Journal of Biomedical Science最新文献

{"title":"Decoding innate lymphoid cells and innate-like lymphocytes in asthma: pathways to mechanisms and therapies.","authors":"Christina Li-Ping Thio, Jheng-Syuan Shao, Chia-Hui Luo, Ya-Jen Chang","doi":"10.1186/s12929-025-01142-w","DOIUrl":"10.1186/s12929-025-01142-w","url":null,"abstract":"<p><p>Asthma is a chronic inflammatory lung disease driven by a complex interplay between innate and adaptive immune components. Among these, innate lymphoid cells (ILCs) and innate-like lymphocytes have emerged as crucial players in shaping the disease phenotype. Within the ILC family, group 2 ILCs (ILC2s), in particular, contribute significantly to type 2 inflammation through their rapid production of cytokines such as IL-5 and IL-13, promoting airway eosinophilia and airway hyperreactivity. On the other hand, innate-like lymphocytes such as invariant natural killer T (iNKT) cells can play either pathogenic or protective roles in asthma, depending on the stimuli and lung microenvironment. Regulatory mechanisms, including cytokine signaling, metabolic and dietary cues, and interactions with other immune cells, play critical roles in modulating their functions. In this review, we highlight current findings on the role of ILCs and innate-like lymphocytes in asthma development and pathogenesis. We also examine the underlying mechanisms regulating their function and their interplay with other immune cells. Finally, we explore current therapies targeting these cells and their effector cytokines for asthma management.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"48"},"PeriodicalIF":9.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009395","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":"Keratin 6A promotes skin inflammation through JAK1-STAT3 activation in keratinocytes.","authors":"Mengting Chen, Yaling Wang, Mei Wang, San Xu, Zixin Tan, Yisheng Cai, Xin Xiao, Ben Wang, Zhili Deng, Ji Li","doi":"10.1186/s12929-025-01143-9","DOIUrl":"https://doi.org/10.1186/s12929-025-01143-9","url":null,"abstract":"<p><strong>Background: </strong>Skin barrier dysfunction and immune activation are hallmarks of inflammatory skin diseases such as rosacea and psoriasis, suggesting shared pathogenic mechanisms. While barrier disruption may trigger or exacerbate skin inflammation, the precise underlying mechanisms remain unclear. Notably, epidermal barrier compromise leads to a marked increase in barrier alarmin expression. Among these, keratin 6A (KRT6A) plays a role in maintaining skin barrier integrity.</p><p><strong>Methods: </strong>We treated mouse skin and human keratinocytes, with and without KRT6A expression, with LL37/TNF-α and assessed the severity of inflammation. The specific mechanism by which KRT6A promotes skin inflammation was investigated using mass spectrometry and immunoprecipitation assays.</p><p><strong>Results: </strong>KRT6A expression was elevated in lesional skin from patients and mouse models of rosacea and psoriasis. In mice with LL37-induced rosacea-like and imiquimod (IMQ)-induced psoriasis-like skin inflammation, KRT6A knockdown alleviated inflammation, whereas KRT6A overexpression exacerbated inflammatory responses. Mechanistically, KRT6A activated signal transducer and activator of transcription 3 (STAT3) and enhanced proinflammatory cytokine expression in keratinocytes by reducing Janus kinase 1 (JAK1) ubiquitination. This occurred through inhibition of ring finger protein 41 (RNF41)-mediated JAK1 binding.</p><p><strong>Conclusions: </strong>Our findings indicate that KRT6A expression increases following epidermal barrier disruption and contributes to exacerbated skin inflammation in disease conditions. Targeting KRT6A may represent a novel therapeutic approach for inflammatory skin diseases associated with epidermal dysfunction.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"47"},"PeriodicalIF":9.