American Journal of Pathology最新文献

{"title":"Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 Drives Subchondral Bone Damage in Temporomandibular Joint Osteoarthritis through Peroxisome Proliferator-Activated Receptor γ/Cellular FOS Proto-oncogene–Regulated Dual Pathways","authors":"Ziyan Jiang ,&nbsp;Jie Zhao ,&nbsp;Youde Liang ,&nbsp;Zhao Gao ,&nbsp;Yanan Sun ,&nbsp;Yaying Hu ,&nbsp;Junchen Pan ,&nbsp;Xing Long ,&nbsp;Jiali Zhang","doi":"10.1016/j.ajpath.2025.04.008","DOIUrl":"10.1016/j.ajpath.2025.04.008","url":null,"abstract":"<div><div>Overactivated osteoclastogenesis leading to abnormal subchondral bone loss is the main feature of temporomandibular joint osteoarthritis (TMJOA) deterioration. The role of N6-methyladenosine in osteoclast-mediated subchondral bone loss in TMJOA remains unknown. Here, it was found that an N6-methyladenosine reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was essential for mature osteoclast induction. In TMJ tissues of patients with TMJOA, the expression of IGF2BP2 was increased. Moreover, IGF2BP2 was augmented in subchondral bone of monosodium iodoacetate (MIA)–induced TMJOA mice. <em>Igf2bp2</em> deficiency attenuated MIA-induced subchondral bone loss and suppressed osteoclast function. Mechanistically, IGF2BP2 directly stabilized <em>Pparg</em> and <em>Fos</em> mRNA to enhance the nuclear factor of activated T cells 1 (NFATC1) signaling, thereby inducing osteoclast maturation. Furthermore, the stabilized peroxisome proliferator-activated receptor γ (PPARγ) promoted the transcription of <em>Fos</em>, resulting in a further amplified signaling of NFATC1. In <em>Igf2bp2</em>-deficient cells, overexpression of PPARγ and cellular FOS proto-oncogene (C-FOS) rescued the function of osteoclasts through restoring reduced levels of NFATC1. On the other hand, the IGF2BP2/PPARγ/C-FOS axis facilitated the formation of osteoclasts by restoring the inhibited autophagy levels through the down-regulation of autophagy-related 16-like 2. IGF2BP2 inhibitor, CWI1-2, hindered osteoclast formation and mitigated synovial inflammation, cartilage degeneration, and bone destruction in MIA-induced TMJOA mice. In summary, IGF2BP2 may be a novel regulator of osteoclastogenesis of TMJOA pathogenesis, which aggravates TMJOA pathology via stabilizing <em>Pparg</em> and <em>Fos</em> mRNA, thereby promoting NFATC1-mediated osteoclast signaling and autophagy-related 16-like 2–mediated autophagy.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1484-1503"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957567","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":"Notch Signaling Aggravates Helicobacter pylori–Induced Inflammation by Promoting Macrophage Activation and Proinflammatory Th1/Th17 Responses","authors":"Yunxuan He,&nbsp;Danli Xiao,&nbsp;Hongfei Zhu,&nbsp;Chuxi Chen,&nbsp;Qiaoyuan Liu,&nbsp;Jinling Xie,&nbsp;Lvying Wei,&nbsp;Yueqi Dai,&nbsp;Yunshan Ning,&nbsp;Yan Li","doi":"10.1016/j.ajpath.2025.04.007","DOIUrl":"10.1016/j.ajpath.2025.04.007","url":null,"abstract":"<div><div>The role of Notch signaling in regulating the immune response in infectious diseases has been extensively reported. However, its specific involvement in <em>Helicobacter pylori</em> infection is yet to be fully understood. In this study, <em>in vitro</em> analysis utilizing real-time quantitative PCR and Western blot revealed that <em>H. pylori</em> triggerred the activation of Notch signaling in murine bone marrow–derived macrophages (BMDMs) and co-cultured CD4⁺ T cells, a process mediated by jagged-1 (Jag1). There was a reciprocal enhancement between Jag1-Notch signaling and NF-κB pathway in <em>H. pylori</em>–infected macrophages. Pretreatment with a Notch signaling inhibitor, DAPT, reduced the expression of inflammatory mediators in macrophages, modulated their phenotype, and inhibited Th1 differentiation. <em>In vivo</em>, after DAPT treatment in <em>H. pylori</em>–infected mice, the differentiation of Th1 and Th17 was decreased as indicated by flow cytometry. Hematoxylin and eosin staining revealed reduced gastric mucosa inflammation, and enzyme-linked immunosorbent assay results demonstrated decreased levels of serum inflammatory cytokines. The terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) results showed that DAPT treatment improved the apoptosis of gastric mucosal cells. Collectively, the findings indicate that Notch signaling is implicated in exacerbating <em>H. pylori–</em>induced inflammation by promoting macrophage activation and Th1/Th17 responses, highlighting its potential for alleviating the progression of <em>H. pylori</em>–related diseases.