American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Fetal Tracheal Occlusion Correlates with Normalized YAP Expression and Alveolar Epithelial Differentiation in Congenital Diaphragmatic Hernia.","authors":"Ophelia Aubert, Yuichiro Miyake, Gaurang M Amonkar, Olivia M Dinwoodie, Brian M Varisco, Mario Marotta, Caiqi Zhao, Richard Wagner, Ya-Wen Chen, Alessandra Moscatello, Caterina Tiozzo, Xaralabos Varelas, Paul H Lerou, Jose L Peiro, Richard Keijzer, Xingbin Ai","doi":"10.1165/rcmb.2024-0323OC","DOIUrl":"10.1165/rcmb.2024-0323OC","url":null,"abstract":"<p><p>Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm. Although the ensuing compression to the fetal lung causes lung hypoplasia, specific cellular phenotypes and developmental signaling defects in the alveolar epithelium in CDH are not fully understood. Employing lung samples from human CDH, a surgical lamb model, and a nitrofen rat model, we investigated whether lung compression impairs alveolar epithelial differentiation and Yes-associated protein (YAP)-mediated mechanosensing. We showed that CDH in humans and lambs caused defective alveolar epithelial differentiation manifested by more alveolar epithelial type II (ATII) cells, fewer ATI cells, and the emergence of cells coexpressing ATI and ATII markers. Associated with these alveolar epithelial defects, we found a decrease in the level and nuclear localization of YAP. Reduced YAP and abnormal distal lung development were evident as early as 21 weeks of gestation in human CDH. In addition, rat fetuses with CDH also showed diminished nuclear YAP and more abundant ATII cells. In contrast, the littermates without the hernia had no such alveolar phenotypes. Furthermore, fetal tracheal occlusion in the surgical lamb model of CDH fully normalized nuclear YAP and rescued alveolar epithelial defects in a gestational age-dependent manner. Taken together, our findings across species indicate that lung compression in CDH is sufficient to disrupt alveolar epithelial differentiation and impair YAP signaling. Tracheal occlusion can restore nuclear YAP and rescue the alveolar defects in CDH, depending on the timing and the duration of this prenatal surgical intervention.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"688-697"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KLF5 Shapes Developing Respiratory Tubules by Inhibiting Actin Asymmetry in Epithelial Cells.","authors":"Qing Li, Yong Liao, Junwei Zeng, Silu Hu, Chunjie Li, Jeffrey A Whitsett, Yi Zheng, Fengming Luo, Chang Xu, Taozhen He, Xinhua Lin, Huajing Wan","doi":"10.1165/rcmb.2024-0140OC","DOIUrl":"10.1165/rcmb.2024-0140OC","url":null,"abstract":"<p><p>Tubulogenesis depends on precise cell shape changes driven by asymmetric tension from the actin cytoskeleton. How actin asymmetry is dynamically controlled to coordinate epithelial cell shape changes required for respiratory tubulogenesis remains unknown. Herein, we unveiled a critical role for the transcription factor KLF5, regulating actin asymmetry, inducing epithelial cell shape changes by balancing RHOA and CDC42 GTPase activity via RICH2. Conditional <i>Klf5</i> expression or deletion in pulmonary epithelial cells affected apical actin organization and the positioning of apical polarity proteins in cell membranes, disrupting branching and sacculation of respiratory tubules during mouse lung morphogenesis. Increased KLF5 concentrations were observed in epithelial cells lining dilated tubules in lungs from patients with congenital pulmonary airway malformation. Together, our results demonstrate that dynamic regulation of apical actin organization by KLF5 is essential for respiratory tubulogenesis, providing a mechanistic framework for comprehending the morphogenesis of respiratory tubules.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"663-677"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Epigenetic Regulator CBX5 Promotes Fibroblast Metabolic Reprogramming and Inhibits Lung Fibrosis.","authors":"Jeongmin Hong, Tho X Pham, Jisu Lee, Ahmed A Raslan, Kristina Nicolas, Andrei Sharov, Jeffrey A Meridew, Raul A Urrutia, Gwen Lomberk, Steven K Huang, Giovanni Ligresti","doi":"10.1165/rcmb.2024-0255OC","DOIUrl":"10.1165/rcmb.2024-0255OC","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is characterized by the sustained activation of interstitial fibroblasts leading to excessive collagen deposition and progressive organ failure. Epigenetic and metabolic abnormalities have been shown to contribute to the persistent activated state of scar-forming fibroblasts. However, how epigenetic changes regulate fibroblast metabolic responses to promote fibroblast activation and progressive fibrosis remains largely unknown. Here, we show that the epigenetic regulator CBX5 (chromobox protein homolog 5) is critical to the transition