Biology Direct最新文献

{"title":"Functional and structural characterization of the human indolethylamine N-methyltransferase through fluorometric, thermal and computational docking analyses.","authors":"Matteo Ardini, Francesco Angelucci, Francesca Rea, Luca Paluzzi, Federica Gabriele, Marta Palerma, Luana Di Leandro, Rodolfo Ippoliti, Giuseppina Pitari","doi":"10.1186/s13062-025-00632-z","DOIUrl":"https://doi.org/10.1186/s13062-025-00632-z","url":null,"abstract":"<p><strong>Background: </strong>The \"psychedelic renaissance\" is sparking growing interest in clinical research, along with a rise in clinical trials. Substances such as 3,4-methylenedioxymethamphetamine (MDMA), psilocybin and N,N-dimethyltryptamine (DMT) are involved. The focus of this paper is on indolethylamine N-methyltransferase (INMT), a crucial enzyme in the biosynthesis of key compounds, including DMT, which meets science, medicine and spirituality. The presence of DMT in animals and plants raises many questions about its biological role. Meanwhile, the distribution of INMT in various organs and its involvement in diseases like cancer and mental disorders also fuel investigations worldwide. However, INMT remains largely unexplored, particularly its enzymatic mechanism and structural properties, leaving a significant gap in potential applications.</p><p><strong>Results: </strong>This study examines for the first time the catalytic activity of the human INMT (hINMT) using a simple fluorometric steady-state assay employing the substrate quinoline. The findings are supported by thermal shift and docking analyses, providing valuable information about optimal chemical conditions and potential binding sites for substrates. The thermal shift assays indicate that recombinant hINMT is unstable and requires acidic or near-neutral pH and low salt levels. These experiments also allow for the estimation of dissociation constants for its natural coenzymes SAM and SAH, helping to determine the appropriate setup for the fluorometric assays and calculate kinetic constants, which are comparable to other methyltransferases. The docking indicates that quinoline occupies the same site as the natural substrate tryptamine, further validating the fluorometric approach.</p><p><strong>Conclusions: </strong>The paper provides a foundation for thoroughly studying hINMT under consistent conditions, which is crucial for obtaining reliable kinetic data and maintaining molecular stability for future structural analysis. This represents a valid alternative over previous endpoint radioactive-based and chromatography-mass spectrometry assays, which can provide only apparent steady-state parameters. Given the polymorphisms observed in hINMT and their potential association with psychiatric disorders, e.g., schizophrenia, and cancer, this strategy could serve as an invaluable tool for understanding the structure-function relationship of enzyme mutants and their role in diseases. Furthermore, these findings for the first time provide insights into the interaction modalities of hINMT with its substrates and lay the groundwork for inhibition experiments aimed at practical applications.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"50"},"PeriodicalIF":5.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of PD-L1 expression by Wnt pathway inhibition to enhance PD-1 blockade efficacy in hepatocellular carcinoma.","authors":"Yu-Yun Shao, Han-Yu Wang, Hung-Wei Hsu, Rita Robin Wo, Ann-Lii Cheng, Chih-Hung Hsu","doi":"10.1186/s13062-025-00645-8","DOIUrl":"https://doi.org/10.1186/s13062-025-00645-8","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy targeting the programmed death-ligand 1 (PD-L1) pathway is a standard treatment for advanced hepatocellular carcinoma (HCC). The Wnt signaling pathway, often upregulated in HCC, contributes to an immunosuppressive tumor microenvironment. This study investigated the impact of Wnt pathway inhibition on PD-L1 expression in HCC and evaluated the potential therapeutic benefit of combining Wnt pathway inhibition with PD-L1 blockade.</p><p><strong>Methods: </strong>The effects of Wnt pathway inhibitors XAV939 and IWR-1 on PD-L1 expression were examined in human HCC cell lines HuH7 and Hep3B. Beta-catenin overexpression and knockdown experiments confirmed these findings. For in vivo efficacy, the BNL 1ME A.7R.1 mouse HCC cell line was orthotopically implanted in mice, which were subsequently treated with XAV939, anti-PD-L1 antibodies, or both.