Journal of Cellular Physiology最新文献

{"title":"Fasting-Induced Hepatic Gluconeogenesis Is Compromised In Anxa6−/− Mice","authors":"Anna Alvarez-Guaita,&nbsp;Marc Bernaus-Esqué,&nbsp;Patricia Blanco-Muñoz,&nbsp;Yangjing Liu,&nbsp;David Sebastian,&nbsp;Elsa Meneses-Salas,&nbsp;Mai K. Linh Nguyen,&nbsp;Antonio Zorzano,&nbsp;Francesc Tebar,&nbsp;Carlos Enrich,&nbsp;Thomas Grewal,&nbsp;Carles Rentero","doi":"10.1002/jcp.70084","DOIUrl":"https://doi.org/10.1002/jcp.70084","url":null,"abstract":"<p>Maintaining constant blood glucose levels is essential for energizing glucose-dependent tissues. During the fed state, insulin lowers elevated blood glucose, while in the fasted state, glucagon maintains blood glucose levels through hepatic stimulation of fatty acid oxidation, glycogenolysis, and gluconeogenesis (GNG). The liver plays a crucial role in these metabolic adaptations. Deregulation of GNG is a hallmark of type 2 diabetes mellitus (T2DM), driven by hepatic insulin resistance, elevated glucagon levels, and excess circulating free fatty acids. The glucose metabolism of 8- to 12-week-old WT and <i>Anxa6</i> knock-out (<i>Anxa6</i>^{<i>−/−</i>}) mice was analysed during regular feeding and fasting using indirect calorimetry, tolerance tests and biochemical analysis. Despite normal insulin-sensitive control of glucose levels and effective glycogen mobilization, <i>Anxa6</i>^{<i>−/−</i>} mice display rapid hypoglycaemia during fasting. This metabolic disarrangement, in particular during the early stages of fasting is characterized by a low respiratory exchange ratio (RER) and increased lipid oxidation during the diurnal period, indicating a reliance on lipid oxidation due to hypoglycaemia. Elevated glucagon levels during fasting suggest deficiencies in GNG. Further analysis reveals that <i>Anxa6</i>^{<i>−/−</i>} mice are unable to utilize alanine for hepatic GNG, highlighting a specific impairment in the glucose-alanine cycle in fasted <i>Anxa6</i>^{<i>−/−</i>} mice, underscoring the critical role of ANXA6 in maintaining glucose homeostasis under metabolic stress. During fasting, slightly reduced expression levels of alanine aminotransferase 2 (<i>Gpt2</i>) and lactate dehydrogenase (<i>Ldha2</i>), enzymes converting alanine to pyruvate, and the hepatic alanine transporter SNAT4 might contribute to these observations in the <i>Anxa6</i>^{<i>−/−</i>} mice. These findings identify that ANXA6 deficiency causes an inability to maintain glycolytic metabolism under fasting conditions due to impaired alanine-dependent GNG.</p>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcp.70084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832767","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":"Mitochondrial Pyruvate Carrier Differentially Controls the Self-Renewal and Differentiation of Human Pluripotent Stem Cells","authors":"Dacheng Jiang,&nbsp;Yuchen Wang,&nbsp;Yanhao Chen,&nbsp;Cheng Tian,&nbsp;Xin Li,&nbsp;Shuang Li,&nbsp;Xiaosong Gu,&nbsp;Chunping Jiang,&nbsp;Qiurong Ding","doi":"10.1002/jcp.70083","DOIUrl":"https://doi.org/10.1002/jcp.70083","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitochondria are crucial for cell fate determination, yet their roles in human pluripotent stem cell (hPSC) fate changes have remained underexplored. Here, we designed a CRISPR library targeting 661 mitochondrial proteins and identified the MPC (mitochondrial pyruvate carrier) as a critical regulator of hPSC self-renewal and pluripotency. Notably, MPC inhibition reduced hPSC self-renewal and endoderm differentiation while promoting mesoderm differentiation, with no effect on ectoderm differentiation, all mediated by influencing glycolytic acetyl-CoA production. Specifically, the decrease in acetyl-CoA following MPC inhibition affected histone acetylation in hPSCs, compromising self-renewal. In contrast, MPC inhibition did not impact histone acetylation in differentiated cells; instead, it reduced the acetylation of non-histone proteins—EP300 and SMAD2—thereby enhancing mesoderm differentiation and repressing endoderm differentiation, respectively. These findings suggest that distinct effector proteins respond to variations in acetyl-CoA levels at different developmental stages, leading to a context-dependent regulation of cell fate determination by glycolytic acetyl-CoA in hPSCs.