Frontiers in bioscience (Landmark edition)最新文献

{"title":"Inhibition of S100A9 Improves Aortic Dissection in Association With Mitochondrial Function Enhancement.","authors":"Keyu Zhang, Linman Li, Yiying Zhang, Kai Guo, Zhao Zhang, Mengning Wan, Yongzheng Guo, Yu Zhao, Xiaowen Wang","doi":"10.31083/FBL44666","DOIUrl":"https://doi.org/10.31083/FBL44666","url":null,"abstract":"<p><strong>Background: </strong>Aortic dissection (AD) is a high-mortality cardiovascular emergency with unclear pathophysiological mechanisms. This study investigated S100 calcium-binding protein A9 (S100A9) as a therapeutic target for AD and explored its underlying mechanisms.</p><p><strong>Methods: </strong>Proteomic analysis compared aortic tissues from patients with acute type A and matched non-dissected vascular tissues from the same patients. An AD model was induced in wild-type and <i>S100A9</i> knockout mice via β-aminopropionitrile (BAPN). Survival, aortic diameter, and S100A9 expression were quantified. Furthermore, single-cell RNA sequencing was used to analyze cell populations and mitochondrial pathways in AD mice treated with an S100A9 inhibitor. Finally, the effect of S100A9 on mitochondrial function was investigated in Tohoku Hospital Pediatrics-1 (THP-1) cells.</p><p><strong>Results: </strong>Proteomics identified that S100A9 is significantly upregulated in AD tissue. Furthermore, <i>S100a9</i> knockout (<i>S100a9</i> KO) mice conferred protection against AD-induced mortality and aortic dilation. Single-cell RNA analysis revealed that S100A9 is predominantly expressed within the granulocyte population. <i>S100A9</i> inhibition activated mitochondrial oxidative phosphorylation pathways and upregulated mtDNA-encoded gene expression. Human tissue mRNA levels confirmed decreased mtDNA in AD. Moreover, recombinant human S100A9 and angiotensin-II treatment in THP-1 cells reduced mitochondrial membrane potential and increased oxidative stress.</p><p><strong>Conclusions: </strong>S100A9 is a potential contributor to AD pathogenesis. Inhibition of S100A9 might be a promising therapeutic target for AD.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"44666"},"PeriodicalIF":3.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276708","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":"Identification of <i>TRIM59</i> as a Key Biomarker for Ferroptosis Resistance and Immunotherapy Response in Bladder Cancer via Multi-Omics Integration and Machine Learning.","authors":"Jianyuan Lei, Ping Wang, Yanchun Qu, Xingfen Wang, Xianglian Zhang, Hui Li, Pengyu Zhang","doi":"10.31083/FBL44395","DOIUrl":"https://doi.org/10.31083/FBL44395","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer (BCa) is a highly heterogeneous malignancy, and precision treatment remains challenging. Identifying molecular biomarkers and risk factors is essential for improving prognosis and therapeutic strategies.</p><p><strong>Methods: </strong>We integrated expression quantitative trait loci (eQTL) data with Mendelian randomization (MR) analysis to identify candidate risk genes associated with BCa. Subsequently, a prognostic risk model was developed using machine learning methods to explore its correlation with molecular features, immune cell infiltration, and ferroptosis-related pathways. Based on these findings, the Tripartite Motif Containing 59 (<i>TRIM59</i>) protein was selected for further experimental validation. The functional role of <i>TRIM59</i> in BCa progression was further investigated using MTT assays in BCa cell lines. Additionally, western blotting (WB) was conducted to confirm the potential association between <i>TRIM59</i> expression and ferroptosis regulation.</p><p><strong>Results: </strong>The risk model identified distinct signaling pathways that differentiate the high-risk and low-risk BCa groups. The low-risk group demonstrated greater infiltration of CD8+ T cells. Conversely, the high-risk group exhibited enhanced immune evasion, as evidenced by increased infiltration of macrophages and fibroblasts. Furthermore, <i>TRIM59</i> exerts a regulatory influence on ferroptosis progression in BCa by modulating key genes involved in this process, including Solute Carrier Family 7 Member 11 (<i>SLC7A11</i>), Glutathione Peroxidase 4 (<i>GPX4</i>), and Acyl-CoA Synthetase Long Chain Family Member 4 (<i>ACSL4</i>).</p><p><strong>Conclusion: </strong>Our integrative approach highlights the potential of genomic and immune microenvironment data in developing personalized risk models for BCa, offering insights into individualized treatment strategies. Importantly, <i>TRIM59</i> is involved in ferroptosis resistance in BCa. These findings have potential implications for identifying diagnostic biomarkers and therapeutic targets for BCa treatment.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"44395"},"PeriodicalIF":3.