Cellular and Molecular Life Sciences最新文献

{"title":"Rare biochemical & genetic conditions: clues for broader mechanistic insights.","authors":"Alexios-Fotios A Mentis, Maria Dalamaga","doi":"10.1007/s00018-025-05652-6","DOIUrl":"https://doi.org/10.1007/s00018-025-05652-6","url":null,"abstract":"<p><p>Rare disorders often represent a molecular deviation from hi-fidelity genomic integrity networks and are often perceived as too difficult or unimportant for further mechanistic studies. Here, we synthesize evidence demonstrating how valuable knowledge of biochemical pathways related to rare disorders can be for biomedicine. To this end, we describe several rare congenital lipid, protein, organic acid, and glycan metabolism disorders and discuss how rare phenotypes (such as \"extreme responders\") and case reports (such as the lenalidomide cases) have provided clues for drug discovery or repurposing. We also discuss how rare disorders such as Gaucher disease and ultra-rare genetic syndromes can provide insights into cancer and mTOR-driven metabolism, respectively. Our discussion highlights the continued value of biochemical pathways and studies in understanding human pathophysiology and drug discovery even in the genomics era.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"156"},"PeriodicalIF":6.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11985829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977195","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":"Epigenetic modulation of RIPK3 by transglutaminase 2-dependent serotonylation of H3K4me3 affects necroptosis.","authors":"Alessio Vecchio, Fiorella Colasuonno, Luca Occhigrossi, Consuelo Pitolli, Veronica Bellanca, Fabio Ciccarone, Manuela D'Eletto, Federica Di Sano, Vittoria Pagliarini, Claudio Sette, Mauro Piacentini, Federica Rossin","doi":"10.1007/s00018-025-05640-w","DOIUrl":"https://doi.org/10.1007/s00018-025-05640-w","url":null,"abstract":"<p><p>The receptor interacting protein kinase 3 (RIPK3) is the main player in the activation of necroptosis, a pro-inflammatory regulated cell death modality induced by many different stimuli. RIPK3 is epigenetically regulated by DNA methylation and can be expressed when its promoter is associated with H3K4me3 histone. In this study, we show that Transglutaminase 2 protein (TG2) is necessary to induce necroptosis pathway allowing the expression of Ripk3 gene. Indeed, cells lacking TG2 show a strong downregulation of Ripk3 gene and are resistant to necroptotic stimuli. TG2 is known to promote the serotonylation of H3K4me3 histone (H3K4me3Q5ser) regulating in this way the target gene expression. Interestingly, we find that TG2 interacts with both histones H3K4me3 and H3K4me3Q5ser and these post-translational modifications are associated with the Ripk3 promoter only in presence of TG2. In addition, the absence of the H3K4me3Q5ser, in cells lacking TG2, is correlated with Ripk3 gene methylation. Altogether, these results indicate that RIPK3 expression requires TG2 mediated serotonylation of H3K4me3 to prevent Ripk3 promoter methylation, thus favouring its expression and necroptosis induction.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"154"},"PeriodicalIF":6.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11985880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987448","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":"Portal venous circulating tumor cells as a biomarker for relapse prediction in resected pancreatic cancer.","authors":"Dannel Yeo, Doruk Seyfi, Althea Bastian, Heidi Strauss, Anna Leach, Vera Klemm, Anthony Pirrello, Kevin Spring, Payal Saxena, Sara Wahlroos, Sarah Sutherland, Peter Grimison, Jin-Soo Park, Charbel Sandroussi, John Ej Rasko","doi":"10.1007/s00018-025-05669-x","DOIUrl":"https://doi.org/10.1007/s00018-025-05669-x","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer is an aggressive disease with poor prognosis. The only potentially curative treatment option is surgical resection, however recurrence is common. Biomarkers to detect minimal residual disease, assist with risk stratification, relapse and real time monitoring, are required. Circulating tumor cells (CTCs) are a promising liquid biopsy biomarker for solid tumors. However, their role in monitoring minimal residual disease in pancreatic cancer remains to be determined. Our study aimed to investigate whether detection and enumeration of CTCs could predict recurrence and provide monitoring of disease status.</p><p><strong>Method: </strong>Participants planned for Whipple procedure or partial pancreatectomy were enrolled in this prospective pilot study. Intraoperatively, 7.5 mL of portal and peripheral venous blood were collected, and peripheral venous blood was also collected post-surgery. CTC identification and enumeration were performed using the AccuCyte-CyteFinder platform and CellSieve microfiltration.