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We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3's pro-tumorigenic function. GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo , and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-β growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors. • GPX3 knock-down abrogates intraperitoneal tumor development in a syngeneic IP xenograft model of ovarian cancer. • GPX3 modulates pro-tumorigenic gene expression and regulates the TGF-β family member GDF15. • GPX3 expression correlates with regulatory T-cell and macrophage signatures, and PD-L1 expression in ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: To construct a prediction model for early recurrence and metastasis of non-small cell lung cancer (NSCLC) patients after radical surgery based on serum carcinoembryonic antigen (CEA), glutathione peroxidase 3 (GPX3) and C-X-C chemokine ligand 9 (CXCL9) . Methods: 95 cases of NSCLC patients who underwent radical resection of lung cancer in the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine from July 2018 to December 2019 were selected. Serum CEA, GPX3 and CXCL9 levels were detected by enzyme-linked immunosorbent assay. The patients were followed up for 3 years after the surgery,according to the occurrence of recurrence and metastasis during the follow-up period, the patients were divided into non-recurrence and metastasis group and recurrence and metastasis group. Logistic regression model analysis of influencing factors of postoperative recurrence and metastasis in NSCLC patients, and the prediction model of early recurrence and metastasis in NSCLC patients after radical surgery was established. The predictive efficiency of the prediction model was analyzed by receiver operating characteristic (ROC) curve. Results: After 3 years of follow-up, 2 cases of 95 patients were lost to follow-up, there were 36 cases of recurrence and metastasis. Serum CEA and CXCL9 levels in the recurrence and metastasis were higher than those in the non-recurrence and metastasis group, and GPX3 level was lower than that in the non-recurrence and metastasis group (P＜0.05) . There were statistically significant differences in tumor type, TNM stage and lymph node dissection count between the recurrence and metastasis group and the non-recurrence and metastasis group (P ＜0.05) . Logistic regression model showed that TNM stage, lymph node dissection count and serum CEA, GPX3 and CXCL9 levels were influencing factors of postoperative recurrence and metastasis in NSCLC patients (P＜0.05) .ROC-AUC (0.95CI) of Log P prediction model was 0.862 (0.772～0.943) . Conclusion: The increase of serum CEA and CXCL9 levels,and the decrease of GPX3 level are influencing factors for recurrence and metastasis in NSCLC patients after radical resection of lung cancer. The prediction model constructed by combining the Serum CEA, CXCL9, and GPX3 can assist in predicting the risk of recurrence and metastasis of NSCLC after radical resection of lung cancer. [ABSTRACT FROM AUTHOR]

The escalating prevalence of carbohydrate metabolism disorders (CMDs) prompts the need for early diagnosis and effective markers for their prediction. Hyperglycemia, the primary indicator of CMDs including prediabetes and type 2 diabetes mellitus (T2DM), leads to overproduction of reactive oxygen species (ROS) and oxidative stress (OxS). This condition, resulting from chronic hyperglycemia and insufficient antioxidant defense, causes damage to biomolecules, triggering diabetes complications. Additionally, aging itself can serve as a source of OxS due to the weakening of antioxidant defense mechanisms. Notably, previous research indicates that miR-196a, by downregulating glutathione peroxidase 3 (GPx3), contributes to insulin resistance (IR). Additionally, a GPx3 decrease is observed in overweight/obese and insulin-resistant individuals and in the elderly population. This study investigates plasma GPx3 levels and miR-196a expression as potential CMD risk indicators. We used ELISA to measure GPx3 and qRT-PCR for miR-196a expression, supplemented by multivariate linear regression and receiver operating characteristic (ROC) analysis. Our findings included a significant GPx3 reduction in the CMD patients (n = 126), especially in the T2DM patients (n = 51), and a decreasing trend in the prediabetes group (n = 37). miR-196a expression, although higher in the CMD and T2DM groups than in the controls, was not statistically significant, potentially due to the small sample size. In the individuals with CMD, GPx3 levels exhibited a negative correlation with the mass of adipose tissue, muscle, and total body water, while miR-196a positively correlated with fat mass. In the CMD group, the analysis revealed a weak negative correlation between glucose and GPx3 levels. ROC analysis indicated a 5.2-fold increased CMD risk with GPx3 below 419.501 ng/mL. Logistic regression suggested that each 100 ng/mL GPx3 increase corresponded to a roughly 20% lower CMD risk (OR = 0.998; 95% CI: 0.996–0.999; p = 0.031). These results support the potential of GPx3 as a biomarker for CMD, particularly in T2DM, and the lack of a significant decline in GPx3 levels in prediabetic individuals suggests that it may not serve reliably as an early indicator of CMDs, warranting further large-scale validation. [ABSTRACT FROM AUTHOR]

The role of selenium in the developmental process of esophageal cancer (EC) requires further investigation. To explore the relationship between selenium-related factors and EC through bioinformatic analysis, a case-control study was conducted to verify the results. Utilizing the GEPIA and TCGA databases, we delineated the differential expression of glutathione peroxidase 3 (GPx3) in EC and normal tissues, identified differentially expressed genes (DEGs), and a performed visualization analysis. Additionally, 100 pairs of dietary and plasma samples from esophageal precancerous lesions (EPLs) of esophageal squamous cancer (ESCC) cases and healthy controls from Huai'an district, Jiangsu, were screened. The levels of dietary selenium, plasma selenium, and related enzymes were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) or ELISA kits. The results showed lower GPx3 expression in tumor tissues compared to normal tissues. Further analysis revealed that DEGs were mainly involved in the fat digestion and absorption pathway, and the core protein fatty acid binding protein 1 (FABP1) was significantly upregulated and negatively correlated with GPx3 expression. Our case-control study found that selenium itself was not associated with EPLs risk. However, both the decreased concentration of GPx3 and the increase in FABP1 were positively correlated with the EPLs risk (p for trend = 0.035 and 0.046, respectively). The different expressions of GPx3 and FABP1 reflect the potential of selenium for preventing ESCC at the EPLs stage. GPx3 may affect myocardial infarction through FABP1, which remains to be further studied. [ABSTRACT FROM AUTHOR]