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276788","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":"Single-cell Analyses Highlight the Proinflammatory Contribution of Low-density Neutrophils in the Acute Phase of Severe Fever With Thrombocytopenia Syndrome.","authors":"Jiaying Zhao, Chunhui Wang, Ke Jin, Yan Dai, Yaqin Zhang, Tingting Zhou, Zhan Yang, Tao Yang, Yuan Liu, Nannan Hu, Yinghua Mao, Chuanlong Zhu, Ping Shi, Xuewei Sun, Jin Zhu, Jun Li","doi":"10.31083/FBL40723","DOIUrl":"https://doi.org/10.31083/FBL40723","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Severe fever with thrombocytopenia syndrome (SFTS), caused by &lt;i&gt;Dabie bandavirus&lt;/i&gt; (DBV) infection, is characterized by early cytokine storm as a primary pathological feature, although the precise mechanisms remain unclear. Low-density neutrophils (LDNs) are elevated in the peripheral blood of patients with autoimmune or infectious diseases and are closely associated with inflammatory damage and disease severity. However, the pathogenic contribution of LDNs to the progression of SFTS is largely unexplored. This study employed single-cell RNA sequencing (scRNA-seq) to profile the transcriptomic characteristics of LDNs during the acute phase of SFTS, aiming to reveal their compositional and functional heterogeneity following DBV infection, explore their role in the cytokine storm, and further understand their impact on disease progression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Cells were isolated from 13 acute-phase SFTS patients with varying disease severity and 3 healthy controls using density gradient centrifugation, followed by preparation of single-cell suspensions for 3'-end scRNA-seq. Sequencing data were processed using the Seurat pipeline, including dimensionality reduction, clustering, cell-type annotation, and visualization with Uniform Manifold Approximation and Projection (UMAP). Low-density granulocytes (LDGs) and their subclusters were identified using canonical gene markers. Functional enrichment of differentially expressed genes (DEGs) was analyzed by high-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA), Gene Ontology (GO), AddModuleScore, single-sample Gene Set Enrichment Analysis (ssGSEA), and immune-related Gene Set Enrichment Analysis (irGSEA), while cellular interactions were explored using CellCall.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;1. Compositional heterogeneity: The proportion of LDNs in peripheral blood increased in SFTS patients with greater disease severity during the acute phase. 2. Functional heterogeneity: (1) LDN subclusters showed functional diversity but consistently displayed pro-inflammatory or anti-infective properties. (2) With intensification of the systemic inflammatory response, the expression of multiple cytokine genes (e.g., &lt;i&gt;IL6&lt;/i&gt;, &lt;i&gt;IL8&lt;/i&gt;, &lt;i&gt;TNFA&lt;/i&gt;) and gene sets of the inflammatory pathway (&lt;i&gt;e.g.&lt;/i&gt;, TNFA-SIGNALING-VIA-NFKB, INFLAMMATORY-RESPONSE) were significantly upregulated in LDNs. Concurrently, the expression of gene sets of type I interferon response pathway (&lt;i&gt;e.g.&lt;/i&gt;, INTERFERON-ALPHA-RESPONSE, INTERFERON-GAMMA-RESPONSE) and genes of interferon-induced antiviral proteins (&lt;i&gt;e.g.&lt;/i&gt;, &lt;i&gt;EIF2AK2&lt;/i&gt;, &lt;i&gt;OAS1&lt;/i&gt;, &lt;i&gt;MX1&lt;/i&gt;) were also elevated. (3) In severe cases, glucocorticoid therapy downregulated expression of these inflammatory genes, demonstrating anti-inflammatory effects but potentially increasing infection risk.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study revealed an increased proportion and heightened pro-inflammatory ac","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"40723"},"PeriodicalIF":3.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276836","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":"Astrocytic Biomarkers in Epilepsy: A Critical Review on Clinical Utility and Mechanistic Implications.","authors":"Ting-Rong Hsu, Pei-Hao Chen, Wei-Sheng Lin","doi":"10.31083/FBL39022","DOIUrl":"https://doi.org/10.31083/FBL39022","url":null,"abstract":"<p><p>Epilepsy is one of the most common neurological disorders in both children and adults, characterized by significant clinical heterogeneity and dynamic natural course. The pathophysiological roles of astrocytes in epilepsy have been increasingly recognized. Fluid biomarkers derived from astrocytes are actively studied in epileptic disorders, although their use remains limited in clinical practice. This review aims to compile and analyze clinical and experimental findings concerning astrocytic biomarkers in epilepsy and related conditions, with a focus on glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B). Herein we examine their roles in assessing seizure burden and temporal dynamics, explore their potential in distinguishing epileptic from psychogenic non-epileptic seizures, and discuss their therapeutic, prognostic, and mechanistic implications in the context of epileptic disorders.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"39022"},"PeriodicalIF":3.