of quiescent fibroblasts to activated collagen-producing fibroblasts in response to bleomycin-induced lung injury. Loss of mesenchymal CBX5 attenuated fibrosis development, and this effect was accompanied by the downregulation of pathogenic fibroblast genes, including <i>Cthrc1</i>, <i>Col1a1</i>, and <i>Spp1</i>, and by the upregulation of metabolic genes with antifibrotic activity such as <i>Ppara</i> and <i>Pparg</i>. Single-cell RNA sequencing and immunohistochemistry analyses revealed that CBX5 expression was enriched in pathogenic fibroblasts and fibroblastic foci of IPF lungs. Bulk RNA-sequencing analysis combined with metabolic assessments demonstrated that CBX5 silencing in IPF fibroblasts potently inhibited transforming growth factor-stimulated glycolysis while enhancing AMPK signaling and mitochondrial metabolism. Finally, interruption of the CBX5 pathway in IPF fibroblasts <i>in vitro</i> and in IPF lung explants <i>ex vivo</i> synergistically potentiated the activation of metformin-induced AMP-activated protein kinase activation and inhibited collagen secretion. Collectively, our findings identify CBX5 as an epigenetic regulator linking metabolic maladaptation to the persistent activated state of lung fibroblasts during IPF progression.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"627-642"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved Annotation of Asthma Gene Variants with Cell Type Deconvolution of Nasal and Lung Expression Quantitative Trait Loci.","authors":"Zaid W El-Husseini, Tatiana Karp, Andy Lan, Tessa E Gillett, Cancan Qi, Dmitry Khalenkow, Thys van der Molen, Chris Brightling, Alberto Papi, Klaus F Rabe, Salman Siddiqui, Dave Singh, Monica Kraft, Bianca Beghé, Philippe Joubert, Yohan Bossé, Don Sin, Ana H Cordero, Wim Timens, Corry-Anke Brandsma, Ke Hao, David C Nickle, Judith M Vonk, Martijn C Nawijn, Maarten van den Berge, Reinoud Gosens, Alen Faiz, Gerard H Koppelman","doi":"10.1165/rcmb.2024-0251MA","DOIUrl":"10.1165/rcmb.2024-0251MA","url":null,"abstract":"<p><p>Asthma is a genetically complex inflammatory airway disease associated with more than 200 SNPs. However, the functional effects of many asthma-associated SNPs in lung and airway epithelial samples are unknown. Here, we aimed to conduct expression quantitative trait loci (eQTL) analysis using a meta-analysis of nasal and lung samples. We hypothesize that incorporating cell type proportions of airway and lung samples enhances eQTL analysis outcomes. Nasal brush (<i>n</i> = 792) and lung tissue (<i>n</i> = 1,087) samples were investigated separately. Initially, a general eQTL analysis identified genetic variants associated with gene expression levels. Estimated cell type proportions were adjusted based on the Human Lung Cell Atlas. In addition, the presence of significant interaction effects between asthma-associated SNPs and each cell type proportion was explored and considered evidence for cell type-associated eQTL. In nasal brush and lung parenchyma samples, 44 and 116 asthma-associated SNPs were identified as eQTL. Adjusting for cell type proportions revealed eQTL for an additional 17 genes (e.g., <i>FCER1G</i>, <i>CD200R1</i>, and <i>GABBR2</i>) and 16 genes (e.g., <i>CYP2C8</i>, <i>SLC9A2</i>, and <i>SGCD</i>) in nose and lung, respectively. Moreover, we identified eQTL for nine SNPs annotated to genes such as <i>VASP</i>, <i>FOXA3</i>, and <i>PCDHB12</i> displayed significant interactions with cell type proportions of club, goblet, and alveolar macrophages. Our findings demonstrate increased power for identifying eQTL among asthma-associated SNPs by considering cell type proportion of the bulk RNA-sequencing data from nasal and lung tissues. Integration of cell type deconvolution and eQTL analysis enhances our understanding of asthma genetics and cellular mechanisms, uncovering potential therapeutic targets for personalized interventions.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"607-614"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary Fibrosis - Focusing on the Future: Aspen Lung Conference 2024 Summary.","authors":"Margaret A T Freeberg, Elizabeth F Redente, Apostolos Perelas, David Wh Riches, David A Schwartz, Patricia J Sime","doi":"10.1165/rcmb.2025-0137TR","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0137TR","url":null,"abstract":"<p><p>As medical and scientific communities, we have enjoyed exciting advances in our mechanistic understanding, diagnosis, and therapy of different types of lung fibrosis. However, much still needs to be learned as we are challenged to make earlier diagnoses, improve our ability to assess active disease and risks for disease progression, advance our understanding of the complex interplay of molecular, genetic and cellular crosstalk processes that underly the disease, and develop transformative