In SARS-CoV-2 infection, excessive activation of the immune system intensively increases reactive oxygen species levels, causing harmful hyperinflammatory and oxidative state cumulative effects which may contribute to COVID-19 severity. Therefore, we assumed that antioxidant genetic profile, independently and complemented with laboratory markers, modulates COVID-19 severity. The study included 265 COVID-19 patients. Polymorphism of GSTM1, GSTT1, Nrf2 rs6721961, GSTM3 rs1332018, GPX3 rs8177412, GSTP1 rs1695, GSTO1 rs4925, GSTO2 rs156697, SOD2 rs4880 and GPX1 rs1050450 genes was determined with appropriate PCR-based methods. Inflammation (interleukin-6, CRP, fibrinogen, ferritin) and organ damage (urea, creatinine, transaminases and LDH) markers, complete blood count and coagulation status (d-dimer, fibrinogen) were measured. We found significant association for COVID-19 progression for patients with lymphocytes below 1.0 × 109/L (OR = 2.97, p = 0.002). Increased IL-6 and CRP were also associated with disease progression (OR = 8.52, p = 0.001, and OR = 10.97, p < 0.001, respectively), as well as elevated plasma AST and LDH (OR = 2.25, p = 0.021, and OR = 4.76, p < 0.001, respectively). Of all the examined polymorphisms, we found significant association with the risk of developing severe forms of COVID-19 for GPX3 rs8177412 variant genotype (OR = 2.42, p = 0.032). This finding could be of particular importance in the future, complementing other diagnostic tools for prediction of COVID-19 disease course. [ABSTRACT FROM AUTHOR]

Background Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common malignancies with increasing mortality. In this study, we aim to determine the alteration and diagnostic value of GXP3 expression for HBV-related HCC. Methods We recruited 243 subjects, including 132 HBV-related HCC patients, 78 chronic hepatitis B (CHB) patients and 33 healthy controls (HCs). The mRNA level of GPX3 in peripheral blood mononuclear cells (PBMCs) was assessed by quantitative real-time PCR. The GPX3 plasma level was detected by ELISA. Results The GPX3 mRNA level was significantly decreased in HBV-related HCC patients compared with in CHB patients and HCs (p<0.05). The plasma GPX3 level was significantly lower in patients with HBV-related HCC than in CHB patients and HCs (p<0.05). In the HCC subgroup, the GPX3 mRNA level was significantly lower in patients with positive HBeAg, ascites, advanced stage and poor differentiation compared with in the other groups (p<0.05). The receiver operating characteristic curve was constructed to estimate the diagnostic value of the GPX3 mRNA level for HBV-related HCC. The GPX3 mRNA level showed a significantly better diagnostic ability compared with alpha fetoprotein (AFP) (area under the curve 0.769 vs 0.658, p<0.001). Conclusions A decreased GPX3 mRNA level might be a potential non-invasive biomarker for HBV-related HCC. It showed better diagnostic ability than AFP. [ABSTRACT FROM AUTHOR]

Conditions associated with selenium (Se) and/or vitamin E (VitE) deficiency are still being reported in high-yielding pigs fed the recommended amounts. Here, the dietary effects of Se source (sodium selenite, NaSe, 0.40 or 0.65 mg Se/kg; l-selenomethionine, SeMet, 0.19 or 0.44 mg Se/kg; a NaSe-SeMet mixture, SeMix, 0.44–0.46 mg Se/kg) and VitE concentration (27, 50–53 or 101 mg/kg) on the antioxidant status of finisher pigs were compared with those in pigs fed non-Se-supplemented diets (0.08–0.09 mg Se/kg). Compared to NaSe-enriched diets, SeMet-supplemented diets resulted in significantly (p < 0.0018) higher plasma concentrations of total Se (14–27%) and selenospecies (GPx3, SelP, SeAlb; 7–83%), significantly increased the total Se accumulation in skeletal muscles, myocardium, liver and brain (10–650%), and enhanced the VitE levels in plasma (15–74%) and tissues (8–33%) by the end of the 80-day trial, proving better Se distribution and retention in pigs fed organic Se. Injecting lipopolysaccharide (LPS) intravenously half-way into the trial provoked a pyrogenic response in the pigs followed by a rapid increase of inorganic Se after 5–12 h, a drastic drop of SeMet levels between 12 and 24 h that recovered by 48 h, and a small increase of SeCys by 24–48 h, together with a gradual rise of GPx3, SelP and SeAlb in plasma up to 48 h. These changes in Se speciation in plasma were particularly significant (0.0024 > p > 0.00007) in pigs receiving SeMet- (0.44 mg Se/kg, above EU-legislated limits) or SeMix-supplemented (SeMet and NaSe both at 0.2 mg Se/kg, within EU-legislated limits) diets, which demonstrates Se metabolism upregulation to counteract the LPS-induced oxidative stress and a strengthened antioxidant capacity in these pigs. Overall, a Se source combination (without exceeding EU-legislated limits) and sufficient VitE supplementation (≥ 50 mg/kg) improved the pigs' antioxidant status, while doubling the allowed dietary organic Se increased the Se in tissues up to sixfold without compromising the animal's health due to toxicity. This study renders valuable results for revising the current dietary SeMet limits in swine rations. [ABSTRACT FROM AUTHOR]

Kidney fibrosis is associated with tubular injury, oxidative stress and activation of interstitial fibroblasts. However, whether these events are somehow connected is poorly understood. In this study, we show that glutathione peroxidase-3 (GPX3) depletion in renal tubular epithelium after kidney injury plays a central role in orchestrating an oxidatively stressed extracellular microenvironment, which drives interstitial fibroblast activation and proliferation. Through transcriptional profiling by RNA-sequencing, we found that the expression of GPX3 was down-regulated in various models of chronic kidney disease (CKD), which was correlated with induction of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-4 (NOX4). By using decellularized extracellular matrix (ECM) scaffold, we demonstrated that GPX3-depleted extracellular microenvironment spontaneously induced NOX4 expression and reactive oxygen species (ROS) production in renal fibroblasts and triggered their activation and proliferation. Activation of NOX4 by advanced oxidation protein products (AOPPs) mimicked the loss of GPX3, increased the production of ROS, stimulated fibroblast activation and proliferation, and activated protein kinase C-α (PKCα)/mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3) signaling. Silencing NOX4 or inhibition of MAPK with small molecule inhibitors hampered fibroblast activation and proliferation. In mouse model of CKD, knockdown of NOX4 repressed renal fibroblast activation and proliferation and alleviated kidney fibrosis. These results indicate that loss of GPX3 orchestrates an oxidatively stressed extracellular microenvironment, which promotes fibroblast activation and proliferation through a cascade of signal transduction. Our studies underscore the crucial role of extracellular microenvironment in driving fibroblast activation and kidney fibrosis.

Background: Gemcitabine (GEM) is a second-line anticancer drug of choice for some colorectal cancer (CRC) patients, and GEM inability to be commonly available in the clinic due to the lack of clarity of the exact action targets. Methods: The half maximal inhibitory concentration (IC50) of GEM treatment for 42 CRC cell lines were accessed from the Genomics of Drug sensitivity in Cancer (GDSC) database. High-throughput sequencing data of CRC patients were captured in The Cancer Genome Atlas (TCGA) and Weighted correlation network analysis (WGCNA) was conducted. Pearson correlations were derived for GEM potency-related genes. Differential analysis was conducted in the TCGA cohort to obtain CRC development-related genes (CDRGs), and univariate COX model analysis was performed on CDRGs overlapping with GEM potency-related genes to obtain CDRGs affecting CRC prognosis. Hub genes affecting GEM potency were identified by Spearman correlation. Results: CALB2 and GPX3 were identified as potential targets for GEM treatment of CRC via prognostic analysis, which we also observed to be elevated with elevated clinical stage in CRC patients. The enhanced expression of CALB2 and GPX3 genes identified in the pathway analysis might inhibit the body metabolism as well as activate immune and inflammation related pathways. In addition, we found that CALB2 and GPX3 could also be considered as prognostic biomarkers in pancancer. Finally, we found that CALB2 and GPX3 were remarkably associated with the drug sensitivity of MG-132, Dasatinib, Shikonin, Midostaurin, MS-275, and ZLNle- CHO, which were expected to be the drugs of choice for GEM combination. Conclusion: CALB2 and GPX3 represent prognostic biomarkers for CRC and they might be potential action targets for GEM. Our study offered innovative ideas for GEM administration strategies. [ABSTRACT FROM AUTHOR]

Although disturbance of redox homeostasis might be responsible for COVID-19 cardiac complications, this molecular mechanism has not been addressed yet. We have proposed modifying the effects of antioxidant proteins polymorphisms (superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GPX1), glutathione peroxidase 3 (GPX3) and nuclear factor erythroid 2-related factor 2, (Nrf2)) in individual susceptibility towards the development of cardiac manifestations of long COVID-19. The presence of subclinical cardiac dysfunction was assessed via echocardiography and cardiac magnetic resonance imaging in 174 convalescent COVID-19 patients. SOD2, GPX1, GPX3 and Nrf2 polymorphisms were determined via the appropriate PCR methods. No significant association of the investigated polymorphisms with the risk of arrhythmia development was found. However, the carriers of variant GPX1*T, GPX3*C or Nrf2*A alleles were more than twice less prone for dyspnea development in comparison with the carriers of the referent ones. These findings were even more potentiated in the carriers of any two variant alleles of these genes (OR = 0.273, and p = 0.016). The variant GPX alleles were significantly associated with left atrial and right ventricular echocardiographic parameters, specifically LAVI, RFAC and RV-EF (p = 0.025, p = 0.009, and p = 0.007, respectively). Based on the relation between the variant SOD2*T allele and higher levels of LV echocardiographic parameters, EDD, LVMI and GLS, as well as troponin T (p = 0.038), it can be proposed that recovered COVID-19 patients, who are the carriers of this genetic variant, might have subtle left ventricular systolic dysfunction. No significant association between the investigated polymorphisms and cardiac disfunction was observed when cardiac magnetic resonance imaging was performed. Our results on the association between antioxidant genetic variants and long COVID cardiological manifestations highlight the involvement of genetic propensity in both acute and long COVID clinical manifestations. [ABSTRACT FROM AUTHOR]

Spermatogenesis is regulated by genetic and epigenetic factors. However, the genes and signaling pathways mediating human spermatogenesis remain largely unknown. Here, we have for the first time explored the expression, function, and mechanism of glutathione peroxidase 3 (GPx3) in controlling the proliferation and apoptosis of human spermatogonial stem cells (SSCs). We found that GPx3 was expressed in human SSCs. Notably, we revealed that GPx3 knockdown resulted in the decrease in the proliferation, DNA synthesis, and cyclin B1 level in human SSC lines, which possessed the phenotypic features of human primary SSCs. Flow cytometry and TUNEL assays showed that GPx3 silencing led to enhancement of early apoptosis of human SSC line. RNA sequencing was utilized to identify CXCL10 as a target of GPx3 in human SSCs, and notably, both double immunostaining and co-immunoprecipitation (co-IP) demonstrated that there was an association between GPx3 and CXCL10 in these cells. CXCL10-shRNA resulted in the reduction in the proliferation and DNA synthesis of human SSC line and an increase in apoptosis of these cells. Taken together, these results implicate that GPx3 regulates the proliferation, DNA synthesis, and early apoptosis of human SSC line via mediating CXCL10 and cyclin B1. This study, thus, offers a novel insight into the molecular mechanism regulating the fate determinations of human SSCs and human spermatogenesis.

The aim is to clone and have bioinformatics analysis of GPX3 gene in Tibetan chickens, to detect its expressions in different tissues, and to identify the mRNA expressions of GPX3 interacting proteins and analyse their correlations for laying the foundation for further exploring the effect of GPX3 gene on immune function in Tibetan chickens. In this experiment, having 70-day-old healthy Tibetan chickens as study material, RT-PCR was applied to clone the CDS sequence of GPX3 gene and to perform the biological analysis. Real-time fluorescent quantitative PCR (qPCR) was used to detect the expression differences of GPX3 gene in the hearts, livers, spleens, lungs and kidneys of Tibetan chickens, and to analyze the mRNA expressions of 10 related proteins that may interact with GPX3 protein in spleen. A full length of 799 bp GPX3 gene sequence was cloned successfully, including 78 bp of 5' UTR, 660 bp of CDS, and 61 bp of 3' UTR, encoding 219 amino acids. GPX3 mRNA was expressed in 5 tissues of Tibetan chickens, and the highest in the spleen, predicting that the result of the highest expression of GPX3 in the spleen might be related to this protein immune function. GPX3 protein showed a highly and significantly positive correlation with the predicted reciprocal protein SOD2, suggesting that GPX3 might play an important role in drug resistance and reproductive regulation. A 660 bp CDS of GPX3 gene was cloned successfully in this study, predicting that it might be highly significantly and positively correlated with SOD2. This study may provide a theoretical basis for further understanding the role of the antioxidant function of GPX3 gene in the immune mechanism of Tibetan chickens. [ABSTRACT FROM AUTHOR]

Background: Renal ischemia reperfusion injuries (IRIs) are very common in clinical diagnoses and treatments, which are a common cause of impaired renal functions, worsening pathological damage, affecting disease progression and hindering recovery. Renal IRIs are an inflammatory disease mediated by the adaptive and innate immune system. There is a complex interaction between oxidative stress and immune cell infiltration. Therefore, we aimed to determine biomarkers associated with oxidative stress during renal IRIs and their relationship with immune cell infiltration. Method: A differential gene expression analysis was made based on the GSE148420 dataset from the NCBI Gene Expression Comprehensive Database (GEO) combined with 92 oxidative-stress (OS)-related genes identified in the Molecular Signatures Database. Then we identified differentially-expressed genes (DEOSGs) associated with oxidative stress, which were used for gene ontology (GO) and a Kyoto Encyclopedia of Genomes (KEGG) enrichment analysis. At the same time, we used PPI protein interaction networks and Lasso regression analysis to identify key genes, which were verified by the validation sets GSE58438 and GSE71647, as well as Western Blot detection on rat renal IRI models. At the same time, PAS staining, HE staining and immunohistochemistry were used to detect tissue damage and expression of markers related to oxidative stress during renal ischemia-reperfusion. Single-gene enrichment analysis (GSEA) was used to further clarify the underlying biological functions of key genes. Cibersort was used to analyze the immune cell infiltration during renal IRI and the correlation of key genes with immune cells. At the same time, we constructed a network of transcription-factor (TF)-Hub genes and miRNAHub genes. DGIDB was used to predict drugs and molecular compounds that might interact with the Hub genes. Results: Compared with the control group, a total of 5456 differential genes (DEGs) were measured in the renal IRI group, 2486 of which were upregulated and 2970 were down-regulated. Among them, we found 30 DEGs (DEOSGs) associated with oxidative stress. The results of GO and KEGG enrichment analysis showed that these DEOSGs were mainly enriched in glutathione metabolism, the response to oxidative stress stimulation, the regulation of T cell activation and apoptosis signaling pathways. Through a protein interaction network (PPI) and a LASSO regression analysis, a total of two Hub genes were identified, namely GPX3 and GSTT1, which were validated through external validation sets and animal experiments. Through pathological methods, we found that the pathological damage of renal tissue and the expression of oxidative stress markers increased after renal ischemia-reperfusion. The results of GSEA showed that the Hub genes were related to oxidative stress pathways, apoptosis signaling pathways and immune-response-related signaling pathways. An immunoinfiltration correlation analysis showed that genes GPX3 and GSTT1 were significantly positively correlated with plasma cells and macrophage M0, while were negatively correlated with monocytes and macrophages M1 and M2. Using the Strust, Starbase and DGIDB database, we predicted that 81 transcription factors, 49 miRNAs and 13 drug or molecular compounds might interact with the Hub genes. Conclusion: Through a comprehensive analysis of gene expression, our findings may provide new potential biomarkers for the pathogenesis of renal IRIs and a reliable basis for its early diagnosis as well as treatment. [ABSTRACT FROM AUTHOR]

Tendinopathy, a degenerative disease, is characterized by pain, loss of tendon strength, or rupture. Previous studies have identified multiple risk factors for tendinopathy, including aging and fluoroquinolone use; however, its therapeutic target remains unclear. We analyzed self-reported adverse events and the US commercial claims data and found that the short-term use of dexamethasone prevented both fluoroquinolone-induced and age-related tendinopathy. Rat tendons treated systemically with fluoroquinolone exhibited mechanical fragility, histological change, and DNA damage; co-treatment with dexamethasone attenuated these effects and increased the expression of the antioxidant enzyme glutathione peroxidase 3 (GPX3), as revealed via RNAsequencing. The primary role of GPX3 was validated in primary cultured rat tenocytes treated with fluoroquinolone or H2O2, which accelerates senescence, in combination with dexamethasone or viral overexpression of GPX3. These results suggest that dexamethasone prevents tendinopathy by suppressing oxidative stress through the upregulation of GPX3. This steroidfree approach for upregulation or activation of GPX3 can serve as a novel therapeutic strategy for tendinopathy. [ABSTRACT FROM AUTHOR]

Background: The c.194+2 T>C variant of serine protease inhibitor Kazal type 1 (SPINK1) is a known genetic risk factor found in Chinese patients with idiopathic chronic pancreatitis (ICP), but the early‐onset mechanisms of ICP are still unclear. Methods: Complementary experimental approaches were used to pursue other potential pathologies in the present study. The serum level of SPINK1 of ICP patients in the Han population in China was detected and verified by an enzyme‐linked immunosorbent assay. Next, differentially expressed proteins and microRNAs from plasma samples of early‐onset and late‐onset ICP patients were screened by proteomic analysis and microarray, respectively. Results: Combined with these advanced methods, the data strongly suggest that the regulatory effects of microRNAs were involved in the early‐onset mechanism of the ICP by in vitro experiments. There was no significant difference in the plasma SPINK1 expression between the early‐onset ICP and the late‐onset patients. However, the expression of plasma glutathione peroxidase (GPx3) in early‐onset ICP patients was markedly lower than that in late‐onset ICP patients, although the level of hsa‐miR‐323b‐5p was lower in late‐onset patients compared to the early‐onset ICP group. In vitro experiments confirmed that hsa‐miR‐323b‐5p could increase apoptosis in caerulein‐treated pancreatic acinar cells and inhibit the expression of GPx3. Conclusions: The up‐regulated hsa‐miR‐323b‐5p might play a crucial role in the early‐onset mechanisms of ICP by diminishing the antioxidant activity through the down‐regulation of GPx3. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) often results in significant loss of cardiomyocytes (CMs), contributing to adverse ventricular remodelling and heart failure. Therefore, promoting CM survival during the acute stage of MI is crucial. This study aimed to investigate the potential role of GPX3 in cardiac repair following MI. First, plasma GPX3 levels were measured in patients with acute MI (AMI), and myocardial GPX3 expression was assessed in a mouse MI model. Furthermore, the effects of GPX3 on MI were investigated through CM-specific overexpression or knockdown in vitro and in vivo models. RNA sequencing and subsequent experiments were performed to uncover the molecular mechanisms underlying GPX3-related effects. Multi-omics database analysis and experimental verification revealed a significant upregulation of GPX3 expression in ischemic myocardium following MI and in CMs exposed to oxygen-glucose deprivation (OGD). Immunofluorescence results further confirmed elevated cytoplasmic GPX3 expression in CMs under hypoxic conditions. In vitro, GPX3 overexpression mitigated reactive oxygen species (ROS) production and enhanced CM survival during hypoxia, while GPX3 knockdown inhibited these processes. In vivo, CM-specific GPX3 overexpression in the infarct border zone significantly attenuated CM apoptosis and alleviated myocardial injury, promoting cardiac repair and long-term functional recovery. Mechanistically, GPX3 overexpression upregulated LSD1 and Hif1α protein expression, and rescue experiments confirmed the involvement of the LSD1/Hif1α pathway in mediating the protective effects of GPX3. Overall, our findings suggest that GPX3 exerts a protective role in ischemic myocardium post-MI, at least partially through the LSD1/Hif1α axis, highlighting its potential as a therapeutic target for MI treatment., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