</p><p><strong>Results: </strong>Wnt pathway inhibitors XAV939 and IWR-1 significantly reduced PD-L1 protein expression in a dose-dependent manner in HuH7 and Hep3B cells, without affecting mRNA levels. CTNNB1 knockdown produced similar results, and beta-catenin overexpression reversed the effects of Wnt pathway inhibitors on PD-L1 expression. Wnt pathway inhibition did not promote PD-L1 protein degradation but instead increased the level of unphosphorylated 4EBP1, which could prevent the translation function of eIF-4E. In vivo, mice treated with a combination of XAV939 and an anti-PD-L1 antibody had significantly smaller tumors compared to those treated with either agent alone. The combination treatment also enhanced multiple immune-related pathways in harvested tumors.</p><p><strong>Conclusion: </strong>Inhibition of the Wnt pathway reduced PD-L1 expression in HCC cells and enhanced the efficacy of PD-L1 blockade, supporting its potential as HCC treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"49"},"PeriodicalIF":5.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ELK4 induced upregulation of HOMER3 promotes the proliferation and metastasis in glioma via Wnt/β-catenin/EMT signaling pathway.","authors":"Furong Wang, Hui Zhou, Yu Tian, Xiaoling Wang, Youcai Huang, Yanyang Tu, Liwen Li, Haining Zhen","doi":"10.1186/s13062-025-00643-w","DOIUrl":"https://doi.org/10.1186/s13062-025-00643-w","url":null,"abstract":"<p><p>Glioma is an aggressive brain tumor characterized by its high invasiveness, which complicates prognosis and contributes to patient resistance against various treatment options. The HOMER family, consisting of HOMER1, HOMER2, and HOMER3, has been implicated in various cancers, yet their specific roles in glioma remain inadequately understood. This study conducted a comprehensive pan-cancer analysis to evaluate the expression profiles of HOMER family members across different tumor types, utilizing data from public databases such as TCGA and GTEx. Our findings indicate significant dysregulation of HOMER1, HOMER2, and HOMER3 in multiple cancers, with HOMER3 emerging as a potential prognostic biomarker, particularly for lower-grade glioma. Elevated expression levels of HOMER3 were associated with shorter overall survival and disease-specific survival in LGG patients, supported by Cox regression analysis that confirmed HOMER3 as an independent prognostic factor. Furthermore, HOMER3 expression correlated positively with advanced clinical stages and key tumor markers. To elucidate the mechanisms behind HOMER3 dysregulation, we identified ELK4 as a transcription factor that binds to the HOMER3 promoter, promoting its expression in glioma cells. Functional assays demonstrated that silencing HOMER3 significantly reduced glioma cell proliferation and metastatic potential in vitro and in vivo, highlighting its oncogenic role. Additionally, HOMER3 was found to influence the Wnt/β-catenin/EMT signaling pathway, with knockdown resulting in altered expression of critical EMT markers. Collectively, our results indicated that HOMER3 plays a crucial role in glioma progression and metastasis, underscoring its potential as a therapeutic target and prognostic biomarker in glioma management.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"48"},"PeriodicalIF":5.7,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deubiquitination of DNM1L by USP3 triggers the development and metastasis of gallbladder carcinoma.","authors":"Ruopeng Liang, Xiaoxue Zhang, Shitao Wu, Jing Liu, Yunpeng Zhai, Chaojie Lin, Zhenya Wang, Yi Zhang, Hao Chen, Rongtao Zhu","doi":"10.1186/s13062-025-00637-8","DOIUrl":"10.1186/s13062-025-00637-8","url":null,"abstract":"<p><strong>Background: </strong>Patients diagnosed with gallbladder carcinoma (GBC) accompanied by hepatic metastasis exhibit unfavorable prognoses generally. Mitochondrial dysfunction promotes cellular transformation and cancer cell survival implicating its importance in cancer development. Previous studies have indicated that dynamin 1 like (DNM1L) is a key mediator of mitochondrial fission. However, whether DNM1L regulates mitochondrial homeostasis in GBC remains unknown.</p><p><strong>Methods: </strong>The morphological changes of mitochondria were investigated by transmission electron microscopy and mitoTracker red staining. Co-immunoprecipitation assay was performed to detect the interaction of ubiquitin-specific protease-3 (USP3) and DNM1L. The cell-derived xenograft and liver metastasis tumor models were established to validate the function of DNM1L in vivo. The metabolomics data from transcriptomics/metabolomics were analyzed to identify the differentially expressed genes/metabolites of DNM1L in GBC.