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Peroxidasin (PXDN), a human homolog of Drosophila PXDN, belongs to the family of heme peroxidases and has been found to promote oxidative stress in cardiovascular tissue, however, its role in prostate cancer has not been previously elucidated. We hypothesized that PXDN promotes prostate cancer progression via regulation of metabolic and oxidative stress pathways. We analyzed PXDN expression in prostate tissue by immunohistochemistry and found increased PXDN expression with prostate cancer progression as compared to normal tissue or cells. PXDN knockdown followed by proteomic analysis revealed an increase in oxidative stress, mitochondrial dysfunction and gluconeogenesis pathways. Additionally, Liquid Chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomics confirmed that PXDN knockdown induced global reprogramming associated with increased oxidative stress and decreased nucleotide biosynthesis. We further demonstrated that PXDN knockdown led to an increase in reactive oxygen species (ROS) associated with decreased cell viability and increased apoptosis. Finally, PXDN knockdown decreased colony formation on soft agar. Overall, the data suggest that PXDN promotes progression of prostate cancer by regulating the metabolome, more specifically, by inhibiting oxidative stress leading to decreased apoptosis. Therefore, PXDN may be a biomarker associated with prostate cancer and a potential therapeutic target.

Abdominal aortic aneurysm (AAA) represents the serious vascular degenerative disorder, which causes high incidence and mortality. Alpha-ketoglutarate (AKG), a crucial metabolite in the tricarboxylic acid (TCA) cycle, has been reported to exert significant actions on the oxidative stress and inflammation. However, its role in AAA still remains elusive. Herein, we examined the effects of AKG on the formation of AAA. The study established an elastase-induced mouse abdominal aortic aneurysms model as well as a TNF-α-mediated vascular smooth muscle cells (VSMCs) model, respectively. We displayed that AKG pre-treatment remarkably prevented aneurysmal dilation assessed by diameter and volume and reduced aortic rupture. In addition, it was also observed that AKG treatment suppressed the development of AAA by attenuating the macrophage infiltration, elastin degradation and collagen fibers remodeling. In vitro, AKG potently decreased TNF-α-induced inflammatory cytokines overproduction, more apoptotic cells and excessive superoxide. Mechanistically, we discovered that upregulation of vpo1 in AAA was significantly suppressed by AKG treatment. By exploring the RNA-seq data, we found that AKG ameliorates AAA mostly though inhibiting oxidative stress and the inflammatory response. PXDN overexpression neutralized the inhibitory effects of AKG on ROS generation and inflammatory reaction in MOVAS. Furthermore, AKG treatment suppressed the expression of p-ERK1/2, 3-Cl Tyr in vivo and in vitro. ERK activator disrupted the protective of AKG on TNF-α-induced VSMCs phenotypic switch. Conclusively, AKG can serve as a beneficial therapy for AAA through regulating PXDN/HOCL/ERK signaling pathways.

Background Recurrence and metastasis remain the primary causes of treatment failure in nasopharyngeal carcinoma (NPC). This study aims to explore the functional role and regulatory mechanisms of peroxidasin (PXDN) in NPC progression. Methods Weighted gene co-expression network analysis was performed to screen the module most relevant to the malignant progression of NPC from our internal cohort (Fujian cohort 1, N  = 192), from which the PXDN was identified as the key molecule. Clinical significance of PXDN was assessed in the GEO database and NPC tissue microarrays from Fujian cohort 2 ( N  = 103). Functional experiments were used to determine the biological role of PXDN in NPC. Methylated RNA immunoprecipitation sequencing was used to identify PXDN N6-methyladenosine (m 6 A) modification site, and verified by a dual-luciferase reporter gene assay. RNA immunoprecipitation, RNA stability assay, and RNA pull-down assay were used to verify the relationship between PXDN and YTHDF1. The CRISPR/Cas9 system was used to disrupt the m⁶A motif in the PXDN gene to further validate its role. Next, transcriptome, proteomic analysis, and immunoprecipitation assay were conducted to assess downstream targets. Results PXDN was highly expressed in NPC and associated with poor prognosis. Suppression of PXDN drastically reduced proliferation, migration, invasion, and resistance to chemoradiation in vitro, concomitant with attenuated epithelial-mesenchymal transition. Knockdown of PXDN remarkably suppressed NPC tumorigenicity and liver metastasis in vivo. Mechanistically, PXDN promotes aggressiveness by extracellular matrix remodelling to activate the ITGB1-PI3K-AKT pathway. The aberrant expression of PXDN is governed by an m 6 A-based regulatory axis, wherein YTHDF1 recognizes WTAP-mediated PXDN m 6 A methylation to enhance its RNA stability and translation. Targeted specific demethylation of PXDN m 6 A by CRISPR/Cas9 system significantly decreased the expression of PXDN. Conclusions We reveal the crucial role of PXDN in driving NPC malignancy and the regulatory role of m 6 A methylation modification. Targeting PXDN expression or activity could be used to effectively control NPC progression.