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276748","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":"Unconjugated Bile Acids and Alcohols Inhibit Degranulation of Stimulated RBL-2H3 Cells.","authors":"Michiko Yoshii, Ai Tarao, Yasuko Ichinose, Naomi Iwasa, Fumi Tanaka, Yuhki Yanase, Koichiro Ozawa","doi":"10.31083/FBL44504","DOIUrl":"https://doi.org/10.31083/FBL44504","url":null,"abstract":"<p><strong>Background: </strong>Steroid hormones are widely used as anti-allergic drugs because of their potent anti-inflammatory properties and ability to suppress histamine release by 60-80%. Ursodeoxycholic acid (UDCA; 3α,7β-dihydroxy-5β-cholan-24-oic acid), used to treat liver disease, exerts immunosuppressive effects by binding to glucocorticoid receptors and inhibiting histamine release from mast cells. In contrast, other bile acids, such as chenodeoxycholic acid (CDCA; 3α,7α-dihydroxy-5β-cholan-24-oic acid) and deoxycholic acid (DCA; 3α,12α-dihydroxy-5β-cholan-24-oic acid), have been reported to promote histamine release. The mechanisms underlying these divergent effects remain unclear, raising questions regarding structural differences, receptor interactions, and downstream signaling. To address this knowledge gap, we examined the effects of several bile acids and C₂₄ bile alcohols on the degranulation of rat basophilic leukemia (RBL-2H3) cells, a model for mast cell activation.</p><p><strong>Methods: </strong>The effects of bile acids and alcohols on degranulation were tested in stimulated RBL-2H3 cells; furthermore, whether they affected store-operated calcium (SOC) channel-mediated Ca²⁺ entry-a critical step in mast cell degranulation-was investigated. To identify molecular targets, biotinylated bile acids were immobilized on magnetic beads and incubated with lipid raft fractions from RBL-2H3 cells to capture the interacting proteins.</p><p><strong>Results: </strong>All tested bile acids and alcohols significantly suppressed RBL-2H3 cell degranulation, thereby correlating with reduced extracellular Ca²⁺ influx via SOC channels. Further analysis revealed interference by Orai1, a key subunit of calcium release-activated calcium (CRAC) channels. This interaction appears to be mediated by the steroidal structures of the bile acids and alcohols.</p><p><strong>Conclusions: </strong>These findings demonstrate that bile acids and alcohols inhibit SOC-mediated Ca²⁺ entry by directly interacting with Orai1, thereby blocking mast cell degranulation. Although the concentrations required for this effect were near cytotoxic levels owing to detergent-like properties, the results uncovered a novel molecular interaction between steroid structures and Orai1. This mechanistic insight provides a foundation for the development of targeted small molecule modulators of Orai1-mediated calcium entry, offering potential therapeutic strategies for allergic and inflammatory disorders.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"44504"},"PeriodicalIF":3.1,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276876","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":"Fto-Mediated m6A Demethylation of Anxa1 Attenuates Cardiac Ischemia-Reperfusion Injury With Suppression of Nlrp3 Inflammasome Signals.","authors":"Chaojie He, Haojie Yang, Lijia Xu, Hao Zhang, Huilin Hu","doi":"10.31083/FBL42765","DOIUrl":"https://doi.org/10.31083/FBL42765","url":null,"abstract":"<p><strong>Background: </strong>Myocardial ischemia-reperfusion (I/R) injury represents the major obstacle to achieving successful therapeutic outcomes in acute myocardial infarction patients. Fat mass and obesity-associated protein (Fto), an N6-methyladenosine (m6A) RNA demethylase, has been shown to protect cardiomyocytes against oxygen-glucose deprivation/reperfusion-mediated injury by regulating annexin A1 (<i>Anxa1</i>) expression <i>in vitro</i>. The present study aims to confirm the cardioprotective role of the Fto/Anxa1 axis using <i>in vivo</i> myocardial I/R injury models.</p><p><strong>Methods: </strong>Wild-type (WT) and <i>Anxa1</i> knockout (KO) mice underwent 30-min left coronary artery ligation and 2-h reperfusion after intramyocardial delivery of recombinant adeno-associated virus serotype 9 encoding <i>Fto</i> (ad<i>Fto</i>) or a control vector (adnull). The effects of Fto overexpression on cardiac function, fibrosis, apoptosis, and inflammatory response were examined using echocardiography, Masson's trichrome staining, western blot analysis, enzyme-linked immunosorbent assay, and immunohistochemical staining. m6A-RNA immunoprecipitation-quantitative polymerase chain reaction quantified <i>Anxa1</i> mRNA methylation.</p><p><strong>Results: </strong>Fto overexpression by ad<i>Fto</i> significantly improved cardiac function, reduced serum creatine kinase-myocardial band and troponin T levels, and alleviated cardiac fibrosis in I/R-injured WT mice. Mechanistically, Fto weakened I/R-induced global m6A levels and decreased m6A enrichment on <i>Anxa1</i> mRNA, thereby enhancing <i>Anxa1</i> expression. In <i>Anxa1</i> KO mice, ad<i>Fto</i> did not confer functional or molecular benefit.