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1428-1442"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970246","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":"Ovarian Cancer Detection in Ascites Cytology with Weakly Supervised Model on Nationwide Data Set","authors":"Jiwon Lee ,&nbsp;Seonggyeong Choi ,&nbsp;Seoyeon Shin ,&nbsp;Mohammad Rizwan Alam ,&nbsp;Jamshid Abdul-Ghafar ,&nbsp;Kyung Jin Seo ,&nbsp;Gisu Hwang ,&nbsp;Daeky Jeong ,&nbsp;Gyungyub Gong ,&nbsp;Nam Hoon Cho ,&nbsp;Chong Woo Yoo ,&nbsp;Hyung Kyung Kim ,&nbsp;Yosep Chong ,&nbsp;Kwangil Yim","doi":"10.1016/j.ajpath.2025.04.004","DOIUrl":"10.1016/j.ajpath.2025.04.004","url":null,"abstract":"<div><div>Conventional ascitic fluid cytology for detecting ovarian cancer is limited by its low sensitivity. To address this issue, this multicenter study developed patch image (PI)-based fully supervised convolutional neural network (CNN) models and clustering-constrained attention multiple-instance learning (CLAM) algorithms for detecting ovarian cancer using ascitic fluid cytology. Whole-slide images (WSIs), 356 benign and 147 cancer, were collected, from which 14,699 benign and 8025 cancer PIs were extracted. Additionally, 131 WSIs (44 benign and 87 cancer) were used for external validation. Six CNN algorithms were developed for cancer detection using PIs. Subsequently, two CLAM algorithms, single branch (CLAM-SB) and multiple branch (CLAM-MB), were developed. ResNet50 demonstrated the best performance, achieving an accuracy of 0.973. The performance when interpreting internal WSIs was an area under the curve (AUC) of 0.982. CLAM-SB outperformed CLAM-MB with an AUC of 0.944 for internal WSIs. Notably, in the external test, CLAM-SB exhibited superior performance with an AUC of 0.866 compared with ResNet50's AUC of 0.804. Analysis of the heatmap revealed that cases frequently misinterpreted by AI were easily interpreted by humans, and vice versa. Because AI and humans were found to function complementarily, implementing computer-aided diagnosis is expected to significantly enhance diagnostic accuracy and reproducibility. Furthermore, the WSI-based learning in CLAM, eliminating the need for patch-by-patch annotation, offers an advantage over the CNN model.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1254-1263"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952531","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":"Phosphatidylinositol 3-Kinase Signaling Enhances Intestinal Crypt Epithelial Cell Recovery after Radiation","authors":"Evan B. Lynch ,&nbsp;Neeraj Kapur ,&nbsp;Tatiana Goretsky ,&nbsp;Emily M. Bradford ,&nbsp;Hemendra Vekaria ,&nbsp;Sarayu Bhogoju ,&nbsp;Syed A. Hassan ,&nbsp;Emily Pauw ,&nbsp;Margarita G. Avdiushko ,&nbsp;Goo Lee ,&nbsp;Tianyan Gao ,&nbsp;Patrick G. Sullivan ,&nbsp;Terrence A. Barrett","doi":"10.1016/j.ajpath.2025.04.010","DOIUrl":"10.1016/j.ajpath.2025.04.010","url":null,"abstract":"<div><div>Intestinal stem cell (ISC) signaling maintains the balance of self-renewal and differentiation. Herein, the role of phosphatidylinositol 3-kinase (PI3K) signaling in ISC responses to radiation was interrogated using Villin-Cre pik3r1^lox/lox (p85^ΔIEC) mice and p85α-deficient human enteroids (shp85α). Lethal whole-body irradiation in mice was performed to monitor PI3K-mediated survival responses. Rectal biopsies from patients with radiation proctitis were examined by immunohistochemistry for the PI3K/Akt- and Wnt-target survivin. The intestinal epithelial cells (IECs) from p85^ΔIEC mice showed increased protein levels of phosphorylated phosphatase and tensin homolog, phosphorylated Akt^Ser473, survivin, cyclin D1, and ρ-β-catenin^Ser552, as well as increased mRNA for ISC/progenitor cell. <em>In situ</em> hybridization showed that enhanced PI3K signaling reduced leucine-rich repeat-containing G-protein coupled receptor 5 (<em>Lgr5</em>^<em>+</em>) cells but enhanced AXIS inhibition protein 2 (<em>Axin2</em>^<em>+</em>) cells. The shp85α enteroids showed increased mRNA expression of Wnt targets and transcription factor <em>ASCL2</em>, needed for dedifferentiation-mediated restoration of ablated ISCs. The p85α-deficient enteroids showed reduced <em>HES1</em> mRNA and increases in secretory (<em>ATOH1</em>/<em>MATH1</em>) signaling determinants <em>GFI1</em> and <em>SPDEF</em>, indicative of reduced NOTCH signaling. Seahorse analyses and phosphorylated p38 staining in IEC^Δp85 mice indicated that enhanced PI3K signaling led to increased IEC mitochondrial respiration and reactive oxygen species generation. Expression of survivin correlated with the radiation injury in patients. The current data indicate that PI3K signaling increased mitochondrial reactive oxygen species generation and ISC activation that improved IEC recovery from radiation-induced injury. The results suggest that increasing PI3K signaling and induced mitochondrial respiration may improve mucosal healing in patients with radiation injury.