</p></div>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “The Role of TREM-1 in Septic Myocardial Pyroptosis and Septic Cardiomyopathy In Vitro and In Vivo”","authors":"","doi":"10.1002/jcp.70077","DOIUrl":"https://doi.org/10.1002/jcp.70077","url":null,"abstract":"<p>Chen Y, Mao L, Liu S, Huang S, Lin Q, Zeng M, Huang H, Sun X, Chen H, Huang J, Zhou G, Deng L. The role of TREM-1 in septic myocardial pyroptosis and septic cardiomyopathy in vitro and in vivo. J Cell Physiol. 2024 Dec;239(12):e31445. https://doi.org/10.1002/jcp.31445.</p><p>In Figure 5 of “The Role of TREM-1 in Septic Myocardial Pyroptosis and Septic Cardiomyopathy In Vitro and In Vivo,” the authors mistakenly used a scanning electron micrograph from the drug treatment group in Figure 5b (WT control). This has been replaced with the correct control image. The corrected Figure 5 is shown below.</p><p>The authors apologize for this error.</p>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcp.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782632","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":"Interpreting the Origins and Functions of Noncoding RNAs From the Ribosomal Genes","authors":"Tom Moss,&nbsp;Dany S. Sibai,&nbsp;Frédéric Lessard","doi":"10.1002/jcp.70080","DOIUrl":"https://doi.org/10.1002/jcp.70080","url":null,"abstract":"<p>The Ribosomal DNA (rDNA) in mammals is organised into large clusters of tandem repeats each of which encodes a single 47S precursor for the 18S, 5.8S, and 28S ribosomal RNAs (rRNAs) that is flanked upstream and downstream by an Intergenic Spacer (IGS) originally referred to as the Non-Transcribed Spacer (NTS). However, in certain cells and under certain environmental conditions the IGS has been found to be transcribed at low level to generate a range of “Noncoding” RNAs (ncRNAs). These ncRNAs have been implicated in the regulation of rRNA synthesis, rDNA silencing and protein sequestration in response to environmental and oncogenic stresses and tumour suppression. Here we review data on the generation, regulation and potential functions of these ncRNAs. We suggest that the majority of the ncRNAs originate from a failure of RNA polymerase I transcription termination by the Reb1- and Myb-related transcriptional “road-block” factor TTF1 and link their expression with tumour suppression.</p>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcp.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782631","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":"The Role of Cellular Stress, Antioxidant System Response, Mitochondrial Function, and Metabolic Alterations in the Pathophysiology of Propionic Acidemia: A Systematic Review","authors":"Neşe Vardar Acar,&nbsp;R. Köksal Özgül","doi":"10.1002/jcp.70072","DOIUrl":"https://doi.org/10.1002/jcp.70072","url":null,"abstract":"<div>\u0000 \u0000 <p>Propionic acidemia (PA) is a rare, life-threatening inherited metabolic disorder. Despite early therapy and effective metabolic control with current treatments, patients with PA face recurrent severe metabolic decompensations and multisystemic complications. The exact pathophysiological mechanisms of these complications remain unclear. This systematic review aims to enhance understanding of molecular mechanisms underlying PA by simultaneously evaluating ROS-mediated cellular stress, antioxidant response, mitochondrial dysfunction, metabolic alterations, and mitohormesis. For this purpose, a literature search was conducted across PubMed, Scopus, ScienceDirect, Web of Science, Cochrane Library, and ClinicalTrials.gov databases. This review included 42 experimental studies, comprising 13 human studies, 27 animal studies, and 2 studies involving both animals (rat and mice/mouse) and humans. As a result: (i) both oxidative and reductive stress can occur in PA, with individual variability; (ii) ROS-mediated