</p><p><strong>Results: </strong>DNM1L exhibited a marked upregulation in clinical GBC tissues compared to the adjacent tissues, and it promoted proliferation, invasiveness, and migration capability of GBC cells by inducing mitochondrial dysfunction. Mice subcutaneously injected with DNM1L overexpression cells exhibited elevated intrahepatic metastatic nodules within their livers. USP3, a deubiquitinating enzyme, was demonstrated to directly interact with DNM1L and it specifically cleaved the K48-linked polyubiquitin chains to deubiquitinate and stabilize DNM1L. By integrating two omics, we found several altered pathways and speculated that DNM1L disturbed DNA synthesis and glycine, serine, threonine, and pyrimidine metabolism pathways.</p><p><strong>Conclusion: </strong>Our findings suggest that DNM1L is a promising clinical target for GBC treatment and that focusing on DNM1L may provide new insights into GBC strategy.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"47"},"PeriodicalIF":5.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAP1: a novel extracellular vesicle marker linked to endothelial senescence in atherosclerosis.","authors":"Ignacio Hernandez, Laura Botana, Javier Diez-Mata, Laura Tesoro, Beatriz Jimenez-Guirado, Claudia Gonzalez-Cucharero, Nunzio Alcharani, Jose Luis Zamorano, Marta Saura, Carlos Zaragoza","doi":"10.1186/s13062-025-00646-7","DOIUrl":"10.1186/s13062-025-00646-7","url":null,"abstract":"<p><p>Endothelial senescence (ES) contributes to aging-related disorders and triggers a senescence-associated secretory-pattern (SASP), releasing Extracellular Vesicles (EVs), potentially impacting atherosclerosis. We used EVs from young (8 weeks) and aged (24 months) ApoE-knockout mice to detect ES in human aortic (HAEC) and coronary (CAEC) endothelial cells. Age-related atherosclerosis was confirmed by increased atheroma plaque formation in aged compared to young ApoE-knockout mice fed a high-fat diet, and the contribution of EVs from aged ApoE-knockout mice on ES was evidenced by a replicative senescence assay in cultured HAEC and CAEC, starting with the promotion of ES. A proteomic analysis depicted the recently PCSK9-associated CAP1 protein as a cargo component in EVs from aged animals and highly expressed in mouse and human endarterectomy plaques. Gene silencing of CAP1 inhibited HAEC and CAEC ES while overexpressing CAP1 in these cells restored the senescent-phenotype. The in vivo contribution of CAP1 was assessed by injecting CAP1-containing EVs isolated from aged ApoE-knockout mice into wild-type (WT) mice fed either a regular or high-fat diet. Compared to the EVs from young mice, the CAP1-containing EVs led to a pronounced ES along with the formation of intraluminal atheroma plaques. Similarly, young ApoE-knockout mice developed thickened and calcified atheroma plaques, along with increased ß-Gal-positive aortic staining when injected with EVs isolated from aged ApoE-knockout mice, like the atheroma plaques observed in aged ApoE-knockout animals. In conclusion, early molecular targets of ES may contribute to better management of atherosclerosis, in which here we unveiled CAP1 as a new molecular target.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"46"},"PeriodicalIF":5.7,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale bulk and single-cell RNA sequencing combined with machine learning reveals glioblastoma-associated neutrophil heterogeneity and establishes a VEGFA⁺ neutrophil prognostic model.","authors":"Yufan Yang, Ziyuan Liu, Zhongliang Wang, Xiang Fu, Zhiyong Li, Jianlong Li, Zhongyuan Xu, Bohong Cen","doi":"10.1186/s13062-025-00640-z","DOIUrl":"10.1186/s13062-025-00640-z","url":null,"abstract":"<p><strong>Background: </strong>Neutrophils play a key role in the tumor microenvironment (TME); however, their functions in glioblastoma (GBM) are overlooked and insufficiently studied. A detailed analysis of GBM-associated neutrophil (GBMAN) subpopulations may offer new insights and opportunities for GBM immunotherapy.</p><p><strong>Methods: </strong>We analyzed single-cell RNA sequencing (scRNA-seq) data from 127 isocitrate dehydrogenase (IDH) wild-type GBM samples to characterize the GBMAN subgroups, emphasizing developmental trajectories, cellular communication, and transcriptional networks. We implemented 117 machine learning combinations to develop a novel risk model and compared its performance to existing glioma models. Furthermore, we assessed the biological and molecular features of the GBMAN subgroups in patients.