Background: Ubiquitination is a basic post-translational modification of intracellular proteins and can be reversed enzymatically by DUBs (deubiquitinating enzymes). More than 90 DUBs have been identified. Among them, the deubiquitinating enzyme YOD1, a member of the ovarian tumor domain protease (OTUs) subfamily, is involved in the regulation of endoplasmic reticulum (ER)-related degradation pathways. In fact, it is reported that YOD1 is an important proliferation and metastasis-inducing gene, which can stimulate the characteristics of cancer stem cells and maintain circulating tumor cells (CTC). However, the expression level, prognostic effect and biological functional mechanism of YOD1 in pancreatic cancer are still unclear. Results: In the GEO and TCGA databases, YOD1 mRNA expression is significantly up regulated in a variety of human pancreatic cancer tissues. Survival analysis showed that the up regulation of YOD1 can predict poor prognosis of pancreatic cancer. Cox analysis showed that high YOD1 expression is an independent prognostic factor of pancreatic cancer. ROC analysis shows that YOD1 has significant diagnostic value. The immunohistochemistry (IHC) results showed that the protein expression level of YOD1 in pancreatic cancer tissue was higher than that in neighboring non-pancreatic cancer tissues (P < 0.001). In addition, we found that YOD1 expression is negatively correlated with the infiltration level of CD8 + T cells, macrophages, neutrophils and dendritic cells (DC) in pancreatic cancer. The expression of YOD1 has a strong correlation with the different immune marker sets in PAAD. Co-expression network and functional enrichment analysis indicate that YOD1 may participate in the development of pancreatic cancer through cell adhesion molecules, p53, Hippo, TGF-β and other pathways. The experimental results of EDU, Transwell, Immunohistochemistry (IHC), Western blot and Flow Cytometry indicate that YOD1 is highly expressed in pancreatic cancer cells and pancreatic cancer tissues, and its overexpression can promote the proliferation and metastasis of pancreatic cancer cells and affect the immune microenvironment. Conclusion: Our results indicate that YOD1 may be a useful biomarker for the prognosis of human pancreatic cancer, and it may also be a potential molecular target for the diagnosis and treatment of pancreatic cancer.

Liver fibrosis plays an important role in the progression of liver disease, but there is a severe shortage of direct and efficacious pharmaceutical clinical interventions. Literature research indicates that aspartic acid exhibits hepatoprotective properties. In this paper, 32 target compounds were designed and synthesized utilizing aspartic acid as the lead compound, of which 22 were new compounds not reported in the literature. These compounds were screened for their inhibitory effects on the COL1A1 promoter to assess in vitro anti-liver fibrosis activity and summarized structure–activity relationships. Four compounds exhibited superior potency with inhibition rates ranging from 66.72% to 97.44%, substantially higher than EGCG (36.46 ± 4.64%) and L-Asp (11.33 ± 0.35%). In an LPS-induced inflammation model of LX-2 cells, both 41 and 8a could inhibit the activation of LX-2 cells, reducing the expression of COL1A1, fibronectin, and α-SMA. Upon further investigation, 41 and 8a ameliorated liver fibrosis by inhibiting the IKKβ-NF-κB signaling pathway to alleviate inflammatory response. Overall, the study evaluated the anti-liver fibrosis effects of aspartic acid derivatives, identified the potency of 41, and conducted a preliminary exploration of mechanisms, laying the foundation for the discovery of novel anti-liver fibrosis agents.

The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12β-O-(γ-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure–activity relationship (SAR) and identified the most potent compound, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg·Kg⁻¹) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of 10b extends into the H11–H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12β-alkonate. These findings suggest that 12-glutamyl OA derivative 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH).