Frontiers in bioscience (Landmark edition)最新文献

{"title":"Memory T Cells, Recombinant <i>Listeria monocytogenes</i>, and Cancer Vaccines.","authors":"Abolaji Samson Olagunju, Maribel Limachi Loza, Marielly Câmara Rocha, Gustavo P Amarante-Mendes","doi":"10.31083/FBL36329","DOIUrl":"https://doi.org/10.31083/FBL36329","url":null,"abstract":"<p><p>Memory T cells are essential for effective and durable immune responses, as they provide long-term immunological surveillance and rapid reactivity upon re-exposure to a given pathogen or cancer cell. In solid tumors, the immunosuppressive tumor microenvironment (TME) often hinders immune activation, making enhancing memory T cell formation and persistence a key goal in cancer immunotherapy. Novel strategies are exploring ways to support these memory T cells, including using <i>Listeria monocytogenes</i> as a cancer vaccine vector. Notably, <i>L. monocytogenes</i> has unique properties that make it an ideal candidate for this purpose: it is highly effective at activating T cells, promoting the differentiation and survival of memory T cells, and modulating the TME to favor immune cell function. Thus, by leveraging the ability of <i>L. monocytogenes</i> to induce a strong, sustained T-cell response, researchers aim to develop vaccines that provide lasting immunity against tumors, reduce recurrence rates, and improve patient survival outcomes. This mini-review highlights the potential of memory T cell-focused cancer immunotherapy and the promising role of <i>L. monocytogenes</i> in advancing these efforts.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"36329"},"PeriodicalIF":3.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comparative Analysis of Genetic and Epigenetic Factors in METH Addiction: A Focus on <i>SLC</i> (<i>SLC6A4</i>) and <i>COMT</i> Genes.","authors":"Haider K Hussain, Yolanda Loarce Tejada, Anna Barbaro","doi":"10.31083/FBL43887","DOIUrl":"10.31083/FBL43887","url":null,"abstract":"<p><strong>Background: </strong>Methamphetamine (METH) addiction is a global concern due to its severe impact on public health, including heightened aggression and neurotoxic effects. Genetic and epigenetic factors, particularly involving the <i>SLC6A4</i> and <i>COMT</i> genes, are implicated in individual vulnerability to METH addiction. Thus, understanding the molecular mechanisms involved is crucial for developing targeted prevention and treatment strategies.</p><p><strong>Methods: </strong>A systematic literature review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Six major databases (MEDLINE/PubMed, Scopus, ScienceDirect, ResearchGate, Web of Science, Google Scholar) and Spanish-language platforms (Dialnet, Redalyc, CSIC, RECyT) were searched for studies published in English, Spanish, and Portuguese over the last 40 years. The inclusion criteria encompassed original research focusing on genetic and/or epigenetic determinants of METH addiction, with particular emphasis on the <i>SLC6A4</i> and <i>COMT</i> genes. Studies focusing on substances other than METH, non-human subjects, or those that did not meet the language or temporal restrictions were excluded. Data on genetic variants, epigenetic alterations (e.g., DNA methylation, histone modifications), and relevant behavioral outcomes were extracted.</p><p><strong>Results: </strong>From an initial 600 articles, 25 studies met the inclusion criteria and were included in the qualitative synthesis. Polymorphisms in <i>SLC6A4</i> (e.g., 5-HTTLPR) were associated with an increased risk of METH addiction (odds ratio (OR) = 2.31, 95% confidence interval (CI): 1.45-3.68; <i>p</i> = 0.001); meanwhile, variations in <i>COMT</i> (Val158Met) were linked to both susceptibility and executive function deficits. Epigenetic modifications-most notably DNA methylation in <i>SLC6A4</i> and <i>COMT</i>-also emerged as important contributors to addiction pathways, potentially influencing dopamine and serotonin regulation. Gene-environment interactions, including factors such as childhood trauma and socioeconomic status, were found to modulate genetic predispositions, suggesting a multifaceted etiology for METH dependence.</p><p><strong>Conclusions: </strong>Both genetic polymorphisms and epigenetic alterations play a critical role in METH addiction vulnerability. The reviewed evidence highlights the need for more comprehensive, regionally diverse studies and integrative approaches that combine genetics, neurobiology, and psychosocial factors. Such strategies could inform personalized prevention and treatment interventions, improving patient outcomes and mitigating the global burden of METH addiction.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"43887"},"PeriodicalIF":3.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMP10 in Cardiovascular Disease: From Pathogenesis to Therapeutic Strategies.","authors":"Qiuyan Jiang, Chaofu Li, Yingying Jiang, Zhengmeng Ye, Gang Xu, Yiqiong Zhang, Fan Yang, Jun Xiao, Chuanwei Li","doi":"10.31083/FBL31356","DOIUrl":"https://doi.org/10.31083/FBL31356","url":null,"abstract":"<p><p>Cardiovascular diseases (CVD) remain the leading cause of global mortality, highlighting the urgent need for the identification of novel biomarkers and the development of therapeutic approaches to improve patient outcomes. Despite great progress in CVD diagnosis, treatment, and predicting risk, current methods fall short of effectively reducing its prevalence. Recently, bone morphogenetic protein 10 (BMP10), a cardiac-specific growth factor with a role in cardiac development and vascular homeostasis, has emerged as a potential biomarker and therapeutic target in CVD. While studies have demonstrated BMP10's diagnostic potential in atrial fibrillation (AF), its precise role across the broader CVD landscape remains poorly understood. We review the current knowledge of BMP10's involvement across a spectrum of cardiovascular conditions, including AF, heart failure, myocardial infarction, pulmonary arterial hypertension, dilated cardiomyopathy, and diabetic cardiomyopathy. This analysis provides an in-depth examination of the mechanisms through which BMP10 may influence CVD progression and highlights its potential utility as a diagnostic and therapeutic target.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"31356"},"PeriodicalIF":3.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Ctnna3</i> Deficiency Promotes Heart Regeneration by Enhancing Cardiomyocyte Proliferation in Neonatal Mice.","authors":"Sha Zou, Wuhou Dai, Wufan Tao, Jifen Li, Zeyi Cheng, Hongyan Wang","doi":"10.31083/FBL39676","DOIUrl":"https://doi.org/10.31083/FBL39676","url":null,"abstract":"<p><strong>Background: </strong>Heart regeneration requires renewal of lost cardiomyocytes. However, the mammalian heart loses its proliferative capacity soon after birth, and the molecular signaling underlying the loss of cardiac proliferation postnatally is not fully understood.</p><p><strong>Purpose: </strong>This study aimed to investigate the role of Catenin alpha 3 (<i>Ctnna3</i>), coding for alpha T catenin (αT-catenin) protein in regulating cardiomyocyte proliferation and heart regeneration during the neonatal period.</p><p><strong>Methods: </strong>Here we report that ablation of <i>Ctnna3</i> and highly expressed in hearts, accelerated heart regeneration following heart apex resection in neonatal mice.</p><p><strong>Results: </strong>Our results show that <i>Ctnna3</i> deficiency enhances cardiomyocyte proliferation in hearts from postnatal day 7 (P7) mice by upregulating Yes-associated protein (Yap) expression.</p><p><strong>Conclusion: </strong>Our study demonstrates that <i>Ctnna3</i> deficiency is sufficient to promote heart regeneration and cardiomyocyte proliferation in neonatal mice and indicates that functional interference of α-catenins might help to stimulate myocardial regeneration after injury.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"39676"},"PeriodicalIF":3.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunosenescence and Ageing: An Entangled Web of Senescence and Declining Immunity.","authors":"Afsar U Ahmed","doi":"10.31083/FBL42709","DOIUrl":"https://doi.org/10.31083/FBL42709","url":null,"abstract":"<p><p>Ageing is a progressive functional decline in health conditions and a risk factor for many chronic diseases. To address the elevated burden of age-related pathologies, the ageing process has been extensively studied over the past decades, and yet the underlying mechanisms remain to be fully understood. One of the prominent features of ageing is cellular senescence, a special form of durable cell-cycle arrest. While senescent cells release the senescence-associated secretory phenotype (SASP) molecules that recruit immune cells to facilitate the clearance of senescent cells, senescence is also indispensable for many essential physiological functions. However, a 'chronic' nature of senescence arises due to immune deficiencies and persists during ageing. Immunosenescence, the ageing of immune cells, is the underlying key driving the pathological burdens of senescence, leading to systemic ageing as demonstrated by animal studies. Thymic regeneration has been shown by several studies to be a potential anti-ageing intervention, restoring immunity as well as reversing immunosenescence and ageing. The specific targeting of senescent cells by senolytic and/or senomorphic drugs is also promising but needs to be dealt with caution to protect the essential physiological roles of senescence. A deeper understanding of the biological origins of immunosenescence is crucial for unveiling the potential root cause of ageing.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"42709"},"PeriodicalIF":3.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel 14-Gene Panel Associated With Efferocytosis for Predicting Pancreatic Cancer Prognosis Through Bulk and Single-Cell Databases.","authors":"Yaheng Wu, Lin Zhao, Dingyan Yi, Zhihua Tian, Bin Dong, Chunxiang Ye, Jingtao Liu, Huachong Ma, Wei Zhao","doi":"10.31083/FBL40818","DOIUrl":"https://doi.org/10.31083/FBL40818","url":null,"abstract":"<p><strong>Background: </strong>Efferocytosis (ER) plays a crucial role in the programmed clearance of dead cells, a process that is mediated by phagocytic immune cells. However, further exploration is needed to determine the full extent of its impact on the progression of pancreatic ductal adenocarcinoma (PDAC), particularly through interactions among tumor cells, stromal cells, and immune cells within the tumor microenvironment (TME).</p><p><strong>Methodology and results: </strong>In this study, we comprehensively analyzed the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, as well as additional databases from multiple bioinformatics websites, utilizing 167 ER features derived from the integration of single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic data. A set of 14 ER-associated prognostic signatures, referred to as the \"14-gene panel\" genes, was identified based on overall survival (OS)/disease-free survival (DFS) data, Pearson correlation coefficients, and multivariate Cox regression analyses. The model pathways enriched by the four-gene combination represented by \"LEAF\" and the 14-gene combination represented by the \"14-gene panel\" presented a high degree of similarity, including among the adhesion, mitotic, G2/M checkpoint, and epithelial‒mesenchymal transition (EMT) signaling pathways. Least absolute shrinkage and selection operator (LASSO) regression was subsequently employed to construct an ER risk scoring system using deep learning, based on the following formula: <i>LGALS3</i>, <i>EMP1</i>, <i>ASPH</i>, and <i>FNDC3B</i>, collectively termed the \"LEAF\" panel. Additionally, random survival forest (RSF) algorithms facilitated the identification of a key panel of genes, designated \"LEAP\" genes, including <i>LGALS3</i>, <i>EREG</i>, <i>ASPH</i>, and <i>PLS3</i>; three of which genes (<i>ASPH</i>, <i>LGALS3</i>, and <i>EREG</i>) were identified as key factors influencing the behaviors of PDAC tumors, tumor-associated stroma, and macrophages. Finally, we utilized experimental methods, including Boyden chamber analyses, immunohistochemical staining, and cell cycle analyses, to demonstrate that interference with <i>ASPH</i> suppresses the malignant properties of tumors, including proliferation and migration. Multiplex immunofluorescence staining was employed to identify <i>EREG</i> as highly relevant to the M2 macrophage subpopulation.</p><p><strong>Conclusion: </strong>Our findings underscore the importance of considering a novel prognostic signature comprising 14 ER genes in the context of the TME when investigating the biology of PDAC. Future studies may explore how modulating these interactions could lead to novel therapeutic opportunities.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"40818"},"PeriodicalIF":3.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Analysis of AMPK and Ferroptosis in Cancer: A Potential Regulatory Axis.","authors":"Ting Zhang, Xi Wang, Peter G Alexander, Peng Feng, Jianying Zhang","doi":"10.31083/FBL36618","DOIUrl":"https://doi.org/10.31083/FBL36618","url":null,"abstract":"<p><p>Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is an energy homeostasis controller that regulates various metabolic pathways to promote adenosine triphosphate (ATP) generation and suppress energy expenditure, thereby restoring energy homeostasis. As a co-factor in many enzymes, iron is an essential mineral for maintaining ATP levels in our bodies. Ferroptosis is an iron-dependent mode of cell death that occurs in various pathological processes, including cancer, metabolic disorders, and autoimmune diseases, by regulating iron metabolism, lipoperoxidation, and anti-oxidation functions. Ferroptosis is triggered by oxidative and energy stress, both controlled by cancer-associated signaling pathways. Emerging studies have demonstrated that AMPK directly influences ferroptosis by modulating lipid metabolism, redox homeostasis, and iron transport. Cancer cells exhibiting elevated baseline AMPK activity demonstrate resistance to ferroptosis, whereas AMPK suppression enhances their susceptibility to this regulated form of cell death. While the precise mechanistic details are yet to be fully elucidated, accumulating evidence suggests that AMPK-mediated ferroptosis regulation may contribute to cancer development and therapeutic responses. This review summarizes recent advances in understanding the interplay between AMPK and ferroptosis in cancer biology and discusses the potential of targeting the AMPK-ferroptosis axis for innovative anticancer strategies.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"36618"},"PeriodicalIF":3.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Identification and Unveiling Key Nitrate-Transporting Proteins in Oat (<i>Avena sativa</i> L.).","authors":"Rong Cheng, Qiang Xiao, Jie Gong, Renwei Sun, Yinke Du, Wei Zhao, Wei Zheng, Shiqing Gao","doi":"10.31083/FBL39679","DOIUrl":"https://doi.org/10.31083/FBL39679","url":null,"abstract":"<p><strong>Background: </strong>Nitrate transporter NRT1/PTR family (NPF) proteins are crucial for plant nitrogen uptake and utilization. As an important hexaploid crop for grain and forage, oat (<i>Avena sativa</i> L.) requires substantial levels of nitrogen. However, the oat nitrate transporter 1 (NRT1) family remains uncharacterized.</p><p><strong>Methods: </strong>In this study, the oat <i>NRT1</i> subfamily members were identified through the Hmm and Pfam databases. Bioinformatics analysis was performed using the MEGA 11 and TBtools software to elucidate the physicochemical properties, evolutionary relationships, chromosomal localization, and gene structures. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis and the green fluorescent protein (GFP) fusion expression vector were utilized to investigate the candidate oat <i>NRT1s</i>.</p><p><strong>Results: </strong>Phylogenetic classification categorized oat <i>NRT1s</i> into eight subfamilies, with the most abundant being the NPF5 subfamily. Physicochemical property analysis revealed that the number of amino acids in the proteins encoded by these genes ranged from 235 to 673, with their molecular weights (MWs) ranging from 26 kDa to 74 kDa. Chromosomal localization revealed that these genes were unevenly distributed across all 12 oat chromosomes. Promoter analysis revealed that light-responsive elements appeared most frequently in the promoters of these genes (39.3%), followed by abscisic acid (ABA)-responsive elements (13.5%) and methyl jasmonate (MeJA)-responsive elements (9.4%). qRT-PCR analysis revealed that most of the genes exhibited tissue-specific expression patterns. Among them, <i>AsNPF2.6</i> was highly expressed in the leaves at 1 h post-low nitrogen (LN) treatment, while <i>AsNPF4.5</i> was highly expressed in the leaves at 12 h. Both these genes exhibited low expression levels in the roots. However, <i>AsNPF7.16</i> and <i>AsNPF7.19</i> were both highly expressed in the roots at 9 h post-LN treatment but exhibited low expression in the leaves. Subcellular localization revealed that all five proteins (AsNPF2.6, AsNPF4.5, AsNPF7.16, AsNPF6.8, and AsNPF7.19) were localized to the cytoplasm and cell membrane.</p><p><strong>Conclusions: </strong>Our results demostrate the involvement of <i>AsNRT1</i> family members in nitrogen transport in oat, providing theoretical support for further investigation into the functions and molecular mechanisms of action of oat <i>NRT1s</i> in nitrogen transport.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"39679"},"PeriodicalIF":3.1,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual Role of Host Toll-Like Receptor 3 in Parasitic Diseases.","authors":"Yixin Yang, Qilong Li, Yiwei Zhang, Ning Jiang, Qijun Chen","doi":"10.31083/FBL35605","DOIUrl":"https://doi.org/10.31083/FBL35605","url":null,"abstract":"<p><p>Parasitic diseases, caused by a diverse array of parasites, remain a substantial threat to global health. Toll-like receptor 3 (TLR3) represents a pivotal element in the innate immune system, distinguished by an ability to signal via the TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathway upon detecting pathogen-derived double-stranded RNA (dsRNA), exosomal RNA (exoRNA), and long non-coding RNA (lncRNA). Predominantly localized on endosomal membranes, TLR3 is extensively expressed in neurons, immune cells, fibroblasts, and epithelial cells. Upon activation, TLR3 engages adaptor molecules such as TRIF, facilitating the phosphorylation of TANK-binding kinase 1 and the subsequent activation of interferon regulatory factors. This signaling cascade triggers the production of type I interferons (IFN-α/β) and proinflammatory cytokines such as interleukin (IL)-6, IL-8, IL-12, and tumor necrosis factor-alpha, which are crucial for effective immune defense against infections. Recent findings highlight the essential role of TLR3 in parasitic infections by detecting nucleic acids from damaged cells to activate dendritic and natural killer cells. TLR3 also functions with other receptors, such as TLR2 and TLR4, to enhance cytokine production and improve parasite clearance. However, TLR3 overactivation can induce excessive, harmful inflammation and tissue damage, highlighting its dual role in balancing immune defense. This review comprehensively examines the TLR3 signaling pathway and its multifaceted role in various parasitic infections, including those caused by <i>Plasmodium</i> spp., <i>Leishmania</i> spp., <i>Clonorchis sinensis</i>, <i>Schistosoma japonicum</i>, <i>Trichinella spiralis</i>, and <i>Neospora caninum</i>.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"35605"},"PeriodicalIF":3.1,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of THBS4 in Chronic Kidney Disease Fibrosis: From Clinical Observations to Molecular Mechanisms.","authors":"Xu Yan, Kun Zhao, Ye Yao, Lihui Wang, Wei Shan, Yan Zhang","doi":"10.31083/FBL26076","DOIUrl":"https://doi.org/10.31083/FBL26076","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD), driven by progressive renal fibrosis, lacks effective therapeutic targets. This study investigates thrombospondin-4 (THBS4) as a novel mediator of CKD-related fibrosis and explores its mechanistic basis.</p><p><strong>Methods: </strong>This study collected 100 patients diagnosed with chronic kidney disease and 30 healthy individuals. Enzyme-linked immunosorbent assay (ELISA) analysis was conducted to assess the expression of THBS4 in CKD patients. Mouse unilateral ureteral obstruction (UUO) renal fibrosis model and Human Kidney-2 (HK2) cell fibrosis model were constructed to analyze the expression changes of THBS4 in renal fibrosis. To examine the effects of inhibiting THBS4 expression on the process of renal fibrosis, these two models were analyzed using Sirius red staining, Masson staining, immunohistochemistry, real-time quantitative PCR (qPCR) and western blot methods.</p><p><strong>Results: </strong>The expression of THBS4 in the serum of CKD patients was found to be significantly higher (<i>p</i> < 0.05), and its concentration showed a negative correlation with the eGFR levels (r = -0.77, <i>p</i> < 0.05) and an increase corresponding to the progression of CKD stages (<i>p</i> < 0.05). THBS4 expression was dramatically increased in UUO-treated mouse kidneys as well as in TGF-β1-stimulated HK2 cells (<i>p</i> < 0.05). <i>In vitro</i>, the expression of renal fibrosis-associated proteins was also significantly reduced after interfering with THBS4 expression (<i>p</i> < 0.05). UUO-induced renal fibrosis and related protein expression were suppressed in <i>THBS4</i> knockdown mice when compared to control mice (<i>p</i> < 0.05). The levels of p-AKT and p-PI3K exhibited a significant rise in conjunction with the onset of renal fibrosis (<i>p</i> < 0.05). The expression of p-AKT as well as p-PI3K showed a significant reduction upon inhibition of THBS4 expression (<i>p</i> < 0.05). Insulin-like growth factor 1 (IGF-1) treatment reversed these effects.</p><p><strong>Conclusion: </strong>THBS4 was significantly overexpressed in CKD patients. By suppressing the expression of proteins associated with renal fibrosis and inhibiting the activation of the PI3K/AKT pathway, THBS4 has the potential to mitigate renal fibrosis.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 7","pages":"26076"},"PeriodicalIF":3.1,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}