IntroductionCancer is a crucial public health problem and one of the leading causes of death worldwide. Previous studies have suggested that GPX3 may be involved in cancer metastasis and chemotherapy resistance. However, how GPX3 affects cancer patients’ outcomes and the underlying mechanism remains unclear.MethodsSequencing data and clinical data from TCGA, GTEx, HPA, and CPTAC were used to explore the relationship between GPX3 expression and clinical features. Immunoinfiltration scores were used to assess the relationship between GPX3 and the tumor immune microenvironment. Functional enrichment analysis was used to predict the role of GPX3 in tumors. Gene mutation frequency, methylation level, and histone modification were used to predict the GPX3 expression regulation method. Breast, ovarian, colon, and gastric cancer cells were used to investigate the relationship between GPX3 expression and cancer cell metastasis, proliferation, and chemotherapy sensitivity.ResultsGPX3 is down-regulated in various tumor tissues, and GPX3 expression level can be used as a marker for cancer diagnosis. However, GPX3 expression is associated with higher stage and lymph node metastasis, as well as poorer prognosis. GPX3 is closely related to thyroid function and antioxidant function, and its expression may be regulated by epigenetic inheritance such as methylation modification or histone modification. In vitro experiments, GPX3 expression is associated with cancer cell sensitivity to oxidant and platinum-based chemotherapy and is involved in tumor metastasis in oxidative environments.DiscussionWe explored the relationship between GPX3 and clinical features, immune infiltration characteristics, migration and metastasis, and chemotherapy sensitivities of human cancers. We further investigated the potential genetic and epigenetic regulation of GPX3 in cancer. Our results suggested that GPX3 plays a complicated role in the tumor microenvironment, simultaneously promoting metastasis and chemotherapy resistance in human cancers.

Simple Summary: Despite the fact that human assisted reproduction has undergone extensive development with positive effects on pregnancy, the rates of success are still low. The morphokinetic score of preimplanted embryos is the common routine procedure for ART centres as a reliable predictor of implantation. However, the morphological quality of the embryo is not sufficient to fully ensure implantation success. Therefore, the identification of good predictors of implantation is mandatory to optimise assisted reproduction technology (ART). In this regard, the transcriptome study of the cumulus cells (CCs) is a non-invasive procedure that reflexes the physiological state of oocytes, given the molecular crosstalk between both types of cells. The present study shows a significant down-regulation of the GPX3 gene expression in the CCs isolated from oocytes in pregnant women compared to CCs from non-pregnant women who underwent assisted reproduction. Interestingly, CCs of the highest quality morphotype (A embryos), which achieved implantation success, expressed significantly lower levels of GPX3 expression compared to the embryo morphotype A with implantation failure. Therefore, our observations point to the expression of the GPX3 gene as a potential prognostic marker of bad implantation. Morphological embryo quality is an accurate prognostic tool for the success of assisted reproduction implantation, although complete certainty cannot be guaranteed. The transcriptome of the cumulus cells could be monitored as a faithful reflex of the physiological state of the oocytes, given the molecular crosstalk between both types of cells. Here, we compare the expression of specific genes related to oocyte competence, such as hyaluronic acid synthase 2 (HAS2), cell division control protein 42 (CDC42), connexin 43 (CX43), and glutathione peroxidase 3 (GPX3), in cumulus cells from implanted versus non-implanted embryos in 25 women, using RT-qPCR. After embryo transfer, two cohorts were differentiated: the pregnant group (women with the implantation of 100% of embryos transferred) versus the non-pregnant group (with an absence of embryo implantation), aiming to compare the possible differential expression of the selected genes in the cumulus cells of embryos from each group. HAS2, CDC42 and CX43 did not reveal differential expression between the two cohorts. However, GPX3 showed significantly reduced expression in the cumulus belonging to the pregnant group. Interestingly, even cumulus cells belonging only to morphotype A embryos showed a significantly lower expression of GPX3 in the pregnancy group. GPX3 overexpression in cumulus cells could be a poor prognostic indicator of implantation, discriminating beyond the capacity of the morphokinetic score. Unveiling the cumulus transcriptome could improve successful implantation in assisted reproduction treatments. [ABSTRACT FROM AUTHOR]

Glutathione peroxidase 3 (GPX3) is the main antioxidant enzyme in plasma. Its biological roles are to protect cells from oxidative stress-induced damage. Several studies have been reported the association between GPX3 expression and its correlation with cancer carcinogenesis including breast cancer. The aim of this research was to investigate the GPX3 messenger ribonucleic acid (mRNA) expression in 82 breast tumors and paired normal breast tissues by SYBR green quantitative real-time reverse transcription-polymerase chain reaction and the association with clinicopathological data. Our results show that GPX3 reduced expression was found significantly associated with number of metastatic lymph nodes (odds ratio [OR] = 3.41, 95% confidence interval [CI] = 1.35–8.64, p = 0.01), no distant metastasis (OR = 5.52, 95% CI = 3.74–11.89, p = 0.04), and nonhormone usage breast cancer patients (OR = 0.19, 95% CI = 0.04–0.93, p = 0.04). This finding suggested that GPX3 plays a role in breast carcinogenesis, and might serve as a prognostic biomarker in breast cancer patients.