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020378","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":"Accelerating antibody discovery and optimization with high-throughput experimentation and machine learning.","authors":"Ryo Matsunaga, Kouhei Tsumoto","doi":"10.1186/s12929-025-01141-x","DOIUrl":"https://doi.org/10.1186/s12929-025-01141-x","url":null,"abstract":"<p><p>The integration of high-throughput experimentation and machine learning is transforming data-driven antibody engineering, revolutionizing the discovery and optimization of antibody therapeutics. These approaches employ extensive datasets comprising antibody sequences, structures, and functional properties to train predictive models that enable rational design. This review highlights the significant advancements in data acquisition and feature extraction, emphasizing the necessity of capturing both sequence and structural information. We illustrate how machine learning models, including protein language models, are used not only to enhance affinity but also to optimize other crucial therapeutic properties, such as specificity, stability, viscosity, and manufacturability. Furthermore, we provide practical examples and case studies to demonstrate how the synergy between experimental and computational approaches accelerates antibody engineering. Finally, this review discusses the remaining challenges in fully realizing the potential of artificial intelligence (AI)-powered antibody discovery pipelines to expedite therapeutic development.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"46"},"PeriodicalIF":9.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970806","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":"Impact of large language model (ChatGPT) in healthcare: an umbrella review and evidence synthesis.","authors":"Usman Iqbal, Afifa Tanweer, Annisa Ristya Rahmanti, David Greenfield, Leon Tsung-Ju Lee, Yu-Chuan Jack Li","doi":"10.1186/s12929-025-01131-z","DOIUrl":"10.1186/s12929-025-01131-z","url":null,"abstract":"<p><strong>Background: </strong>The emergence of Artificial Intelligence (AI), particularly Chat Generative Pre-Trained Transformer (ChatGPT), a Large Language Model (LLM), in healthcare promises to reshape patient care, clinical decision-making, and medical education. This review aims to synthesise research findings to consolidate the implications of ChatGPT integration in healthcare and identify research gaps.</p><p><strong>Main body: </strong>The umbrella review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Cochrane Library, PubMed, Scopus, Web of Science, and Google Scholar were searched from inception until February 2024. Due to the heterogeneity of the included studies, no quantitative analysis was performed. Instead, information was extracted, summarised, synthesised, and presented in a narrative form. Two reviewers undertook title, abstract, and full text screening independently. The methodological quality and overall rating of the included reviews were assessed using the A Measurement Tool to Assess systematic Reviews (AMSTAR-2) checklist. The review examined 17 studies, comprising 15 systematic reviews and 2 meta-analyses, on ChatGPT in healthcare, revealing diverse focuses. The AMSTAR-2 assessment identified 5 moderate and 12 low-quality reviews, with deficiencies like study design justification and funding source reporting. The most reported theme that emerged was ChatGPT's use in disease diagnosis or clinical decision-making. While 82.4% of studies focused on its general usage, 17.6% explored unique topics like its role in medical examinations and conducting systematic reviews. Among these, 52.9% targeted general healthcare, with 41.2% focusing on specific domains like radiology, neurosurgery, gastroenterology, public health dentistry, and ophthalmology. ChatGPT's use for manuscript review or writing was mentioned in 17.6% of reviews. Promising applications include enhancing patient care and clinical decision-making, though ethical, legal, and accuracy concerns require cautious integration.</p><p><strong>Conclusion: </strong>We summarise the identified areas in reviews regarding ChatGPT's transformative impact in healthcare, highlighting patient care, decision-making, and medical education. Emphasising the importance of ethical regulations and the involvement of policymakers, we urge further investigation to ensure the reliability of ChatGPT and to promote trust in healthcare and research.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"45"},"PeriodicalIF":9.