Frontiers in Molecular Biosciences最新文献

{"title":"Peripheral myelin protein 2 is underexpressed in early-onset colorectal cancer and inhibits metastasis.","authors":"Zhiyu Yu, Sen Wang, Peng Xu, Cheng Zhang","doi":"10.3389/fmolb.2025.1610003","DOIUrl":"https://doi.org/10.3389/fmolb.2025.1610003","url":null,"abstract":"<p><strong>Background: </strong>The occurrence and fatality rates of early-onset colorectal cancer (EOCRC) are increasing, with metastasis being one of the primary causes of the high mortality rate in EOCRC patients. Currently, there is a shortage of biomarkers for diagnosis and targets for treatment with optimal efficacy and reliability. This study aims to identify biomarkers associated with metastasis to provide effective diagnostic strategies for EOCRC patients.</p><p><strong>Methods: </strong>Expression datasets were retrieved from The Cancer Genome Atlas (TCGA) database and analyzed for differentially expressed genes (DEGs). Subsequently, weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules associated with EOCRC metastasis. Feature genes were selected using machine learning and tdiagnostic performance of these genes was assessed with receiver operating characteristic (ROC) curves. We validated peripheral myelin protein 2 (PMP2) expression levels in EOCRC tissues at the molecular and protein levels using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Finally, the invasive and migratory capabilities of PMP2 were assessed in this study using Transwell assays.</p><p><strong>Results: </strong>The analysis identified 1,411 DEGs in EOCRC and 3,434 DEGs in late-onset colorectal cancer (LOCRC). Subsequently, WGCNA filtered out module genes specifically associated with metastasis in EOCRC, leading to 44 genes. We identified four feature genes by analyzing these genes using machine learning algorithms and taking the intersection: LINC02268, AC092652.1, GRIK1, and PMP2. The ROC curve indicated that these four genes are vitally involved in EOCRC. Further, qRT-PCR and IHC highlighted that PMP2 was downregulated in EOCRC tumor tissues compared to normal tissues. Moreover, Transwell assays revealed that PMP2 inhibited the invasion and migration of EOCRC.</p><p><strong>Conclusion: </strong>PMP2 has low expression in EOCRC tissues and inhibits EOCRC metastasis, serving as a potential biomarker and therapeutic target for EOCRC treatment.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1610003"},"PeriodicalIF":3.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Current trends in targeted and non-targeted metabolomics in analytical toxicology.","authors":"Geraldine M Dowling, Markus R Meyer","doi":"10.3389/fmolb.2025.1614399","DOIUrl":"https://doi.org/10.3389/fmolb.2025.1614399","url":null,"abstract":"","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1614399"},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cold-induced biochemical changes in leaves of two commercial clones of <i>Eucalyptus</i>.","authors":"Patricia Basile, Federico Wallace, Cristina Olivaro, Nicolás De Palma, Omar Borsani, Arthur Fett-Neto","doi":"10.3389/fmolb.2025.1584132","DOIUrl":"10.3389/fmolb.2025.1584132","url":null,"abstract":"<p><strong>Introduction: </strong>Cold weather poses a significant challenge to the growth of crops and subtropical tree species like <i>Eucalyptus</i>. Exposure of plants to stressful temperatures generates changes in their physiology resulting from modifications in gene expression and extensive metabolic reorganization. A direct comparison of several biochemical changes under cold exposure of leaf tissues of <i>E. dunnii</i> and <i>E. grandis</i> clones was carried out.</p><p><strong>Methods: </strong>Leaf discs of <i>E. grandis</i> and <i>E. dunnii</i> were initially maintained for 24 h at 25°C and then 4 days at 6°C to induce cold stress. Sampling was conducted at 0 h (control condition), 2 and 4 days. Several biochemical parameters were measured, and an untargeted metabolomics approach based on ultra-high performance liquid chromatography (UHPLC) coupled to linear ion trap mass spectrometry fingerprinting was carried out.