</p><p><strong>Results: </strong>From integrated large-scale scRNA-seq data (498,747 cells), we identified 5,032 neutrophils and classified them into four distinct subtypes. VEGFA⁺GBMAN exhibited reduced inflammatory response characteristics and a tendency to interact with stromal cells. Furthermore, these subpopulations exhibited significant differences in transcriptional regulation. We also developed a risk model termed the \"VEGFA⁺neutrophil-related signature\" (VNRS) using machine learning methods. The VNRS model showed higher accuracy than previously published risk models and was an independent prognostic factor. Additionally, we observed significant differences in immunotherapy responses, TME interactions, and chemotherapy efficacy between high-risk and low-risk VNRS score groups.</p><p><strong>Conclusion: </strong>Our study highlights the critical role of neutrophils in the TME of GBM, allowing for a better understanding of the composition and characteristics of GBMAN. The developed VNRS model serves as an effective tool for evaluating the risk and guiding clinical treatment strategies for GBM.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"45"},"PeriodicalIF":5.7,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Topological determinants in protein folding dynamics: a comparative analysis of metamorphic proteins.","authors":"Julian Toso, Valeria Pennacchietti, Mariana Di Felice, Eduarda S Ventura, Angelo Toto, Stefano Gianni","doi":"10.1186/s13062-025-00642-x","DOIUrl":"10.1186/s13062-025-00642-x","url":null,"abstract":"<p><p>Protein folding remains a fundamental challenge in molecular biology, particularly in understanding how polypeptide chains transition from denatured states to their functional conformations. Here we analyze the folding mechanisms of the engineered metamorphic proteins B4 and Sb3, which share highly similar sequences but adopt distinct topologies. Kinetic analyses revealed that B4 follows a two-state folding mechanism, whereas Sb3 involves the formation of an intermediate species. We further explore the role of topology in folding commitment using the metamorphic mutant Sb4, which can populate both conformations. By analyzing folding and unfolding behaviors under varying experimental conditions, our findings suggest that topology dictates folding mechanisms at an early stage. These results demonstrate that folding landscapes are primarily shaped by final native structures rather than sequence composition.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"44"},"PeriodicalIF":5.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GAMT facilitates tumor progression via inhibiting p53 in clear cell renal cell carcinoma.","authors":"Bin Zheng, Kan Liu, Ji Feng, Qing Ouyang, Tongyu Jia, Yaohui Wang, Shuo Tian, Xinran Chen, Tianwei Cai, Lequan Wen, Xu Zhang, Xiubin Li, Xin Ma","doi":"10.1186/s13062-025-00641-y","DOIUrl":"10.1186/s13062-025-00641-y","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC. Even though the targeted drugs for the treatment of ccRCC have a certain therapeutic effect, due to the problem of drug resistance, the search for new targets for targeted therapy of ccRCC remains urgent. GAMT is an enzyme involved in creatine metabolism. However, the precise biological roles and molecular mechanisms of GAMT in ccRCC are not fully understood.</p><p><strong>Results: </strong>Here, we found that GAMT was upregulated in ccRCC cells and tissues and associated with poor prognosis. Further, GAMT has pro-oncogenic abilities in promoting ccRCC development and progression. Intriguingly, GAMT exerted biological functions independent of its role in catalyzing creatine synthesis. Mechanistically, GAMT overexpression contributes to the development and progression of ccRCC by inhibiting tumor suppressor p53. Finally, we identified fisetin as a novel GAMT inhibitor and validated its role in suppressing ccRCC progression and sensitizing ccRCC cells to targeted drug axitinib via in vivo and in vitro assays.</p><p><strong>Conclusions: </strong>This study reveals that GAMT has pro-oncogenic abilities in promoting ccRCC development and progression. GAMT exerted its non-enzymatic functions possibly by regulating the expression of p53. Fisetin, the novel GAMT inhibitor identified herein, may serve as a new antitumor drug for ccRCC treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"43"},"PeriodicalIF":5.