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967779","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":"Characterization of binding affinity changes of SARS-CoV-2 omicron variant peptides to population-specific HLA.","authors":"Che-Mai Chang, Chang-Jiun Wu, Maxim Shkurnikov, Chin-Lin Guo, Wan-Chen Huang, Alexander Tonevitsky, Wei-Chiao Chang","doi":"10.1186/s12929-025-01139-5","DOIUrl":"https://doi.org/10.1186/s12929-025-01139-5","url":null,"abstract":"<p><strong>Background: </strong>The evolution of SARS-CoV-2, particularly through new variants, presents significant global health challenges due to their potential for immune evasion and reduced vaccine effectiveness. This study aims to investigate the impact of mutations in the Spike protein of Omicron EG.5 and XBB.1.16 variants on the binding affinities of viral peptides to common human leukocyte antigen (HLA) class I and II alleles across Taiwanese, British, and Russian populations. Understanding these interactions is crucial for elucidating differences in immune responses and disease severity among diverse populations.</p><p><strong>Methods: </strong>We updated the T-CoV portal to incorporate and analyze EG.5 and XBB.1.16 variants. Binding affinities between mutated Spike protein peptides and HLA class I and II alleles were predicted and compared across the three populations. Statistical analyses, including chi-squared tests, were conducted to assess the significance of binding affinity differences across the three populations and between HLA classes.</p><p><strong>Results: </strong>Our findings revealed that mutations in the Spike protein had a more pronounced effect on HLA class II binding affinities than on HLA class I. While binding affinity profiles for HLA class I were largely consistent across populations, significant population-specific variations were observed for HLA class II alleles. Specifically, the British population exhibited lower proportions of tightly binding mutated peptides compared to the Taiwanese and Russian populations. Furthermore, substantial differences were identified in the binding affinity changes of mutated Spike peptides for HLA class II across Taiwanese, British, and Russian populations, as well as between the Omicron EG.5 and XBB.1.16 variants. Subsequent analyses revealed significant differences in the conservation and evolutionary trajectories of binding affinities between mutated Spike peptides and common HLA class II alleles, both between the EG.5 and XBB.1.16 variants and across the three populations for the XBB.1.16 variant.</p><p><strong>Conclusions: </strong>In summary, Spike protein mutations in SARS-CoV-2 variants significantly influence immune responses by altering HLA-peptide interactions, with pronounced population-specific effects on HLA class II alleles. These findings underscore the critical role of HLA class II diversity in shaping immune responses and susceptibility to COVID-19. Integrating population-specific HLA profiles into vaccine development and public health strategies is essential for improving interventions against evolving SARS-CoV-2 variants.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"44"},"PeriodicalIF":9.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987491","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":"Lacking ASIC1a in ASIC4-positive amygdala/bed nucleus of the stria terminalis (BNST) neurons reduces anxiety and innate fear in mice.","authors":"Ya-Chih Chien, Shing-Hong Lin, Cheng-Chang Lien, John N Wood, Chih-Cheng Chen","doi":"10.1186/s12929-025-01138-6","DOIUrl":"https://doi.org/10.1186/s12929-025-01138-6","url":null,"abstract":"<p><strong>Background: </strong>Anxiety is an innate response in the face of danger. When anxiety is overwhelming or persistent, it could be considered an anxiety disorder. Recent studies have shown that acid-sensing ion channels (ASICs) represent a novel class of promising targets for developing effective therapies for anxiety. Especially, ASIC1a and ASIC4 of the ASIC family are widely expressed in the central nervous system and their gene knockouts result in reducing or enhancing anxiety-like responses in mice respectively. However, how ASIC1a and ASIC4 modulate anxiety-associated responses remains unknown.</p><p><strong>Methods: </strong>Here we combined chemo-optogenetic, conditional knockout, gene rescue, molecular biology and biochemistry, and electrophysiological approaches to probe the roles of ASIC4 and ASIC4-expressing cells in anxiety-associated responses in mouse models.