therapeutic options to treat and prevent progressive lung fibrosis. Elucidating cellular phenotypes, function and signaling, and the interplay with matrices and aspects of mechanobiology has the potential to help us identify future targets and even reprogram or rebuild a damaged lung. Key to potential future opportunities will be understanding what aspects of fibrogenesis can be prevented or reversed. Bringing together a group of diverse and respected medical and scientific thought leaders, the 66th Annual Thomas L. Petty Aspen Lung Conference focused on \"Pulmonary Fibrosis-Focusing on the Future\". The conference topics included concepts and technologies for identification of early disease and progression using imaging and omics approaches, identifying and understanding cellular phenotypes and their function, and cross talk between different cell types, matrices, and matrix receptors. A central theme throughout was the integration of these scientific advances to advance novel targets for therapy including aspects of reprogramming and rebuilding a damaged lung. The conference provided an inclusive forum for discussion, debate and exchange of ideas with leaders and trainees in the field with the goal to help advance our shared mission of preventing and curing pulmonary fibrotic disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANT1 Deficiency Impairs Macrophage Metabolism and Migration, Protecting Against Emphysema in COPD.","authors":"Justin Sui, Aaron R Johnson, Theodore S Kapellos, Sruti Shiva, Corrine R Kliment","doi":"10.1165/rcmb.2024-0469OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0469OC","url":null,"abstract":"<p><p>Macrophage-mediated inflammation drives various lung diseases, including chronic obstructive pulmonary disease (COPD). COPD macrophages have dysfunctional mitochondrial metabolism and function which lead to a chronic inflammatory lung environment. However, the factors regulating this altered metabolism have not been elucidated. Adenine nucleotide translocase 1 (ANT1) is a mitochondrial ATP transporter critical to mitochondrial metabolism. We demonstrate that human alveolar macrophages from patients with moderate COPD (GOLD stage 2) have reduced ANT1 expression while macrophages from very severe COPD (GOLD stage 4) have elevated ANT1 compared to normal control subjects. <i>Ant1</i>-deficient mice were protected against cigarette smoke (CS)-induced emphysema with failure of recruited immune cells to migrate into alveoli. <i>Ant1</i>-null alveolar macrophages had reduced ATP production and mitochondrial respiration, upregulated fewer inflammatory pathways after CS and reduced migratory capacity. Conditional <i>Ant1</i> knockout in Cx3cr1-positive monocytes and adoptive transfer of <i>Ant1</i>-deficient bone marrow into CS-treated mice phenocopied the migratory defect in the lung. Our data indicate that ANT1 is a critical regulator of lung macrophage inflammatory signaling and CS-triggered cell migration in the lung, suggesting that metabolic modulation may be a promising therapeutic avenue for COPD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biased Orthosteric Agonism and Allosteric Modulation: Emerging Strategies for Developing New Class of β-Agonists for Obstructive Airway Diseases.","authors":"Sushrut D Shah, Deepak A Deshpande","doi":"10.1165/rcmb.2025-0144TR","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0144TR","url":null,"abstract":"<p><p>The obstructive lung diseases (OLDs) asthma and chronic obstructive pulmonary disease are characterized by bronchoconstriction and difficulty in breathing. Agonists of β2-adrenergic receptors (β-agonists) are the most commonly used bronchodilators. To enhance their clinical effectiveness, extensive attempts have been made to improve their receptor subtype selectivity and duration of action, resulting in the development of long- and ultra-long-acting β-agonists. While these drugs effectively alleviate OLD symptoms, concerns have arisen regarding their safety, reduced therapeutic benefits, and the potential for worsening asthma symptoms. These concerns have led to restrictions on β-agonist use. Recent advances in G protein-coupled receptor (GPCR) pharmacology and biochemistry have introduced new concepts in drug development, such as \"biased agonism\" and \"allosteric modulation.\" These advancements stem from a deeper understanding of the molecular interactions between β2-adrenergic receptors (β2AR) and various intracellular proteins (e.g., heterotrimeric G-proteins and β-arrestins), which induce a diverse array of functional changes in airway cells. Biased agonism and allosteric modulation offer new avenues for developing the next generation of β-agonists with improved pharmacological properties. This review explores the application of these concepts in developing new β2AR ligands, including orthosteric and allosteric ligands, that selectively enhance therapeutically beneficial Gs signaling while minimizing harmful β-arrestin-mediated effects in airway cells.