Polycystic ovary syndrome (PCOS) is an inflammatory endocrine-metabolic disorder related to reproductive system characterized by polycystic ovarian morphology, androgen excess, and chronic anovulation. Current treatments haven't been very successful in PCOS treatment and the problem still remains as a challenge. Therefore, new approaches should be applied to overcome the disease. Previous studies demonstrated immunomodulatory effects of R10 fraction of garlic in the treatment of inflammatory conditions such as cancer. Considering previous studies suggesting immunomodulatory therapy for PCOS, therapeutic effects of R10 fraction was evaluated in a mouse model of PCOS. To do so, PCOS was developed by intramuscular injection of estradiol valerate. Treatment with R10 fraction, isolated from garlic, was performed and the alterations in hormonal levels (estradiol, progesterone, and testosterone), T cell polarization markers (IFN-γ, IL-4, and IL-17), and expression of fertility-related genes (Gpx3 and Ptx3) were evaluated. The results showed that hormonal levels were elevated in PCOS model comparing to normal animals but were markedly modulated after treatment with R10 fraction. Moreover, a severe disturbance in T cell polarization with a significant reduction of fertility-related genes expression were detected in PCOS-induced ovaries. Treatment with R10 fraction also represented modulatory effects on T cell polarization by increasing IL-4 and decreasing IL-17 and IFN-γ levels. Accordingly, fertility-related genes were also modulated following treatment with R10 fraction in PCOS. Our study elucidated that R10 fraction of garlic possess immunomodulatory effects alleviating PCOS symptoms. This approach could be adjusted to give rise the optimum therapeutic results and considered as a candidate therapeutic approach for PCOS. [ABSTRACT FROM AUTHOR]

Background: Glutathione peroxidase 3 (Gpx3) protects cells from oxidative stress, and its reduced expression in human prostate cancer has been reported. Objectives: We hypothesized that Gpx3 might play an important role in the development of prostatic intraepithelial neoplasia (PIN), a pre‐cancerous state of the prostate, and aimed to highlight the underlying molecular mechanism. Materials and Methods: The following double‐knockout mice Nkx3.1−/−; Gpx3+/+, Nkx3.1−/−; Gpx3+/−, Nkx3.1−/−; Gpx3−/− were produced. Randomly divided animals were weighed, and their genitourinary tract (GUT) weights were determined after euthanasia at 4, 8, and 12 months. The mRNA expression of the genes involved in oxidative stress and Wnt signaling was analyzed in the prostate. Histopathology, ROS, and superoxide dismutase (SOD) activities were also measured. Results: Loss of Gpx3 did not affect body weight and GUT weight in Nkx3.1 knockout mice. The mRNA expression of SOD3, iNOS, Hmox, and CISD2, which are associated with oxidative stress, was increased in Nkx3.1−/−; Gpx3−/− mice at 4 months but decreased at 8 and 12 months. There was no change in β‐catenin and its targets associated with Wnt signaling. Increased ROS and decreased SOD activity were observed in Nkx3.1−/−; Gpx3−/− mice at 12 months of age. The histopathologic score and epithelium thickness were increased, and lumen area was decreased in Gpx3 knockout mice. Discussion and Conclusions: Gpx3 loss increased the hyperplasia of PIN in the pre‐cancerous stage of the prostate. Loss of Gpx3 induced oxidative stress. Histopathologically, no invasive carcinoma was identified, and Gpx3 loss did not increase Wnt/β‐catenin signaling. Further research on the role of GPX3 in the transition of PIN to invasive carcinoma is needed. We show, for the first time, that the antioxidant enzyme GPX3 plays a vital role in inhibiting hyperplasia in the PIN stage of the prostate gland in vivo. [ABSTRACT FROM AUTHOR]

Kidney renal clear cell carcinoma (KIRC) is the most common and fatal subtype of renal cancer. Antagonistic associations between selenium and cancer have been reported in previous studies. Selenium compounds, as anti-cancer agents, have been reported and approved for clinical trials. The main active form of selenium in selenoproteins is selenocysteine (Sec). The process of Sec biosynthesis and incorporation into selenoproteins plays a significant role in biological processes, including anti-carcinogenesis. However, a comprehensive selenoprotein mRNA analysis in KIRC remains absent. In the present study, we examined all 25 selenoproteins and identified key selenoproteins, glutathione peroxidase 3 (GPX3) and type 1 iodothyronine deiodinase (DIO1), with the associated prognostic biomarker leucine-rich repeat containing 19 (LRRC19) in clear cell renal cell carcinoma cases from The Cancer Genome Atlas (TCGA) database. We performed validations for the key gene expression levels by two individual clear cell renal cell carcinoma cohorts, GSE781 and GSE6344, datasets from the Gene Expression Omnibus (GEO) database. Multivariate survival analysis demonstrated that low expression of LRRC19 was an independent risk factor for OS. Gene set enrichment analysis (GSEA) identified tyrosine metabolism, metabolic pathways, peroxisome, and fatty acid degradation as differentially enriched with the high LRRC19 expression in KIRC cases, which are involved in selenium therapy of clear cell renal cell carcinoma. In conclusion, low expression of LRRC19 was identified as an independent risk factor, which will advance our understanding concerning the selenium adjuvant therapy of clear cell renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Epigenetic control of gene expression is a major determinant of tumor phenotype and has been found to influence sensitivity to individual chemotherapeutic agents. Glutathione peroxidase 3 (GPX3, plasma glutathione peroxidase) is a key component of cellular antioxidant regulation and its gene has been reported to be methylated in specific tumor types. GPX3 role in oxidative damage has been associated with sensitivity to platinums in other tumors but its importance in colorectal cancer (CRC) has not been determined. We examined the role of GPX3 methylation in colorectal carcinoma in determining sensitivity to platinum drugs using primary tumor specimens, cell lines, knockdown cell lines, and tumor cell line xenografts. We find GPX3 promoter region methylation in approximately one third of CRC samples and GPX3 methylation leads to reduced GPX3 expression and increased oxaliplatin and cisplatin sensitivity. In contrast, in cell lines with high baseline levels of GPX3 expression or with the ability to increase GPX3 expression, platinum resistance is increased. The cisplatin IC50 in GPX3-methylated cell lines is approximately 6-fold lower than that in GPX3-unmethylated lines. Additionally, knockdown cell lines with essentially no GPX3 expression require N-acetylcysteine to survive in culture underscoring the importance of GPX3 in redox biology. In vivo, GPX3 methylation predicts tumor xenograft sensitivity to platinum with regression of GPX3 knockdown xenografts with platinum treatment but continued growth of GPX3 wild type xenografts in the presence of platinum. These studies demonstrate the importance of GPX3 for CRC cells resistance to platinums and the potential utility of GPX3 methylation status as a predictive biomarker for platinum sensitivity in CRC.