Background Diabetic retinopathy (DR) is the leading cause of blindness-related eye diseases in adults. The pathogenesis of DR is attributed to the excessive proliferation of microvessels, which leads to vitreous haemorrhage and retinal traction, thereby significantly damaging the patient’s vision. In this study, we investigated the role and molecular mechanism of Peroxidasin (PXDN) and the active ingredient baicalin (BAI) of traditional Chinese medicine in regulating the senescence and pathological angiogenesis of human retinal microvascular endothelial cells (HRMECs) to identify the key genes and signalling pathways involved in the progression of DR. Methods In this study, key hub genes were screened using relevant datasets. The expression levels of PXDN, fibronectin (FN1), and PI3K/AKT pathway-related proteins were verified in clinical specimens, animal models, and DR cell models using enzyme-linked immunosorbent assays (ELISA), quantitative real-time PCR, Western blot, and immunohistochemistry (IHC). The binding ability of BAI to the receptor for advanced glycation end products (RAGE) was verified by molecular docking technology analysis and Western blot. Moreover, the direct binding relationship between PXDN and FN1 was verified by protein–protein interaction (PPI) and western blot. By further applying gene knockdown and overexpression techniques in combination with Western blot analysis, the molecular pathways through which BAI affects RAGE/PXDN(FN1)/PI3K/AKT signalling were investigated. Results In the DR model, the expression level of PXDN significantly increased. Direct protein interactions between PXDN and FN1 were verified through PPI and coimmunoprecipitation (Co-IP) experiments. Moreover, knockdown of PXDN in vivo and in vitro significantly reduced the formation of lesions. BAI inhibited the expression of PXDN and FN1 by binding to RAGE, thereby effectively alleviating the senescence and pathological angiogenesis of HRMECs induced by high glucose (HG) conditions through regulation of the PI3K/AKT signalling pathway. Conclusions This study revealed that BAI regulates the progression of DR by regulating the RAGE/PXDN (FN1)/PI3K/AKT signalling pathway. These findings not only provide new molecular insights into the pathogenesis of DR but also lay an important theoretical foundation for the development of new therapeutic strategies. Graphical Abstract

Stomach adenocarcinoma (STAD) is known for its high prevalence and poor prognosis, which underscores the need for novel therapeutic targets. Peroxidasin (PXDN), an enzyme with peroxidase activity, has been linked to cancer development in previous studies. However, its specific role in STAD is not well understood. In our study, we used public databases and clinical specimens to determine that PXDN expression is significantly elevated in STAD tissues and serves as an independent prognostic marker for patient outcomes. Our in vitro assays demonstrated that silencing PXDN significantly reduced STAD cell proliferation, invasion, and migration. Mechanistically, we found that PXDN promotes epithelial‒mesenchymal transition and angiogenesis in STAD cells and may be regulated by the PI3K/AKT pathway. Further analysis revealed that PXDN levels affect the sensitivity of STAD cells to various chemotherapeutic and small molecule drugs. Additionally, we observed a significant association between PXDN levels and the abundances of various immune cell types in patients with STAD. Our study highlighted a strong link between PXDN levels and the tumor immune microenvironment (TIM), suggesting that PXDN is a useful metric for evaluating the response to immune checkpoint inhibitors. Moreover, we found that PXDN is significantly associated with multiple immune checkpoints. In summary, our findings indicate that PXDN plays a critical role in STAD and that its level could serve as a potential prognostic biomarker. Thus, targeting PXDN may represent an effective treatment strategy for STAD.

Despite dramatic progress in cancer diagnosis and treatment, the five-year survival rate of oral squamous cell carcinoma (OSCC) is still only about 50%. Thus, the need for elucidating the molecular mechanisms underlying OSCC is urgent. We previously identified the peroxidasin gene (PXDN) as one of several novel genes associated with OSCC. Although the PXDN protein is known to act as a tumor-promoting factor associated with the Warburg effect, its function and role in OSCC are poorly understood. In this study, we investigated the expression, function, and relationship with the Warburg effect of PXDN in OSCC. In immunohistochemical analysis of OSCC specimens, we observed that elevated PXDN expression correlated with lymph node metastasis and a diffuse invasion pattern. High PXDN expression was confirmed as an independent predictor of poor prognosis by multivariate analysis. The PXDN expression level correlated positively with that of pyruvate kinase (PKM2) and heme oxygenase-1 (HMOX1) and with lactate and ATP production. No relationship between PXDN expression and mitochondrial activation was observed, and PXDN expression correlated inversely with reactive oxygen species (ROS) production. These results suggest that PXDN might be a tumor progression factor causing a Warburg-like effect in OSCC.