</p><p><strong>Results: </strong>Of 29 participants, 20 were confirmed to have epithelial cancer by histopathology, where 15 had pancreatic ductal adenocarcinoma. In those with epithelial cancer, CTCs were detected intraoperatively in 75% of portal venous blood samples, in contrast to 40% detected in peripheral venous blood (median: 6 and 0 per 7.5mL respectively). Only portal venous CTC detection was predictive of pancreatic ductal adenocarcinoma relapse. The positive (> 5) portal venous CTC group had a 6.67 times higher risk of recurring (odds ratio = 20.43, sensitivity = 1.00, specificity = 0.625). Detection of peripheral venous CTCs post-surgery was also correlated with relapse in a small subset of patients.</p><p><strong>Conclusions: </strong>If validated, CTCs may provide a prognostic and monitoring biomarker in patients with pancreatic cancer undergoing surgery.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"155"},"PeriodicalIF":6.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11985722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974760","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":"Complementary approaches define the metabolic features that accompany Richter syndrome transformation.","authors":"Giulia Omezzolli, Andrea Iannello, Francesco E Vallone, Lorenzo Brandimarte, Matilde Micillo, Nadia Bertola, Chiara Lavarello, Nicole Grinovero, Giulio Ferrero, Kevin Mellert, Peter Möller, Silvia Bruno, Richard R Furman, John N Allan, Andrea Petretto, Silvia Deaglio, Silvia Ravera, Tiziana Vaisitti","doi":"10.1007/s00018-025-05670-4","DOIUrl":"https://doi.org/10.1007/s00018-025-05670-4","url":null,"abstract":"<p><p>Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into a high-grade lymphoma with previously unknown metabolic features. Transcriptomic data from primary CLL and RS samples, as well as RS-patient-derived xenografts, highlighted cellular metabolism as one of the most significant differentially expressed processes. Activity assays of key enzymes confirmed the intense metabolic rewiring of RS cells, which is characterized by an elevated rate of Krebs cycle, oxidative phosphorylation, and glutamine metabolism. These pathways were sustained by increased uptake of glucose and glutamine, two critical substrates for these cells. Moreover, RS cells showed activation of anabolic processes that resulted in the synthesis of nucleotides and lipids necessary to support their high proliferation. Exposure to drugs targeting PI3K and NF-kB, two master regulators of cellular metabolism, resulted in the shutdown of ATP production and glycolysis. Overall, these data suggest that metabolic rewiring characterizes the transformation of CLL into RS, presenting new translational opportunities.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"152"},"PeriodicalIF":6.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961398","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":"Rhodosporidium toruloides-a new surrogate model to study rapamycin induced effects on human aging and cancer.","authors":"Philipp M Cavelius, Martina Haack, Dania Awad, Thomas B Brueck, Norbert Mehlmer","doi":"10.1007/s00018-025-05662-4","DOIUrl":"https://doi.org/10.1007/s00018-025-05662-4","url":null,"abstract":"<p><p>The haploid, olegenious yeast Rhodosporidium toruloides accumulates intracellular lipids and carotenoids upon metabolic stress. Target of Rapamycin (TOR) signaling, essential for cell proliferation, is known to affect cellular lipid accumulation. In contrast to the conventional surrugate cell model S. cerevisiae, which harbours two TOR kinases within its TOR complex, R. toruloides only harbours one TOR kinase, mimicking mammalian systems. We used a proteomics centered approach to probe the cellular response, of the two R. toruloides haplotypes, IFO0559 and IFO0880 upon treatment with the TOR inhibitor rapamycin, with an original focus on difference in carotenoid and lipid accumulation. Unexpectedly, IFO0880 displayed severe growth arrest in response to rapamycin, while IFO0559 did not. Proteomic anaysis revealed differential expression of several proteins involved in cell cycle control, lipogensis, amino acid metabolism and autophagy between the two haplotypes. Among those we identified several proteins previously described in both mammalian oncogenic and aging contexts. This differential haplotype response to rapamycin treatment positions R. toruloides as a promising cell surrugate model to study cellular mechanisms underlying rapamycin response especially for systems with high lipid contents, an emerging hallmark of different forms of mammalian cancer and age related disease.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"153"},"PeriodicalIF":6.