cellular damage generally accompanies PA; (iii) the antioxidant response can vary depending on the type, severity, and duration of cellular stress; (iv) secondary mitochondrial dysfunction accompanies PA; (v) ROS-mediated stress effects correlate with alterations in interconnected metabolic pathways in PA; and (vi) mitohormesis can play a role in PA. In conclusion, using antioxidants or preventive treatments for PA without assessing cellular stress during diagnosis and treatment may further disturb the delicate oxidant–antioxidant balance. Simultaneous evaluation of ROS-mediated cellular stress and associated pathways in PA has potential to both revise existing treatments and discover new therapies, thereby improving the quality of life and longevity of patients with PA, as well as elucidating the unclear pathophysiology of PA.</p></div>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting GPX4 to Overcome Sorafenib Resistance of Human Hepatocellular Carcinoma by Inducing Ferroptosis","authors":"Han-Hsuan Tang,&nbsp;Chi-Pei Hsu,&nbsp;Pin-Yu Su,&nbsp;Shu-Ping Tsai,&nbsp;Ly Hien Doan,&nbsp;Ching-Ying Chen,&nbsp;Hsin-Chih Chen,&nbsp;Pao-Yuan Wang,&nbsp;Tai-Shan Cheng,&nbsp;Chi-Ying F. Huang,&nbsp;Chun-Li Su","doi":"10.1002/jcp.70078","DOIUrl":"https://doi.org/10.1002/jcp.70078","url":null,"abstract":"<div>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death. Sorafenib, a multikinase inhibitor, has been approved as a first-line systemic therapeutic for HCC patients based on the results of two large clinical trials, in which sorafenib significantly increased life expectancy of patients with Child Pugh A advanced stage of liver cancer, no matter which races they were or whether being infected with hepatitis B or C virus; however, its efficacy is compromised by the resistance of the tumor cells. By using integrative bioinformatics analysis, we identified ferroptosis as a candidate to modulate sorafenib-resistant HCC. Ferroptosis is a novel, iron-dependent, non-apoptotic regulated cell death with characteristics of impaired lipid peroxide repair, redox active iron, and the oxidation of polyunsaturated fatty acids. Here, glutathione peroxidase 4 (GPX4) was further identified as a favorable prognostic factor in cancer survival by analyzing data repositories. Compared to the parental human HCC Huh7 cells, lower expression of GPX4, dysregulated iron homeostasis, and higher expression of acyl-CoA synthetase long-chain family member 4 were observed in sorafenib-resistant Huh7R cells, and the Huh7R cells exhibited higher sensitivity to ferroptosis induction exerted by RSL3, a GPX4 inhibitor. The RSL3-induced ferroptosis was attenuated by lysosomal blocker bafilomycin A1, indicating that lysosomal degradation of ferritin may confer sensitivity to GPX4-inactivation-induced ferroptosis by providing accessible iron. Taken together, our findings demonstrate that GPX4-inactivation-induced ferroptosis is a promising and effective treatment option capable of overcoming sorafenib resistance in liver cancer, and our novel gene expression-screening platform via integrated analysis of differentially expressed genes and pathways allows efficient identification of therapeutic strategies.</p>\u0000 </div>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: Exosomes Derived From SDF1-Overexpressing Mesenchymal Stem Cells Inhibit Ischemic Myocardial Cell Apoptosis and Promote Cardiac Endothelial Microvascular Regeneration in Mice With Myocardial Infarction","authors":"","doi":"10.1002/jcp.70076","DOIUrl":"https://doi.org/10.1002/jcp.70076","url":null,"abstract":"<p><b>RETRACTION:</b> X.-H. Gong, H. Liu, S.-J. Wang, S.-W. Liang, and G.-G. Wang, “Exosomes Derived From SDF1-Overexpressing Mesenchymal Stem Cells Inhibit Ischemic Myocardial Cell Apoptosis and Promote Cardiac Endothelial Microvascular Regeneration in Mice With Myocardial Infarction.” <i>Journal of Cellular Physiology</i> 234, no. 8 (2019): 13878–13893. https://doi.org/10.1002/jcp.28070.