Early-life adversity (ELA) is characterized by exposure to traumatic events during early periods of life, particularly involving emotional, sexual and/or physical adversities during childhood. Mental disorders are strongly influenced by environmental and lifestyle-related risk factors including ELA. However, the molecular link between ELA and the risk of an adult mental disorder is still not fully understood. Evidence is emerging that long-lasting changes in the epigenetic processes regulating gene expression, such as DNA methylation, play an important role in the biological mechanisms linking ELA and mental disorders. Based on a recent study, we analyzed the DNA methylation of a specific CpG site within the gene PXDN—cg10888111—in blood in the context of ELA across a set of psychiatric disorders, namely Borderline Personality Disorder (BPD), Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD), and its potential contribution to their pathogenesis. We found significant hypermethylation in mentally ill patients with high levels of ELA compared to patients with low levels of ELA, whereas cg10888111 methylation in healthy control individuals was not affected by ELA. Further investigations revealed that this effect was driven by the MDD cohort. Providing a direct comparison of cg10888111 DNA methylation in blood in the context of ELA across three mental disorders, our results indicate the role of PXDN regulation in the response to ELA in the pathogenesis of mental disorders, especially MDD. Further studies will be needed to validate these results and decipher the corresponding biological network that is involved in the transmission of ELA to an adult mental disorder in general.

Background: Primary congenital glaucoma (PCG) is a rare disease with an incidence of 1 in 12,000 to 18,000 in Europeans. The scarcity of the disease and limited access to genetic testing have hindered research, particularly within the Latvian population. Objectives: This study aims to present the preliminary results of a molecular genetic investigation into PCG in a Latvian cohort and to compare the prevalence of gene CYP1B1 variants with other European studies as well as to the general population in Latvia. Methods: Twenty probands with clinically diagnosed PCG and 36 family members enrolled in the study. Genetic testing was conducted using genomic DNA from peripheral blood using next generation sequencing (NGS) of seven selected genes: CYP1B1, FOXC1, FOXE3, PXDN, PITX2, PITX3, PAX6, and CPAMD8. Four probands had whole-genome sequencing (WGS). Results: All participants were of European ancestry, with no family history of PCG. Most probands were diagnosed in their first year of life, with a female to male ratio of 1:1.2 and with 80.0% of cases being unilateral. No CYP1B1 pathogenic variants were identified in the screened subjects. However, a heterozygous missense variant c.4357C>A (p.Pro4357Thr) in the PXDN gene was found in one proband and one of her parents that was classified as a variant of uncertain significance. Conclusions: This study represents the first genetic characterization of PCG in the Latvian population. Using NGS, we identified no pathogenic variants in the CYP1B1 gene among affected individuals. Preliminary evidence from this cohort does not support CYP1B1 variants as a predominant cause of PCG, though larger studies are needed to confirm this observation. Comprehensive genetic screening using whole-exome or whole-genome sequencing will be essential to identify the underlying genetic etiology of PCG in Latvia.

The present study aimed to identify biomarkers for peroxidasin (Pxdn) mutation-induced eye disorders and study the underlying mechanisms involved in this process. The microarray dataset GSE49704 was used, which encompasses 4 mouse samples from embryos with Pxdn mutation and 4 samples from normal tissues. After data preprocessing, the differentially expressed genes (DEGs) between Pxdn mutation and normal tissues were identified using the t-test in the limma package, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed based on the STRING database, and the transcriptional regulatory (TR) network was established using the GeneCodis database. Subsequently, the overlapping DEGs with high degrees in two networks were identified, as well as the sub-network extracted from the TR network. In total, 121 (75 upregulated and 46 downregulated) DEGs were identified, and these DEGs play important roles in biological processes (BPs), including neuron development and differentiation. A PPI network containing 25 nodes such as actin, alpha 1, skeletal muscle (Acta1) and troponin C type 2 (fast) (Tnnc2), and a TR network including 120 nodes were built. By comparing the two networks, seven crucial genes which overlapped were identified, including cyclin-dependent kinase inhibitor 1B (Cdkn1b), Acta1 and troponin T type 3 (Tnnt3). In the sub-network, Cdkn1b was predicted as the target of miRNAs such as mmu-miR-24 and transcription factors (TFs) including forkhead box O4 (FOXO4) and activating enhancer binding protein 4 (AP4). Thus, we suggest that seven crucial genes, including Cdkn1b, Acta1 and Tnnt3, play important roles in the progression of eye disorders such as glaucoma. We suggest that Cdkn1b exert its effects via the inhibition of proliferation and is mediated by mmu-miR-24 and targeted by the TFs FOXO4 and AP4.