FH535

The role of Zona pellucida glycoprotein 3 (ZP3) is unclear in pancreatic adenocarcinoma (PAAD).

This study aimed to explore the role of ZP3 in PAAD.

A comparative analysis of ZP3 gene expression was performed to discern differences between various types of cancer and PAAD, leveraging data sourced from The Cancer Genome Atlas (TCGA). This study aimed to assess the role of ZP3 as a potential diagnostic marker for PAAD. The relationship between ZP3 levels and clinical characteristics, as well as patient outcomes, was scrutinized. Additionally, genomic enrichment analysis was carried out to uncover the underlying regulatory mechanisms associated with ZP3. The study further delved into the association of ZP3 with immune system interactions, checkpoint gene expression, Tumor Mutational Burden (TMB), microsatellite instability (MSI), and tumor stemness index (mRNAsi). The aberrant expression patterns of ZP3 in PAAD cell cultures were confirmed through the application of quantitative reverse transcription PCR (qRT-PCR) techniques.

ZP3 exhibited aberrant expression in both pan-cancer and PAAD. A significant correlation was observed between increased levels of ZP3 expression in PAAD patients and histologic grade (p = 0.026). Elevated ZP3 expression in PAAD was found to be significantly associated with poorer overall survival (p = 0.003), progression-free survival (p = 0.012), and disease-specific survival (p = 0.002). In PAAD, the level of ZP3 gene expression was statistically significant (p < 0.001) and recognized as a key determinant of patient prognosis. ZP3 exhibited associations with various biological pathways, including primary immunodeficiency, oxidative phosphorylation, and other pathways. ZP3 expression demonstrated correlations with immune infiltration, immune checkpoint genes, TMB, MSI, and mRNAsi in PAAD. Moreover, a pronounced negative correlation was detected between ZP3 expression levels and the therapeutic effectiveness of various medications, including selumetinib, bleomycin, FH535, docetaxel, and tanespimycin, within the context of PAAD. Elevated levels of ZP3 were consistently observed in cell line models of PAAD.

ZP3 has the potential to serve as a prognostic biomarker and therapeutic target for patients with PAAD.

Pseudorabies virus (PRV) is one of the highly contagious pathogens causing significant economic losses to the swine industry worldwide. More importantly, PRV is becoming a potential "life-threatening zoonosis" since the human-originated PRV strain was first isolated in 2019. Previously we found that the canonical Wnt/β-catenin pathway facilitates PRV proliferation, while the underlying mechanism remains unknown. In this study, the antiviral activities of the Wnt inhibitors (Adavivint, CCT251545, FH535, and iCRT14) were identified. Applying these inhibitors significantly inhibited PRV proliferation in different cell lines. Among them, CCT251545 presented the strongest anti-PRV activity with IC₅₀ values less than 200 nM. Our in vivo studies showed that treatment with CCT251545 remarkedly decreased the viral loads and protected mice challenged with PRV. Further study found that CCT251545 neither had a virucidal effect nor affected viral adsorption while mainly interfering with the entry process of the PRV life cycle. Using the FITC-dextran uptake assay, we found that CCT251545 inhibited macropinocytosis. The formation of membrane protrusions, which is important for macropinocytosis, was also inhibited by CCT251545. Consistent with this, knockout of β-catenin suppressed the PRV macropinocytosis and the formation of protrusions. On the contrary, LiCl treatment significantly stimulated the protrusion formation and the PRV entry. Together, these findings suggest that suppression of the Wnt/β-catenin pathway inhibits the macropinocytosis-dependent entry of PRV, thereby providing potential targets for developing antiviral agents against PRV.