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary Microvascular Endothelial Cells Support Alveolar Epithelial Growth via Bone Morphogenetic Protein 6 Secretion.","authors":"Luke van der Koog, Xinhui Wu, Dyan F Nugraha, Abilash Ravi, Justina C Wolters, Fien M Verhamme, Peter L Horvatovich, Ken R Bracke, Anne M van der Does, Pieter S Hiemstra, Jill R Johnson, Martin C Harmsen, Anika Nagelkerke, Reinoud Gosens","doi":"10.1165/rcmb.2024-0409OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0409OC","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and emphysema development, associated with enhanced tissue destruction and defective repair. Supporting cells in the alveolar niche play a crucial role in guiding the activation of alveolar epithelial progenitor cells during repair. Despite their close anatomical proximity, understanding of the supportive role of the pulmonary microvascular endothelium in adult alveolar epithelial repair remains limited. We hypothesized that factors secreted by pulmonary endothelial cells support alveolar epithelial cell growth. Here, we report that human pulmonary microvasculature endothelial cells (HPMECs) support murine and human alveolar organoid formation through paracrine signaling via the secretion of extracellular vesicles and soluble factors. Transcriptomic and proteomic analysis pinpointed HPMEC-derived bone morphogenetic protein 6 (BMP6) as a critical factor for alveolar organoid formation. BMP6 promoted alveolar epithelial cell growth, whereas function-blocking antibodies targeting BMP6 inhibited the beneficial effect of endothelial cells on murine alveolar organoid formation. Transcriptomic analysis revealed that BMP6 specifically enhances distal epithelial cell markers and increases Wnt signaling in epithelial progenitors. In contrast, BMP6 deficiency in mouse lungs was associated with reduced Wnt signaling and augmented oxidative stress signaling in murine lung tissue. Taken together, our findings highlight BMP6 as a key regulator of adult epithelial repair and suggest its potential as a therapeutic target for defective epithelial repair, particularly in individuals with early stages of COPD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>HERC6</i> and <i>KCNQ3</i> Expression Associated with Primary Ciliary Dyskinesia and Nasal Nitric Oxide Levels.","authors":"Minako Hijikata, Kozo Morimoto, Masashi Ito, Keiko Wakabayashi, Akiko Miyabayashi, Naoto Keicho","doi":"10.1165/rcmb.2025-0073LE","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0073LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDLBP Promotes Glycolysis and CD8⁺ T Cell Exhaustion in Lung Adenocarcinoma by Stabilizing GJB2 RNA.","authors":"Li Xu, Bin Zhou, Kaiqi Jin, Tao Ge, Ming Deng, Hongdou Ding, Xinnan Xu","doi":"10.1165/rcmb.2024-0648OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0648OC","url":null,"abstract":"<p><p>Gap junction protein beta 2 (GJB2) has been associated with glycolysis and immunosuppression in human tumors. This research aims to explore the roles of GJB2 in these aspects in the context of lung adenocarcinoma (LUAD). GJB2 expression in LUAD was analyzed using bioinformatics tools and verified in human LUAD cells. RNA binding proteins (RBPs) that target GJB2 were predicted using bioinformatics and verified using RNA immunoprecipitation assays. Gain- or loss-of-function assays of GJB2 and high-density lipoprotein binding protein (HDLBP) were performed in LUAD cells, investigating their roles in glycolysis. These LUAD cells underwent co-culture with activated CD8⁺ T cells to examine the effect of gene interference on the exhaustion and activity of T cells. A mouse model of allograft tumor was established for <i>in vivo</i> validation. GJB2 exhibited aberrantly heightened expression in LUAD cells. Further overexpression of GJB2 in cancer cells increased glucose uptake, lactate production, and extracellular acidification rate, augmented aggressive phenotype of cancer cells, and increased exhaustion of the co-cultured CD8⁺ T cells. HDLBP, an RBP that binds to GJB2 RNA, was found to be highly expressed in LUAD as well, which enhanced GJB2 expression by stabilizing the GJB2 mRNA. Overexpression of HDLBP similarly rendered glycolysis and T cell inactivity, with these effects negated by GJB2 knockdown. Parallelly, GJB2 silencing in mouse 3LL cells suppressed tumorigenesis, glycolysis, and T cell exhaustion in mice promoted by HDLBP. This research suggests that HDLBP-mediated GJB2 RNA stabilization augments glycolysis and CD8⁺ T cell exhaustion in LUAD progression.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}