Thiol peroxidases are conserved hydrogen peroxide scavenging and signaling molecules that contain redox-active cysteine residues. We show here that Gpx3, the major H2O2 sensor in yeast, is present in the mitochondrial intermembrane space (IMS), where it serves a compartment-specific role in oxidative metabolism. The IMS-localized Gpx3 contains an 18-amino acid N-terminally extended form encoded from a non-AUG codon. This acts as a mitochondrial targeting signal in a pathway independent of the hitherto known IMS-import pathways. Mitochondrial Gpx3 interacts with the Mia40 oxidoreductase in a redox-dependent manner and promotes efficient Mia40-dependent oxidative protein folding. We show that cells lacking Gpx3 have aberrant mitochondrial morphology, defective protein import capacity, and lower inner membrane potential, all of which can be rescued by expression of a mitochondrial-only form of Gpx3. Together, our data reveal a novel role for Gpx3 in mitochondrial redox regulation and protein homeostasis.

Abstract Glutathione peroxidase 3 (GPx3), a major antioxidant enzyme in plasma, catalyzes the reduction of H 2 O 2 , lipid peroxides and organic hydroperoxides by reducing glutathione (GSH). Hypermethylation of the GPx3 promoter and suppression of GPx3 expression are associated with inflammation, tumorigenesis, and response to chemotherapy in various types of cancer. We previously reported the possibility of GPx3 as a serological marker for lung cancer. In this study, we assessed the role of the microRNA (miRNA) hsa-miR-921 (miR-921) in the regulation of GPx3 expression in A549 lung cancer cells. The expression patterns of the miRNAs of A549, H1650, and H1975 cells were compared and analyzed. Of 25 miRNAs from the A549 cell line, the expression of 10 decreased and the expression of 15 increased in comparison to the miRNAs from the other cell lines. Of the miRNAs with reduced expression, the most reduced miRNA was miR-921 and the expected binding site of which is in the 3′-untranslated region (UTR) of GPx3. We found that miR-921 inhibited the expression of GPx3 and bound directly to the 3′-UTR of GPx3. Highlights • MiR-921 expression was higher in the H1650 and H1975 cell lines than in the A549 cell line. • The miR-921 mimic significantly reduced the expression of GPx3 mRNA in A549 cells. • MiR-921 binds directly to the 797-803nt (CCCTCAC) of the GPx3 3'UTR. [ABSTRACT FROM AUTHOR]

Aim: This study investigated the association between GPX3 methylation and gastric cancer (GC), and explored its prognostic value in patients undergoing radical gastrectomy.Materials& Methods: The methylation levels of tumor and paracancerous tissues were detected by quantitative methylation-specific PCR method.Results: GPX3 was hypermethylated in GC (p = 4E-4), and was specific for patients with lymphatic metastasis (+), tumor invasion depth >3 cm and patients with poor differentiation. Additionally, GPX3 hypermethylation predicts a tumor recurrence in patients aged >60 (p = 0.019). Data from The Cancer Genome Atlas (TCGA) further confirmed GPX3 hypermethylation (cg21504918: -0.08 vs -0.25, p = 0.001). Additionally, TCGA showed an inverse correlation between GPX3 methylation and expression (p = 7E-18, r = -0.427). Data analysis of Gene Expression Omnibus (GEO) database showed that 5-aza-2'-deoxycytidine demethylating agent increased GPX3 expression (fold-change >2.19, p = 0.001).Conclusion: Our results indicated GPX3 hypermethylation in GC, and predicted a shorter tumor recurrence time in patients aged >60. [ABSTRACT FROM AUTHOR]

Glutathione peroxidase 3 (GPx3) belongs to the glutathione peroxidase family of selenoproteins and is a key antioxidant enzyme in multicellular organisms against oxidative damage. Downregulation of GPx3 affects tumor progression and metastasis and is associated with liver and heart disease. However, the physiological significance of GPx3 in vertebrate embryonic development remains poorly understood. The current study aimed to investigate the functional roles of gpx3 during embryogenesis. To this end, we determined gpx3’s spatiotemporal expression using Xenopus laevis as a model organism. Using reverse transcription polymerase chain reaction (RT-PCR), we demonstrated the zygotic nature of this gene. Interestingly, the expression of gpx3 enhanced during the tailbud stage of development, and whole mount in situ hybridization (WISH) analysis revealed gpx3 localization in prospective tail region of developing embryo. gpx3 knockdown using antisense morpholino oligonucleotides (MOs) resulted in short post-anal tails, and these malformed tails were significantly rescued by glutathione peroxidase mimic ebselen. The gene expression analysis indicated that gpx3 knockdown significantly altered the expression of genes associated with Wnt, Notch, and bone morphogenetic protein (BMP) signaling pathways involved in tailbud development. Moreover, RNA sequencing identified that gpx3 plays a role in regulation of cell death in the developing embryo. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone 3 (PH3) staining confirmed the association of gpx3 knockdown with increased cell death and decreased cell proliferation in tail region of developing embryos, establishing the involvement of gpx3 in tailbud development by regulating the cell death. Furthermore, these findings are inter-related with increased reactive oxygen species (ROS) levels in gpx3 knockdown embryos, as measured by using a redox-sensitive fluorescent probe HyPer. Taken together, our results suggest that gpx3 plays a critical role in posterior embryonic development by regulating cell death and proliferation during vertebrate embryogenesis.

Introduction: According to a review of the literature, there is a lack of data on the mechanisms that participate in the suppression of inflammation that accompanies polycystic ovary syndrome (PCOS). Additionally, the changes in oxidative status resulting from a low-calorie diet have not been studied in a group of women with PCOS, and the oxidation and reduction processes associated with PCOS have not been explained. Material and methods: The study involved 49 women who were diagnosed with PCOS according to Rotterdam’s criteria, and 24 women voluntarily agreed to a three-month dietary intervention. The dietary intervention was carried out for 3 months. Glutathione peroxidase (GPx3) activity, the Ferric reducing ability of plasma, and uric acid concentration were measured spectrophotometrically both before and after the intervention. Statistical analysis was performed with the Statistica 10.0 software package, and a Pearson’s correlation matrix was generated. Results: A lower concentration of GPx3 was observed in women with PCOS (before the dietetic intervention began) compared with the GPx3 levels in healthy women. A relationship was shown between GPx3 levels and the concentration of prolactin, insulin on fasting, and triglycerides. After the dietary intervention, increases in uric acid and GPx3 activity were noted, as well as numerous relationships between anthropometric and biochemical parameters. The ferric reducing/antioxidant power did not change significantly. Conclusions: Inhibiting the effect of prolactin (by the level of reactive oxygen species) on the activity of GPx3 could be a starting point for the increase in antioxidative stress and the development of the inflammatory state associated with PCOS pathophysiology. Following a low-calorie diet with a lower glycemic index is proposed to silence inflammation by increasing the concentration of uric acid. During GPx3 mobilization, women with PCOS have a higher demand for selenium, and its deficiencies may contribute to disordered thyroid hormone synthesis. The three-month dietary intervention did not silence redox processes in the examined group of women.