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978319","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":"Mutated sigma-1R disrupts cell homeostasis in dHMN patient cells.","authors":"Sofia Zanin, Francesco Ciscato, Antonio Petrucci, Annalisa Botta, Federico Chiossi, Giovanni Vazza, Rosario Rizzuto, Giorgia Pallafacchina","doi":"10.1007/s00018-025-05676-y","DOIUrl":"10.1007/s00018-025-05676-y","url":null,"abstract":"<p><p>Hereditary-Motor-Neuropathies (dHMNs) are clinically and genetically heterogeneous neurological disorders characterized by degeneration of peripheral motoneurons. We previously identified two sigma-1 receptor (Sigma-1R) variants (p.E138Q; p.E150K) in dHMN Italian patients that behave as \"loss-of-function\" mutations in neuroblastoma cell lines. Here, we characterize the functional effects of Sigma-1R mutation in primary fibroblasts from homozygous patients bearing the E150K mutation, and matched controls, by performing biochemical, gene expression, immunofluorescence and Ca²⁺ imaging analysis. Our results show that Sigma-1R expression and distribution is significantly altered in patient fibroblasts. Moreover, patient cells present a general derangement of cell homeostasis as revealed by impairment of global Ca²⁺ dynamics, disorganization of the ER-mitochondria tethers, enhancement of the autophago-lysosomal pathway and blunting of mitochondrial aerobic metabolism compared to controls. These findings highlight the crucial role of Sigma-1R in the maintenance of cell and protein homeostasis, inter-organelle communication and intracellular Ca²⁺ signalling, supporting the notion that Sigma-1R is protective for motor neuron activity and its down-regulation and/or loss-of-function, as in the case of the E150K mutation, might play the key role in the neuronal degeneration in dHMN patients.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"151"},"PeriodicalIF":6.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810674","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":"Circular RNA circSTX12 regulates osteo-adipogenic balance and proliferation of BMSCs in senile osteoporosis.","authors":"Huimin Gu, Wenhui Yu, Pei Feng, Chenying Zeng, Qian Cao, Fenglei Chen, Ziming Wang, Huiyong Shen, Yanfeng Wu, Shan Wang","doi":"10.1007/s00018-025-05684-y","DOIUrl":"10.1007/s00018-025-05684-y","url":null,"abstract":"<p><p>Increased adipogenic differentiation and decreased osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) along with slow self-renewal are pivotal causes for decreased bone formation in senile osteoporosis. Circular RNAs (circRNAs) play important roles in cell proliferation and differentiation, and are closely related to osteoporosis. Whether circRNAs orchestrate the adipo-osteogenic balance and the proliferation of BMSCs in osteoporosis remains unclear. We found in this study that circSTX12 was abnormally upregulated in bone sections from osteoporosis patients and in BMSCs from aged mice, as well as in later-generation human BMSCs in culture. Knockdown of circSTX12 in BMSCs resulted in enhanced osteogenesis, decreased adipogenesis, and increased proliferation capacity; circSTX12 overexpression had the opposite effect. RNA pull-down and mass spectrometry revealed the interactions between circSTX12 with CBL and LMO7. At the molecular level, circSTX12 regulated cell fate in BMSCs by competitively binding to CBL, reducing the ubiquitination-mediated degradation of MST1 and thereby activating the Hippo pathway, a key regulator of adipo-osteogenic balance. Knockdown of circSTX12 promoted the nuclear localization of YAP. In addition, our findings suggest that LMO7 mediates circSTX12-induced BMSCs proliferation by regulating the transcription of CCNA2, CCNH, and CCND1. In vivo, injection of antisense oligonucleotides (ASOs) to knockdown circSTX12 promoted bone formation in aged mice. Our results provide evidence for circSTX12 as a regulator of adipo-osteogenic differentiation and proliferation of BMSCs through binding to CBL and LMO7, respectively. Targeting circSTX12 may be a novel approach for osteoporosis treatment.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"149"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794721","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":"Dietary advanced glycation end-products exacerbate sarcopenia onset by activating apoptosis through PRMT1-mediated CRTC3 arginine methylation.","authors":"Tian-Jin Huang, Shu Shang, Qin Wan, Qiang Li, Yang-Jingsi Li, Jin-Na Zheng, Fa-Xiu Chen","doi":"10.1007/s00018-025-05657-1","DOIUrl":"10.1007/s00018-025-05657-1","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia, the age-related decline in muscle mass and function, poses a major health risk to the elderly population. Although dietary advanced glycation end-products (AGEs) have been implicated in worsening sarcopenia, the precise molecular mechanisms remain unclear.</p><p><strong>Methods: </strong>A sarcopenia animal model was established by feeding a high AGE diet to C57BL/6 mice. Muscle function and mass were assessed using grip strength tests, and rotarod tests. Proteomic analysis was used to identify differentially expressed proteins. Immunoprecipitation, mass spectrometry, and co-immunoprecipitation were employed to investigate protein interactions both in vivo and in vitro. Quantitative reverse transcription PCR and Western blotting were conducted to measure gene and protein expression levels.