</p><p><strong>Conclusions: </strong>Fto enhances <i>Anxa1</i> and mitigates myocardial I/R injury with suppression of nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (<i>Nlrp3</i>)-inflammasome signaling <i>in vivo</i>, identifying the Fto-<i>Anxa1</i> axis as a mechanistic contributor and potential therapeutic target.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"42765"},"PeriodicalIF":3.1,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276786","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":"Single-cell Transcriptome Analysis Reveals the Potential Role of Hepatic Stellate Cells in Liver Fibrosis.","authors":"Xiaoling Wang, Ying Wang, Meng Yang, Taoran Zhao, Zhiwei Feng, Yujie Zhou, Xuewei Li, Yuanhao Yang, Zhizhen Liu, Guoping Zheng, Jun Xie","doi":"10.31083/FBL42394","DOIUrl":"https://doi.org/10.31083/FBL42394","url":null,"abstract":"<p><strong>Background: </strong>Upon activation, hepatic stellate cells (HSCs) can convert into fibroblasts and increase the production of extracellular matrix, a major cause of liver fibrosis (LF) and a growing health issue worldwide. Other mechanisms by which HSCs may induce fibrosis remain to be explored, and the role of cell dynamic gene expression in liver fibrogenesis is not well understood. In this study, analysis by single-cell transcriptome sequencing (scRNA-seq) was used to explore the potential effects of HSCs in a bile duct ligation (BDL)-induced mouse model of LF, followed by the identification of novel targets for clinical diagnosis.</p><p><strong>Methods: </strong>Liver tissue collected from BDL and sham-operated C57BL/6J mice was used for scRNA-seq. To systematically dissect the molecular and cellular events following fibrosis, the scRNA-seq data was analyzed for differential gene expression, KEGG, pseudotime trajectory, and cellular communication. Morphological changes in the BDL and sham livers were examined by hematoxylin and eosin (H&E) staining, Masson's trichrome staining, fiber staining, and Sirius red staining.</p><p><strong>Results: </strong>The scRNA-seq analysis performed on the BDL and sham groups revealed the gene expression of 20,764 cells across 27 cell types. Antioxidant levels declined markedly in HSCs from BDL mice, leading to a more pronounced occurrence of ferroptosis. We also found evidence suggesting that elevated apelin signaling and platelet activation in HSCs contributed to the increased synthesis of extracellular matrix and collagen fibers. The large accumulation of immune cells in the liver of BDL mice induces different outcomes for HSCs.</p><p><strong>Conclusion: </strong>The results of this study provide further insight into the cellular and molecular alterations that occur within a specific subset of HSCs during LF, offering valuable information on potential targets for therapeutic intervention.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"42394"},"PeriodicalIF":3.1,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276878","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":"Transcriptional Dysregulation of Autophagy in Aging and Potential Interventions: Insights Into TFEB and FOXOs.","authors":"Cheng-Ju Kuo, Denisa M Manastireanu, Jose L Nieto-Torres, Caroline Kumsta","doi":"10.31083/FBL38730","DOIUrl":"https://doi.org/10.31083/FBL38730","url":null,"abstract":"<p><p>Autophagy is a highly conserved cellular degradation and recycling process essential for maintaining cellular homeostasis. However, autophagic activity declines with age, contributing to the accumulation of damaged organelles and protein aggregates. The decline in autophagic activity is considered a primary hallmark of aging, as it contributes to cellular dysfunction and the onset of age-associated diseases, including neurodegenerative disorders and metabolic dysfunction. Sustaining autophagy with age requires transcriptional regulation, which may become impaired with age. In this review, we summarize current understanding of transcriptional regulation of autophagy during aging, with a specific focus on transcription factor EB (TFEB) and forkhead box O (FOXO) transcription factors. We integrate mechanistic insights from both mammalian systems and model organisms to highlight how their regulatory activity declines with age through changes in expression, post-translational modifications, nuclear transport, and transcriptional efficiency. We further explore pharmacological and lifestyle interventions aimed at restoring autophagic function to mitigate cellular decline. Given the pivotal role of autophagy in promoting cellular resilience and disease prevention, targeting autophagy-regulating transcription factors holds promise as a therapeutic strategy to counteract age-related functional decline and extend healthspan.