Heavy metals in the environment are one of the major limiting factors affecting plant growth and development. However, the mechanisms of the heavy metal-induced physiological processes remain to be fully dissected. Here, we explored that SRO1 can physically interact with Glutathione Peroxidase 3 (GPX3) inArabidopsis. Under Hg treatment, similar to thesro1, the growth of thegpx3/sro1was repressed more seriously and the number of true leaves was more reduced and etiolated than that of the wild type andgpx3plants. The electrolyte leakage rates showed that cell membrane integrity ingpx3/sro1was damaged more severely than in the wild type andgpx3mutant. The Real-time PCR results have shown that the expression of theAPX1andCAT3was reduced under mercury stress in thesro1andsro1/gpx3. Our results suggested that the combination of the SRO1 and GPX3 may be contributed to plant response to mercury stress by regulating ROS intracellular oxidative homeostasis. The combination of the SRO1 and GPX3 has an important effect on plant tolerance of mercury stress. [ABSTRACT FROM PUBLISHER]

Epigenetic control of gene expression is a major determinant of tumor phenotype and has been found to influence sensitivity to individual chemotherapeutic agents. Glutathione peroxidase 3 (GPX3, plasma glutathione peroxidase) is a key component of cellular antioxidant regulation and its gene has been reported to be methylated in specific tumor types. GPX3 role in oxidative damage has been associated with sensitivity to platinums in other tumors but its importance in colorectal cancer (CRC) has not been determined. We examined the role ofGPX3methylation in colorectal carcinoma in determining sensitivity to platinum drugs using primary tumor specimens, cell lines, knockdown cell lines, and tumor cell line xenografts. We findGPX3promoter region methylation in approximately one third of CRC samples andGPX3methylation leads to reduced GPX3 expression and increased oxaliplatin and cisplatin sensitivity. In contrast, in cell lines with high baseline levels ofGPX3expression or with the ability to increaseGPX3expression, platinum resistance is increased. The cisplatin IC50inGPX3-methylated cell lines is approximately 6-fold lower than that inGPX3-unmethylated lines. Additionally, knockdown cell lines with essentially noGPX3expression require N-acetylcysteine to survive in culture underscoring the importance of GPX3 in redox biology.In vivo, GPX3methylation predicts tumor xenograft sensitivity to platinum with regression ofGPX3knockdown xenografts with platinum treatment but continued growth ofGPX3wild type xenografts in the presence of platinum. These studies demonstrate the importance ofGPX3for CRC cells resistance to platinums and the potential utility ofGPX3methylation status as a predictive biomarker for platinum sensitivity in CRC. [ABSTRACT FROM PUBLISHER]

Summary Thiol peroxidases are conserved hydrogen peroxide scavenging and signaling molecules that contain redox-active cysteine residues. We show here that Gpx3, the major H 2 O 2 sensor in yeast, is present in the mitochondrial intermembrane space (IMS), where it serves a compartment-specific role in oxidative metabolism. The IMS-localized Gpx3 contains an 18-amino acid N-terminally extended form encoded from a non-AUG codon. This acts as a mitochondrial targeting signal in a pathway independent of the hitherto known IMS-import pathways. Mitochondrial Gpx3 interacts with the Mia40 oxidoreductase in a redox-dependent manner and promotes efficient Mia40-dependent oxidative protein folding. We show that cells lacking Gpx3 have aberrant mitochondrial morphology, defective protein import capacity, and lower inner membrane potential, all of which can be rescued by expression of a mitochondrial-only form of Gpx3. Together, our data reveal a novel role for Gpx3 in mitochondrial redox regulation and protein homeostasis. [ABSTRACT FROM AUTHOR]

Objective: The prognosis for gastric cancer (GC), a prevalent tumor of the digestive system, is unfavorable. The involvement of glutathione peroxidase 3 (GPX3) in tumorigenesis is significant, yet its specific role in GC remains insufficiently investigated. Thus, the aim of this study was to determine the potential impact of GPX3 on GC and elucidate the underlying mechanism. Methods: The expression and survival of GPX3 in GC were analyzed using TCGA data. Additionally, the GPX3 mRNA and protein levels in GC were also assessed using datasets from GTEx, GEPIA, and HPA. A total of 38 pairs of GC tissues, along with their adjacent normal tissues, were collected from the Tianjin Medical University General Hospital, accompanied by detailed clinical information. The expression levels of GPX3 were subsequently determined for the purpose of validation. Following expression, correlation, and survival analyses, we proceeded to investigate the upstream non-coding RNA (ncRNA) of GPX3 using starBase and miRNet. Additionally, the co-expression networks of GPX3 were examined based on LinkedOmics. Lastly, we explored the correlation between GPX3 and immune cell infiltration, as well as the biomarkers of immune cells and immune checkpoints in GC. Furthermore, the GDSC database offered valuable drug sensitivity information. Results: A lower expression of GPX3 was observed in individuals with GC, while a higher expression of GPX3 was associated with a poorer prognosis. The DUBR/hsa-miR-502-3p/GPX3 pathway was identified as the most promising upstream ncRNA pathway related to GPX3 in GC. GO and KEGG enrichment analysis revealed that GPX3 expression was linked to coagulation cascades and cell locomotion. Furthermore, GPX3 levels in GC were positively correlated with immune cell infiltration, immune cell biomarkers, and immune checkpoint expression. The group with low GPX3 expression also exhibited increased sensitivity to 5-fluorouracil, doxorubicin, and other drugs. Conclusions: Collectively, we hypothesized that the potential involvement of non-coding RNAs in the downregulation of GPX3 could contribute to the inhibition of tumor formation during the malignant transition from gastritis to GC. Nevertheless, it was plausible that GPX3 may also facilitate tumor progression to advanced stages by promoting immune cell infiltration and activating immune checkpoints., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)