</p><p><strong>Results: </strong>Our results revealed that dietary AGEs accelerated the onset of sarcopenia in mice by triggering apoptosis. Proteomic analysis showed a marked upregulation of protein arginine methyltransferase 1 (PRMT1) in the muscle tissues of mice fed a high AGE diet. PRMT1 mediated the arginine methylation of CREB-regulated transcription coactivator 3 (CRTC3) at the R534 site within its transactivation domain, leading to CRTC3 activation. The activated CRTC3, together with Forkhead box O3a (FOXO3a), transactivated the BAX (BCL2 associated X) gene, initiating Bax downstream signaling, promoting apoptosis in muscle cells, and contributing to muscle atrophy. Inhibition of PRMT1 prevented CRTC3 methylation and suppressed Bax-mediated apoptotic signaling in vitro. Moreover, in vivo treatment with PRMT1 and Bax inhibitors significantly attenuated AGE-induced sarcopenia in mice.</p><p><strong>Conclusion: </strong>PRMT1-mediated CRTC3 arginine methylation plays a critical role in AGE-induced sarcopenia and suggests potential therapeutic targets for preventing sarcopenia progression.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"142"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794734","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":"Heat shock protein 60 manipulates Foot-and-Mouth disease virus replication by regulating mitophagy.","authors":"Jianli Tang, Sahibzada Waheed Abdullah, Shiqi Sun, Huichen Guo","doi":"10.1007/s00018-025-05623-x","DOIUrl":"10.1007/s00018-025-05623-x","url":null,"abstract":"<p><p>Mitochondria serve as the hubs of cellular signaling, energetics, and redox balance under physiological conditions. Mitochondria play an essential role in defending against pathogenic infections upon virus invasion. As a critical intracellular physiological process, mitophagy is crucial for maintaining mitochondrial homeostasis. Accumulating evidence suggests that mitophagy contributes to modulating viral infection. In our previous study, we reported that heat shock protein 60 (HSP60) is involved in orchestrating autophagy; however, the underlying mechanisms remain elusive. Here, we examined the role of HSP60 in priming mitophagy to regulate foot-and-mouth disease virus (FMDV) replication. We first reported that mitophagy was elicited post-FMDV infection and further restricted FMDV replication. Regarding HSP60, our results showed that HSP60 depletion triggered Parkin-dependent mitophagy via activating dynamin-related protein 1 (Drp1) phosphorylation at Ser616 and promoting Drp1 translocation to mitochondria. Furthermore, calmodulin-dependent protein kinase II (CaMKII) was essential for phosphorylating Drp1 at Ser616 in HSP60-depleted cells. Taken together, HSP60 manipulates FMDV replication by governing mitophagy. Importantly, HSP60 could be a promising antiviral target for controlling FMDV infection.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"141"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794736","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":"Adenine base editing of CFTR using receptor targeted nanoparticles restores function to G542X cystic fibrosis airway epithelial cells.","authors":"Isabelle Rose, Miriam Greenwood, Matthew Biggart, Natalie Baumlin, Robert Tarran, Stephen L Hart, Deborah L Baines","doi":"10.1007/s00018-025-05587-y","DOIUrl":"10.1007/s00018-025-05587-y","url":null,"abstract":"<p><p>The cystic fibrosis (CF) causing variant G542X harbours a premature translation stop signal in the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA. This results in nonsense-mediated decay and loss of functional CFTR protein which leads to defective anion transport and the development of CF disease pathology. Currently available CF modulator therapies cannot be used to treat this variant. We used an adenine base editor (ABE8e Cas9) and guide RNA (sgRNA)/enhanced green fluorescent protein (EGFP) plasmids encapsulated in receptor targeted nanoparticles (RTN), delivered to Bmi-1 transduced basal human CF nasal epithelial cells harbouring the homozygous CFTR G542X variant, to convert the stop codon to G542R, a variant which is amenable to modulator therapy. ABE resulted in 17% of alleles edited to G542R and further selection of GFP fluorescent cells by FACS liberated a population with 52% G542R edited alleles with no editing of neighbouring adenines (A) and few off target edits using a gRNA homology-based approach. In cells differentiated at air-liquid-interface (ALI), 17% and 52% editing of CFTR G542X increased mRNA abundance. 52% editing alone or 17% and 52% editing of CFTR G542X plus treatment with CFTR modulators (VX-445/VX-661/VX-770; ETI/Trikafta/Kaftrio) increased epithelial CFTR protein expression, CFTR protein band C abundance, CFTR₁₇₂ inhibitable anion transport, and changes in airway surface liquid height and pH in response to vasoactive intestinal peptide (VIP) stimulation. Epithelial scratch repair speed and directionality was also improved. These data provide proof-of-concept that ABE of G542X to G542R in human CF airway epithelial cells could provide a feasible therapy for this variant.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"144"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794717","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}