</p><p><strong>Results: </strong>Chemo-optogenetically activating ASIC4-positive cells induced fear and anxiety-like responses in mice. Also, mice lacking ASIC4 (Asic4^-/-) in the amygdala or the bed nucleus of the stria terminalis (BNST) exhibited anxiety-associated phenotypes. Conditional knockout of ASIC1a in ASIC4-positive cells reduced anxiety-associated behaviors. In situ hybridization analyses indicated that ASIC4 transcripts were highly co-localized with ASIC1a in the amygdala and BNST. We identified two glycosylation sites of ASIC4, Asn191 and Asn341, that were involved in interacting with ASIC1a and thus could modulate ASIC1a surface protein expression and channel activity. More importantly, viral vector-mediated gene transfer of wild-type ASIC4 but not Asn191 and Asn341 mutants in the amygdala or BNST rescued the anxiogenic phenotypes of Asic4^-/- mice.</p><p><strong>Conclusions: </strong>Together, these data suggest that ASIC4 plays an important role in fear and anxiety-related behaviors in mice by modulating ASIC1a activity in the amygdala and BNST.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"43"},"PeriodicalIF":9.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026108","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":"Correction: K27-linked RORγt ubiquitination by Nedd4 potentiates Th17-mediated autoimmunity.","authors":"Qiuming Zeng, Hui Guo, Na Tang, Pranav S Renavikar, Nitin J Karandikar, Amy E Lovett-Racke, Michael K Racke, Chengkai Yan, Rong Tang, Sushmita Sinha, Krishnendu Ghosh, Jeremy P Ryal, Song Ouyang, Min Chen, Foued Amari, Coppola Vincenzo, R Marshall Pope, Yalan Li, Huan Yang, Wallace Y Langdon, Jian Zhang","doi":"10.1186/s12929-025-01136-8","DOIUrl":"https://doi.org/10.1186/s12929-025-01136-8","url":null,"abstract":"","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"42"},"PeriodicalIF":9.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020096","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":"Multiple roles of branched-chain amino acid metabolism in tumour progression.","authors":"Lin Wang, Feng Shi, Ya Cao, Longlong Xie","doi":"10.1186/s12929-025-01132-y","DOIUrl":"https://doi.org/10.1186/s12929-025-01132-y","url":null,"abstract":"<p><p>Metabolic reprogramming enables tumour cells to sustain their continuous proliferation and adapt to the ever-changing microenvironment. Branched-chain amino acids (BCAAs) and their metabolites are involved in intracellular protein synthesis and catabolism, signal transduction, epigenetic modifications, and the maintenance of oxidative homeostasis. Alterations in BCAA metabolism can influence the progression of various tumours. However, how BCAA metabolism is dysregulated differs among depending on tumour type; for example, it can manifest as decreased BCAA metabolism leading to BCAA accumulation, or as enhanced BCAA uptake and increased catabolism. In this review, we describe the role of BCAA metabolism in the progression of different tumours. As well as discuss how BCAA metabolic reprogramming drives tumour therapy resistance and evasion of the antitumour immune response, and how these pro-cancer effects are achieved in part by activating the mTORC signalling pathway. In-depth investigations into the potential mechanisms by which BCAA metabolic reprogramming affects tumorigenesis and tumour progression can enhance our understanding of the relationship between metabolism and cancer and provide new strategies for cancer therapy.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"41"},"PeriodicalIF":9.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987496","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":"Molecular insights into the rescue mechanism of an HERG activator against severe LQT2 mutations.","authors":"Amit Kumawat, Elisa Tavazzani, Giovanni Lentini, Alessandro Trancuccio, Deni Kukavica, Amanda Oldani, Marco Denegri, Silvia G Priori, Carlo Camilloni","doi":"10.1186/s12929-025-01134-w","DOIUrl":"10.1186/s12929-025-01134-w","url":null,"abstract":"<p><strong>Background: </strong>Mutations in the HERG potassium channel are a major cause of long QT syndrome type 2 (LQT2), which can lead to sudden cardiac death. The HERG channel plays a critical role in the repolarization of the myocardial action potential, and loss-of-function mutations prolong cardiac repolarization.</p><p><strong>Methods: </strong>In this study, we investigated the efficacy and underlying molecular mechanism of ICA-105574, an HERG activator, in shortening the duration of cardiac repolarization in severe LQT2 variants. We characterized the efficacy of ICA-105574 in vivo, using an animal model to assess its ability to shorten the QT interval and in vitro, in cellular models mimicking severe HERG channel mutations (A561V, G628S, and L779P) to evaluate its impact in enhancing I_Kr current. Additionally, molecular dynamics simulations were used to investigate the molecular mechanism of ICA-105574 action.