</p><p><strong>Results: </strong>Results indicated distinct cold tolerance strategies in <i>Eucalyptus grandis</i> and <i>Eucalyptus dunnii</i>. <i>Eucalyptus dunnii</i> initiated protective mechanism activation after a 2-day exposure period with the accumulation of sugars and phenolic compounds, whereas <i>E. grandis</i> did so after 4 days, accumulating proline and anthocyanins. PLS-DA based on UHPLC-MS fingerprints revealed a clear species-specific effect across the metabolome. This effect was greater than the differences between cold temperatures. Additionally, this methodology allowed the putative identification of 16 phenolic marker compounds with high discriminant potential to differentiate the cold response in these two species.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1584132"},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical metabolomics reveals potential diagnostic biomarkers in serum samples from patients with generalized ligamentous laxity.","authors":"Yu Zhang, Xiaochao Hu, Feng Chen, Tongtong Liu, Ping Cai, Shijia Liu, Luning Sun","doi":"10.3389/fmolb.2025.1554936","DOIUrl":"10.3389/fmolb.2025.1554936","url":null,"abstract":"<p><strong>Objectives: </strong>Discovering the potential metabolic alterations underlying generalized ligamentous laxity (GLL) is crucial for identifying new therapeutic targets and improving patient prognosis. Serum metabolites could mirror systemic and local alterations and help understand the metabolic features of GLL. The present work aimed to determine serum biomarkers for GLL diagnosis and to unveil metabolic pathways linked to GLL.</p><p><strong>Design: </strong>Prospective, observational cohort study.</p><p><strong>Methods: </strong>In this study, serum sample collection was conducted from 65 GLL and 35 healthy control (HC) cases. The obtained specimens were assessed by ultra-performance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS). Orthogonal partial least squares-discriminant analysis (OPLS-DA), random forest (RF), binary logistic regression (BLR) and receiver operating characteristic (ROC) analyses were applied to screen and validate biomarkers.</p><p><strong>Results: </strong>Totally 24 small-molecules were considered differentially expressed metabolites. Of these, hexadecanamide was found to be a specific biomarker for differential diagnosis of GLL, with an area under the ROC curve (AUC) of 0.907. Additionally, the α-linolenic acid and linoleic acid metabolism had the most substantial alteration among various pathways in GLL cases. The altered pathway of α-linolenic acid and linoleic acid metabolism affected bone mineral density and bone metabolism in GLL patients, leading to enhanced inflammation or fracture of the bone and joints. Joint inflammation and dislocation led to systemic ligament relaxation, which induced and aggravated musculoskeletal injury.</p><p><strong>Conclusion: </strong>Through identification of serum biomarkers and analysis of metabolic pathways, the current study provided novel insights into GLL pathogenesis.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1554936"},"PeriodicalIF":3.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis of flavor differences in pectoral muscles between Wuqin 10 duck and Cherry valley duck.","authors":"Ping Gong, Shengqiang Ye, Xing Chen, Lixia Wang, Yunguo Qian, Mingli Zhai, Yu Yang","doi":"10.3389/fmolb.2025.1558907","DOIUrl":"10.3389/fmolb.2025.1558907","url":null,"abstract":"<p><p>This study aimed to explore the impact of breeds on the lipid composition and flavor substances in duck pectoral muscles. In this study, 63-day-old Wuqin 10 ducks (WQ) and Cherry Valley ducks (CV) were selected as the research objects. The pectoral muscle tissues were collected. The composition of volatile flavor substances in pectoral muscles was detected by using headspace solid-phase microextraction combined with comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry. The lipid composition of pectoral muscles was determined by liquid chromatography-mass spectrometry, and the differentially expressed genes in duck pectoral muscles were determined by a high-throughput sequencer. Through integrated analysis, the main substances and main genes that affect the flavor of ducks were identified. The results showed that the detection results of flavor substances indicated that eight differential volatile compounds were screened out in the comparison between WQ ducks and CV ducks, namely, 4(1H)-Pyridinone, 2, 3-dihydro-1-methyl-, 1-Octen-3-ol, Hexanoic acid, trans-4-tert-butylcycloheptanol, 1-Octanol, 2, 4-Decadienal, (E, E)-, N, N'-Diacetylethylenediamine, Pyrimidine, 4-butyl-3, 4-dihydro-5-methyl-. The differential volatile compounds were mainly manifested in hydrocarbons, aldehydes and ketones, esters. A total of 86 differential lipids were screened out in the comparison between WQ ducks and CV ducks. Among them, the lipid differences between WQ and CV ducks were mainly in triglycerides (TG), phosphatidylcholines (PC) and glycerophospholipids (PE). A total of 500 differentially expressed genes were screened out in the comparison between WQ ducks and CV ducks. These differentially expressed genes were mainly involved in pathways such as glycerolipid metabolism, fatty acid degradation, and regulation of lipolysis in adipocytes. In summary, this study screened and determined that eight volatile organic compounds were the key aroma substances in the pectoral muscles of the two groups of ducks, and 86 differential lipids could distinguish the pectoral muscles of the two groups of ducks. Triglycerides (TG), phosphatidylcholines (PC) and glycerophospholipids (PE) played a crucial role in the formation of volatile compounds in pectoral muscles. The differentially expressed genes <i>TPP1</i> and <i>PNPLA2</i> might play an important role in the generation of flavor substances in duck pectoral muscle tissues.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1558907"},"PeriodicalIF":3.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flexible iron: disorder in the ironome brings order to protein structure and function.","authors":"Vladimir N Uversky, Gloria C Ferreira","doi":"10.3389/fmolb.2025.1537164","DOIUrl":"10.3389/fmolb.2025.1537164","url":null,"abstract":"<p><p>Iron is one of the most abundant elements on earth. The most recognized role of iron in living organisms is its incorporation in the heme-containing protein hemoglobin, which is abundantly found in the red blood cells that facilitate the oxygen transportation throughout the body. In fact, about 70% of organism's iron is found in hemoglobin. However, besides being essential for oxygen transport and serving as a crucial component of the molecular oxygen-carrying proteins hemoglobin and myoglobin, iron has a wide range of other biological functions. It is involved in numerous metabolic and regulatory processes and therefore is indispensable for almost all living organisms. Since iron enzymes are responsible for most of the redox metallo-catalysts, it is not surprising that 6.5% of all human enzymes are expected to be iron-dependent. Furthermore, iron-binding proteins account for about 2% of the entire proteome. The ironome encompasses heme-binding proteins, proteins binding individual iron ions, and iron-sulfur cluster-binding proteins. Although the structure-function relations of ordered iron-binding proteins are rather well understood, the prevalence and functionality of intrinsic disorder in iron-binding proteins remain to be evaluated. To fill this knowledge gap, in this study, we evaluate the intrinsic disorder of the human ironome. Our analysis revealed that the human ironome contains a noticeable level of functional intrinsic disorder, with most noticeable applications in protein-protein interactions, posttranslational modifications, and liquid-liquid phase separation.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1537164"},"PeriodicalIF":3.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An immune-related seven-gene signature for predicting lymph node metastasis in breast cancer.","authors":"Yun Hu, Lanqiao Sun, Jinhua Wang, Yuan Ji, Lili Feng","doi":"10.3389/fmolb.2025.1615524","DOIUrl":"10.3389/fmolb.2025.1615524","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) is the leading malignant tumors among females worldwide, which serves as a common chronic disease with several acute postoperative complications, including upper limb edema, hemorrhage, flap necrosis, effusion and so on. A majority of BC patients have lymph node metastasis, suffering from a poor prognosis. The immune system has been reported to participate in regulating BC lymph node metastasis. This study aimed to search for immune-related biomarkers for predicting BC lymph node metastasis.</p><p><strong>Methods: </strong>1057 BC patients were acquired from The Cancer Genome Atlas (TCGA) database as the training dataset while 327 BC patients were obtained from GSE20685 as the validation dataset. We get 2,175 immune genes from four immune-related gene sets. We divided BC patients into lymph node positive and negative groups to identify immune-related lymph node-associated differentially expressed genes (DEGs) for functional enrichment analysis and protein-protein interaction (PPI) network. In order to predict BC lymph node metastasis, we established an immune-related signature and assessed its predictive accuracy. In addition, we applied qRT-PCR to investigate signature gene expressions between normal breast epithelium cells and breast cancer cells.</p><p><strong>Results: </strong>We identified 336 immune-related lymph node-associated DEGs, which were enriched in leukocyte migration, immunoglobulin complex and receptor ligand activity among GO analysis and cytokine-cytokine receptor interaction among KEGG analysis. With the aim of predicting BC lymph node metastasis, we established a seven-gene immune-related signature, consisting of F2R, IKZF2, NAB1, RFX5, S100B, S1PR2 and VEGFA. The immune-related signature was proven to be an independent predictive factor for BC lymph node metastasis in both TCGA and GSE20685 databases. Compared with normal breast epithelium cells, RFX5, VEGFA were upregulated in breast cancer cells, IKZF2, NAB1, S100B were downregulated in breast cancer cells while F2R, S1PR2 showed no significance.</p><p><strong>Conclusion: </strong>We established a seven-gene immune-related signature for predicting lymph node metastasis in BC, which might provide a novel sight for BC diagnosis and treatment.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1615524"},"PeriodicalIF":3.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global and local effects in lipid-mediated interactions between peripheral and integral membrane proteins.","authors":"Tatiana K Rostovtseva, David P Hoogerheide, William A Milhizer, Sergey M Bezrukov","doi":"10.3389/fmolb.2025.1605772","DOIUrl":"10.3389/fmolb.2025.1605772","url":null,"abstract":"<p><p>Amphitropic proteins (APs) are a subfamily of water-soluble peripherally membrane-bound proteins that interact directly with the lipid membrane rather than with intrinsic membrane proteins and are therefore strongly influenced by membrane properties. When an AP interacts with a membrane containing an integral membrane protein, a ternary protein-lipid-protein system is created. Even in the absence of direct interactions between the amphitropic and integral proteins, the two proteins can affect each other by modifying lipid membrane properties, either at the global (i.e., whole-membrane) or local (i.e., confined to a small area around the bound or integrated protein) scale. These lipid-mediated protein-protein interactions are indirect and, therefore, difficult to elucidate; independent experimental data are required to report on each individual interaction to comprehend the whole system. Examples for which comprehensive data are available are remarkably rare. In this article, we describe how these difficulties could be surmounted by using the channel-forming integral membrane protein gramicidin A (grA) reconstituted in a planar lipid membrane and exposed to the amphitropic proteins dimeric tubulin or α-synuclein. Importantly, there are no known direct interactions between these APs and grA, thus revealing the role of the lipid membrane. Here, grA serves a dual role. First, grA reports on the global properties of the lipid membrane; grA results, combined with the well-understood tubulin-lipid interaction, yield a complete picture of the mutual effect of tubulin binding on the lipid membrane. Second, the presence of the grA conducting dimer alters the local membrane curvature and creates binding sites for tubulin in an otherwise inert membrane composition.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1605772"},"PeriodicalIF":3.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced prognostic and immunomodulatory effects of novel cuproptosis-related long noncoding RNAs in wilms tumor.","authors":"Yadong Li, Mingjie Li","doi":"10.3389/fmolb.2025.1566551","DOIUrl":"10.3389/fmolb.2025.1566551","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to develop a model for long non-coding RNA (lncRNA) associated with cuproptosis and assess the efficacy of immunotherapy and chemotherapy in children with Wilms tumor (WT) based on individualized risk scores.</p><p><strong>Methods: </strong>Data was obtained from the online database. Cox proportional hazards analysis and LASSO Cox regression were employed to generate cuproptosis-related lncRNA signatures. Patients were classified into high- and low-risk groups and clinical outcomes were further analysed. Tumor mutation burden and immunoinfiltration were calculated and potential immunotherapy response was evaluated. The sensitivity of immunotherapy and chemotherapy was ultimately analyzed based on individual risk scores associated with cuproptosis.</p><p><strong>Results: </strong>A eight cuproptosis-related lncRNAs signature was established and high-risk group showed a worse prognosis than the low-risk group. This model showed a good diagnostic performance. Low-risk group displayed an elevated tumor immune dysfunction and was more sensitive to 13 drugs.</p><p><strong>Conclusion: </strong>The current study introduces a novel approach for predicting clinical prognosis and determining the appropriate therapy for patients with WT.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1566551"},"PeriodicalIF":3.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12148909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A telomere-associated molecular landscape reveals immunological, microbial, and therapeutic heterogeneity in colorectal cancer.","authors":"Yinmeng Zhang, Jiawei Fan, Jiahui Zhao, He Zhu, Yan Xia, Hong Xu","doi":"10.3389/fmolb.2025.1615533","DOIUrl":"10.3389/fmolb.2025.1615533","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Colorectal cancer (CRC) ranks among the most prevalent malignancies of the gastrointestinal tract and remains a leading cause of cancer-related mortality worldwide. Although telomere biology has been increasingly implicated in immune modulation and tumor progression, its clinical significance in CRC remains poorly understood.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We developed a telomere score, termed TELscore, by integrating transcriptomic and intratumoral microbiome profiles from publicly available colorectal cancer (CRC) cohorts. To comprehensively characterize TELscore subgroups, we performed pathway enrichment analysis, tumor immune microenvironment (TIME) profiling, and microbiome niche assessment. Whole-slide histopathological images (WSIs) and immunohistochemical (IHC) staining were utilized to visualize immune features, including tertiary lymphoid structures (TLSs), across subgroups. Patients were stratified into high and low TELscore categories, and the predictive robustness was validated across multiple independent training and validation cohorts. Chemotherapeutic drug sensitivity was evaluated using pharmacogenomic data from the Genomics of Drug Sensitivity in Cancer (GDSC) database. Furthermore, the predictive capacity of TELscore for immunotherapy response was independently assessed in an external cohort. Finally, single-cell RNA sequencing (scRNA-seq) analysis was conducted to further dissect the cellular landscape and immunological heterogeneity within the TME.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;TELscore stratified patients into two biologically and clinically distinct subgroups. The high TELscore group, which exhibited significantly shorter DFS, showed marked enrichment of tumorigenic pathways such as EMT, along with a distinctly immunosuppressive TME. This was reflected by elevated ESTIMATE/TIDE scores and corroborated by CIBERSORT, which revealed increased infiltration of M0 macrophages and upregulation of immunosuppressive signatures. In contrast, the low TELscore group was enriched for cell cycle related pathways, including E2F targets and the G2/M checkpoint, and demonstrated higher infiltration of pro-inflammatory M1 macrophages. 16S rRNA sequencing further revealed a divergent intratumoral microbiome between subgroups, the high TELscore group harbored significantly greater relative abundance of Selenomonas and Lachnoclostridium, two pathogenic genera previously associated with colorectal tumorigenesis. Complementary histopathological assessment via WSI demonstrated a marked absence of intraTLSs in high TELscore tumors. From a therapeutic standpoint, high TELscore tumors exhibited reduced sensitivity to standard chemotherapeutic agents-including Fluorouracil, Irinotecan, Oxaliplatin, and Docetaxel-as reflected by elevated IC50 values. Conversely, these tumors demonstrated increased susceptibility to MAPK pathway inhibitors, such as Selumetinib and Trametinib. Notably, TELscore also served as a robust p","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1615533"},"PeriodicalIF":3.9,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12146184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}