</p><p>The above article, published online on February 5, 2019, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Robert Heath, and Wiley Periodicals LLC. A third party shared a report from the National Natural Science Foundation of China, which indicated that data in this article had been purchased from an external company (National Natural Science Foundation of China 2015). An investigation by the publisher found that this fact is not reported in the article and also that the article is missing necessary information on the ethical approval for animal and human experiments performed as part of this study.</p><p>The authors responded to an inquiry by the publisher requesting original data and evidence of approval for animal and human experiments. The authors stated that they conducted partial pre-experiments and then commissioned third-party companies to conduct the main experiments. The authors further stated that those companies could not provide raw data. The authors did not provide information regarding ethical approval for the animal and human experiments reported in the article. The authors requested the withdrawal of their article.</p><p>The retraction has been agreed to because the data and ethical approval of experiments reported in this article cannot be validated.</p>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 7","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcp.70076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716741","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":"The Parkinson Disease-Associated Mutant DNAJC13(N855S) Leads to Its Accelerated Degradation and Negatively Affects Macroautophagy and Retromer Complex-Mediated Dynamics","authors":"Anna Stein,&nbsp;Stella Vo,&nbsp;Christian Freese,&nbsp;Joram Kluge,&nbsp;Joanna Maus,&nbsp;Ingrid Koziollek-Drechsler,&nbsp;Beate Silva,&nbsp;Christian Behl,&nbsp;Albrecht M. Clement","doi":"10.1002/jcp.70074","DOIUrl":"https://doi.org/10.1002/jcp.70074","url":null,"abstract":"<p>While Parkinson′s disease has a multifactorial etiology, 5%–10% of cases present with identifiable disease-causing gene mutations. Further investigation into these mutations is a way to identify underlying pathologic mechanism. One of the rare Parkinson-associated genes is <i>DNAJC13</i>, coding for an endosome-associated protein. Several lines of evidence suggest that disturbed endosomal pathways are instrumental in the development of Parkinson pathology. Recently, we have shown that DNAJC13/RME-8 is a positive modulator of autophagy, a lysosome-associated degradative process. Here, we further characterize the role of the disease-linked DNAJC13(N855S) mutant and perform biochemical, cell biological, co-localization, and expression analysis by employing a newly established cell line with reduced DNAJC13 expression and by transiently expressing the DNAJC13(N855S) mutant variant. We observed that the DNAJC13(N855S) variant is less stable than the wild-type protein and might thus impact proteostasis. Furthermore, the protein has functional deficits as it cannot compensate for the impaired autophagic activity in cells with chronically reduced DNAJC13 levels. In addition, the DNAJC13(N855S) showed a dominant negative effect on the distribution of the cation-independent mannose-6-phosphate receptor without affecting overall cathepsin D levels or activity. Lastly, we observed a decreased expression of several genes related to autophagy induction and biogenesis in stable DNAJC13 knockdown cells. Our data point toward a loss-of-function mechanism of the DNAJC13(N855S) variant and that chronically reduced DNAJC13 protein levels result in a reduced expression of genes largely involved in endosomal traffic and autophagosome biogenesis. The DNAJC13(N855S) mutant might thus cause disease in part by its instability and in part by a dominant negative effect on the autophagic pathway. These data support a pivotal role of endosomal pathway impairment in Parkinson′s disease pathogenesis.</p>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 7","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcp.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714893","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":"RETRACTION: Long Non-Coding RNA SNHG15 Promotes CDK14 Expression via miR-486 to Accelerate Non-Small Cell Lung Cancer Cells Progression and Metastasis","authors":"","doi":"10.1002/jcp.70069","DOIUrl":"https://doi.org/10.1002/jcp.70069","url":null,"abstract":"<p><b>RETRACTION</b>: B. Jin, H. Jin, H.-B. Wu, J.-J. Xu, and B. Li, “Long Non-Coding RNA SNHG15 Promotes CDK14 Expression via miR-486 to Accelerate Non-Small Cell Lung Cancer Cells Progression and Metastasis,” <i>Journal of Cellular Physiology</i> 223, no. 9 (2018): 7164-7172, https://doi.org/10.1002/jcp.26543.</p><p>The above article, published online on 06 April 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has been agreed upon following an investigation into concerns raised by a third party regarding unrelated flow cytometry panels in Figure 3a showing implausible similarity. The subsequent investigation by the journal team has identified additional concerns regarding inappropriate duplication of image panels between this article (Figure 2D) and two articles published previously by a different group of authors in an unrelated scientific context, depicting different experimental conditions. Therefore, the editors have lost confidence in the data presented and have decided to retract the article. The authors and their affiliated institution were informed about the concerns and the decision to retract, but they remained unresponsive.</p>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 7","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcp.70069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681611","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":"The Proton-Activated Chloride Channel Inhibits SARS-CoV-2 Spike Protein-Mediated Viral Entry Through the Endosomal Pathway","authors":"Nicholas Koylass,&nbsp;Jaiprasath Sachithanandham,&nbsp;James Osei-Owusu,&nbsp;Kevin Hong Chen,&nbsp;Henry Yi Cheng,&nbsp;Andrew Pekosz,&nbsp;Zhaozhu Qiu","doi":"10.1002/jcp.70063","DOIUrl":"https://doi.org/10.1002/jcp.70063","url":null,"abstract":"<div>\u0000 \u0000 <p>SARS-CoV-2 binds to its obligatory receptor, angiotensin-converting enzyme 2 (ACE2) and capitalizes on decreasing endosomal acidity and cathepsin-mediated spike protein cleavage to enter cells. Endosomal acidification is driven by V-ATPase which pumps protons (H⁺) into the lumen. The driving force for H⁺ is maintained by the import of chloride (Cl⁻) which is mediated by intracellular CLC transporters. We have recently identified the Proton-Activated Chloride (PAC) channel as a negative regulator of endosomal acidification. PAC responds to low pH and releases Cl⁻ from the lumen to prevent endosomal hyperacidification. However, its role in SARS-CoV-2 viral entry remains unexplored. Here, we show that overexpressing the PAC channel in ACE2 expressing HEK 293T cells markedly inhibited SARS-CoV-2 spike-mediated viral entry. Several lines of evidence suggest that this effect was due to the suppression of the endosomal entry pathway. First, the abilities of PAC to regulate endosomal acidification and inhibit pseudoviral entry were both dependent on its endosomal localization and channel activity. Second, the inhibitory effect on viral entry was similar to the suppression mediated by E64-d, a cathepsin inhibitor, while no major additive effect for both treatments was observed. Third, this inhibition was also attenuated in cells expressing TMPRSS2, which provides an alternative entry pathway through the cell surface. Importantly, PAC overexpression also inhibited the number and size of plaques formed by two live SARS-CoV-2 isolates (B.1 and Omicron XBB.1.16) in Vero E6 cells. Altogether, our data indicates that PAC plays a vital role in inhibiting SARS-CoV-2 viral entry and identifies this endosomal channel as a potential novel target against the infection of SARS-CoV-2 and other viruses, which rely on the endosomal pathway.</p>\u0000 </div>","PeriodicalId":15220,"journal":{"name":"Journal of Cellular Physiology","volume":"240 7","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}