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"38730"},"PeriodicalIF":3.1,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276883","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":"Short Overview on the Involvement of Lipid Peroxidation Product 4-Hydroxynonenal in Diverse Pathways of Cell Death.","authors":"Morana Jaganjac, Anita Stojanovic Markovic, Nicola Deiana, Neven Zarkovic","doi":"10.31083/FBL37139","DOIUrl":"https://doi.org/10.31083/FBL37139","url":null,"abstract":"<p><p>The oxidation of lipids, notably of polyunsaturated fatty acids (PUFAs), under oxidative stress is a self-catalyzed chain reaction that generates reactive aldehydes, among which 4-hydroxynonenal (4-HNE) is considered to act as a second messenger of free radicals. The pleiotropic effects of 4-HNE, which include the regulation of cellular antioxidant capacities, proliferation, differentiation, and apoptosis, are concentration-dependent as they depend on cell type. Therefore, 4-HNE has important roles in various pathophysiological processes and the pathogenesis of acute and chronic diseases, especially degenerative and malignant diseases. Before 4-HNE was recognized as a signaling molecule, it was known to be the cytotoxic mediator of oxidative stress, acting even if lipid peroxidation was not present, because it remains bound to proteins, changing their structure and function. Research in this field has revealed several novel modes of activities of 4-HNE associated with cell death, including not only apoptosis/programmed cell death and necrosis but also ferroptosis, autophagy, pyroptosis, necroptosis, parthanatos, oxeiptosis and cuproptosis. This review shortly summarizes these findings, aiming to encourage further research in the field that might open new ways to use 4-HNE as the bioactive factor for targeted cell death, in particular cancer cells.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"37139"},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276888","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":"Excavation of Molecular Subtypes of Cervical Cancer Based on DNA Methylation Patterns.","authors":"Yiwei Zhao, Chutong Zhao, Jiyun Zhao, Yuhan Ma, Shunjin Zhang, Yujie Liu, Yuan Wang, Sijia Liu, Yunyan Zhang","doi":"10.31083/FBL45025","DOIUrl":"https://doi.org/10.31083/FBL45025","url":null,"abstract":"<p><strong>Background: </strong>Cervical cancer remains a major cause of cancer-related death among women worldwide. Despite advances in treatment, prognosis remains poor for many patients due to tumor heterogeneity. DNA methylation, an epigenetic modification, is known to influence tumor development, but its role in defining molecular subtypes and prognostic stratification in cervical cancer remains inadequately understood.</p><p><strong>Methods: </strong>We analyzed DNA methylation profiles from 287 cervical cancer samples obtained from the UCSC Xena database. Univariate and multivariate Cox regression analyses were applied to identify prognostic CpG sites, as these models allow evaluation of individual and combined effects of methylation sites on patient survival. Consensus clustering was performed to define robust molecular subtypes based on methylation patterns, providing insights into tumor heterogeneity. Differentially methylated regions were identified using the Quantitative Differentially Methylated Regions (QDMR) software, an entropy-based tool validated for detecting subtype-specific methylation markers. A Bayesian classifier was constructed and validated in training and test cohorts to evaluate the predictive accuracy of these markers for subtype classification. Additionally, immune cell infiltration was estimated using computational algorithms to assess tumor microenvironment differences, and chemosensitivity was predicted to explore potential clinical implications of the methylation subtypes.</p><p><strong>Results: </strong>Four distinct methylation-based subtypes differed in methylation patterns, histological types, clinical stages, and metastatic status. A total of 501 subtype-specific methylation sites were identified. The Bayesian classifier demonstrated strong predictive performance, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.824 based on 10-fold cross-validation, indicating high classification accuracy and robustness. The immune microenvironment composition varied markedly among subtypes. Notably, Cluster 1 had elevated infiltration of central memory CD8+ and effector memory CD4+ T cells, whereas Cluster 4 exhibited reduced immune activation and the lowest immune checkpoint expression. These findings indicate subtype-specific differences in potential responsiveness to immunotherapy.</p><p><strong>Conclusions: </strong>These DNA methylation-driven subtypes highlight the heterogeneity of cervical cancer and offer new insights for personalized therapy.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"45025"},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276759","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}