</p><p><strong>Results: </strong>In vivo, ICA-105574 significantly shortened the QT interval. LQT2 mutations drastically reduced I_Kr amplitude and suppressed tail currents in cellular models. ICA-105574 restored I_Kr in A561V and G628S. Finally, in silico data showed that ICA-105574 stabilizes a pattern of interactions similar to gain-of-function SQT1 mutations and can reverse the G628S modifications, through an allosteric network linking the binding site to the selectivity filter and the S5P turret helix, thereby restoring its K⁺ ion permeability.</p><p><strong>Conclusions: </strong>Our results support the development of HERG activators like ICA-105574 as promising pharmacological molecules against some severe LQT2 mutations and suggest that molecular dynamics simulations can be used to test the ability of molecules to modulate HERG function in silico, paving the way for the rational design of new HERG activators.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"40"},"PeriodicalIF":9.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803378","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":"Dynamic O-GlcNAcylation and phosphorylation attract and expel proteins from RNA polymerase II to regulate mRNA maturation.","authors":"Aishwarya Gondane, Harri M Itkonen","doi":"10.1186/s12929-025-01135-9","DOIUrl":"10.1186/s12929-025-01135-9","url":null,"abstract":"<p><strong>Background: </strong>Phosphorylation and O-GlcNAcylation are the key modifications regulating RNA Polymerase II (RNA Pol II)-driven transcription. Transcriptional kinases, cyclin-dependent kinase 7 (CDK7), CDK9 and CDK12 phosphorylate RNA Pol II, whereas O-GlcNAcylation is added by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA). Currently, no study has systematically evaluated how inhibiting each of these enzyme activities impacts the assembly of the appropriate protein complexes on the polymerase and the maturation of mRNA.</p><p><strong>Methods: </strong>Here, we systematically evaluate remodeling of RNA Pol II interactome and effects on the nascent mRNA maturation by using mass spectrometry and SLAM-seq, respectively. For validation, we rely predominantly on analysis of intronic polyadenylation (IPA) sites, mitochondrial flux assays (Seahorse), western blotting and patient data.</p><p><strong>Results: </strong>We show that OGT / OGA inhibition reciprocally affect protein recruitment to RNA Pol II, and appropriate O-GlcNAcylation levels are required for optimal function of the RNA Pol II complex. These paradoxical effects are explained through IPA, because despite being prematurely poly-adenylated, these mRNAs are scored as mature in SLAM-seq. Unlike previously proposed, we show that, similar to inhibition of CDK12, also targeting CDK9 stimulates transcription of short genes at the cost of long genes. However, our systematic proteomic- and IPA-analysis revealed that these effects are mediated by distinct molecular mechanisms: CDK9 inhibition leads to a failure of recruiting Integrator complex to RNA Pol II, and we then show that depletion of Integrator subunits phenocopy the gene length-dependent effects. In contrast, CDK12 inhibition triggers IPA. Finally, we show that dynamic O-GlcNAcylation predominantly interplays with CDK9: OGT inhibition augments CDK9 inhibitor effects on mRNA maturation due to defects in transcription elongation, while OGA inhibition rescues mRNA maturation failure caused by targeting CDK9, but induces IPA.</p><p><strong>Conclusion: </strong>We show that dynamic O-GlcNAcylation is a negative regulator of mRNA biosynthesis and propose that the addition and removal of the modification serve as quality control-steps to ascertain successful generation of mature mRNAs. Our work identifies unprecedented redundancy in the regulation of RNA Pol II, which increases resilience towards transcriptional stress, and also underscores the difficulty of targeting transcription to control cancer.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"39"},"PeriodicalIF":9.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788282","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}