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the mechanisms of PANoptosis in osteoarthritis and the therapeutic potential of andrographolide through bioinformatics and single-cell analysis.","authors":"Daqian Zhou, Yingjin Luo, Fengjiang Li, Tao Liu, Yongliang Mei, Feilong Li, Xianghan Hou, Zhijiang Fu, Zongchao Liu","doi":"10.1186/s13062-025-00629-8","DOIUrl":"10.1186/s13062-025-00629-8","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is a degenerative joint disease marked by the breakdown of cartilage, where apoptosis plays a key role. Although apoptosis-related genes in OA have been studied, a detailed analysis of PANoptosis-related genes and the search for therapeutic drugs remains limited.</p><p><strong>Methods: </strong>We performed a bioinformatics analysis combined with single-cell RNA sequencing to examine PANoptosis-related gene expression in OA cartilage. Key PANoptosis genes and critical cell populations involved in OA progression were identified. Drug prediction led to the selection of Andrographolide (AG), whose effects were validated through molecular docking, Western blotting, and qRT-PCR in chondrocyte models.</p><p><strong>Results: </strong>Several PANoptosis-related genes, including CASP8, TLR3, CASP1, and IL18, were significantly differentially expressed in OA. These genes are linked to processes such as apoptosis, pyroptosis, and the inflammasome complex. Pathway analysis revealed necroptosis, Toll-like receptor, and apoptosis signaling pathways as important in OA pathology. Single-cell analysis identified HomC, EC, and preHTC as key cell populations. AG was predicted to regulate PANoptosis genes, which was confirmed experimentally, demonstrating AG's potential to modulate key genes involved in cartilage degeneration.</p><p><strong>Conclusion: </strong>This study highlights PANoptosis-related genes in OA and identifies Andrographolide as a promising therapeutic drug, offering new insights into OA treatment strategies.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"41"},"PeriodicalIF":5.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic single-cell transcriptomic reveals the cellular heterogeneity and a novel fibroblast subpopulation in laryngotracheal stenosis.","authors":"Ziwei Liao, Yangyang Zheng, Mingjun Zhang, Xiaoyan Li, Jing Wang, Hongming Xu","doi":"10.1186/s13062-025-00639-6","DOIUrl":"10.1186/s13062-025-00639-6","url":null,"abstract":"<p><strong>Background: </strong>Laryngotracheal stenosis (LTS), a pathological narrowing of the upper airway caused by excessive extracellular matrix (ECM) deposition, often leads to dyspnea and even respiratory failure. However, systematic studies addressing the specific subpopulations and their contribution to LTS development still remain underexplored.</p><p><strong>Results: </strong>We collected laryngotracheal tissue at multiple time points of LTS rat model, established by injuring their laryngotracheal lining, and performed dynamic single-cell RNA sequencing (scRNA-seq) to elucidate the transcriptomic atlas of LTS development. The results showed, from the inflammatory state to the repair/fibrotic state, infiltration of immune cells such as monocyte macrophages decreased and fibroblast increased. We delineated the markers and functional status of different fibroblasts subsets and identified that fibrotic fibroblasts may originate from multiple fibroblast subpopulations, including a new subpopulation characterized by the expression of chondrogenic markers such as Ucma and Col2a1, we designated this subcluster as chondrocyte injury-related fibroblasts (CIRF). Furthermore, we categorized monocytes/macrophages into several subtypes and identified that SPP1 high macrophages represented the largest macrophage subpopulation in LTS, providing evidence to clarify the importance of SPP1 macrophages in fibrosis disease. Our findings also revealed the interactions among these cells to explore the molecular mechanism associated with LTS pathogenesis.</p><p><strong>Conclusions: </strong>Our study, for the first time, conducted dynamic scRNA-seq on LTS, revealing the cellular heterogeneity and providing a valuable resource for exploring the intricate molecular landscape of LTS. We propose CIRF may represent a tissue-specific fibroblast lineage in LTS and potentially originate from cells in the perichondrium of the trachea and transform into fibrotic fibroblasts. Integration of our study with those of other respiratory fibrotic diseases will allow for a comprehensive understanding of airway remodeling in respiratory diseases and exploring potential new therapeutic targets for their treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"40"},"PeriodicalIF":5.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}