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1411-1427"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956594","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":"Identification of a Growth-Promoting Gene Cluster in the Region 2q24 as a Driver of Tumorigenesis in Childhood Hepatoblastoma","authors":"Martin M. Rodemann ,&nbsp;Verena Dreschmann ,&nbsp;Evelyn Dörner ,&nbsp;Anette Sommer ,&nbsp;Joern Kraetzschmar ,&nbsp;Ludger Klein-Hitpass ,&nbsp;Genta Nagae ,&nbsp;Eiso Hiyama ,&nbsp;Dietrich von Schweinitz ,&nbsp;Roland Kappler ,&nbsp;Christian Vokuhl ,&nbsp;Torsten Pietsch","doi":"10.1016/j.ajpath.2025.04.006","DOIUrl":"10.1016/j.ajpath.2025.04.006","url":null,"abstract":"<div><div>Hepatoblastoma (HB) represents the most common primary malignancy of the liver in childhood. Cytogenetic studies uncovered characteristic copy number alterations in HB. The frequent gain of chromosome 2q and particularly the recurrent 2q24 amplification suggest the presence of a so far unidentified oncogenic driver within this amplicon. Herein, high-resolution copy number profiles from 76 patients with HB were generated by using molecular inversion probe array technology. 2q gain was present in 63.2%, and 2q24 high-gain/amplification was present in 14.5% of patients analyzed. In the smallest overlapping region at 2q24.2q24.3, spanning &gt;5.2 Mbp, 22 protein-coding genes, 2 long noncoding RNA genes, and one miRNA gene were mapped. RNA expression analysis of these smallest overlapping region genes identified <em>RBMS1</em>, <em>BAZ2B</em>, <em>MARCH7</em>, <em>DPP4</em>, <em>FIGN,</em> and <em>TANK</em> as overexpressed in 2q24 high-gain/amplified HB cases. Accordingly, these six genes were selected for further investigation. <em>In situ</em>, immunohistochemical staining showed higher protein expression of these genes in 2q24 high-gain HB tissue sections. <em>In vitro</em>, functional analyses were performed in established human HB cell lines carrying a 2q (high-)gain. Knockdown of these genes by specific siRNAs resulted in reduced proliferation and marked reduction of Wnt pathway activity. These genes located within the 2q24 amplicon might collaborate in driving cellular growth by interaction with the Wnt pathway that is known to be activated pathologically in HB.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1553-1569"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959928","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":"Severe Acute Respiratory Syndrome Coronavirus 2, the Human Placenta, and Adverse Perinatal Outcomes","authors":"Rebecca L. Linn ,&nbsp;Markolline Forkpa ,&nbsp;Rita Leite ,&nbsp;Jessenia C. Guerrero ,&nbsp;Maria C. Reyes ,&nbsp;Lauren E. Schwartz ,&nbsp;Rebecca A. Simmons ,&nbsp;Samuel Parry ,&nbsp;Thea N. Golden","doi":"10.1016/j.ajpath.2025.04.009","DOIUrl":"10.1016/j.ajpath.2025.04.009","url":null,"abstract":"<div><div>The relationship among timing and severity of coronavirus disease 2019 (COVID-19) during pregnancy, placental pathology, and adverse pregnancy outcomes is not well understood. A prospective cohort study of 497 pregnant patients with COVID-19 whose placentas underwent systematic pathologic examination was conducted. The main exposure was timing of COVID-19 during pregnancy (first/second versus third trimester). The primary outcome was composite placental pathology that included high-grade maternal vascular malperfusion or &gt;25% perivillous fibrin deposition. Sixty three patients had the composite placental pathology outcome. In adjusted analyses that controlled for maternal age, parity, active infection at delivery, interval from time of diagnosis to delivery, and COVID-19 variant, timing of COVID-19 during pregnancy was not associated with risk of the composite placental pathology outcome. Among the secondary COVID-19–related exposures investigated, severity of disease and treatment for COVID-19 were associated with risk of the composite placental pathology outcome. In addition, patients with COVID-19 in the first 9 months of the pandemic had the highest rate of the composite placental pathology outcome. In this large cohort, placental vascular pathology was common among COVID-19 cases but was unrelated to the timing of COVID-19 during pregnancy or adverse pregnancy outcomes. These findings suggest that uncomplicated COVID-19 during pregnancy does not require intensive fetal surveillance or detailed pathologic examination of the placenta after delivery.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1457-1466"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956147","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":"Effect of Fibroblast Signaling on Macrophage Polarization","authors":"Samuel T. LoPresti ,&nbsp;Mangesh M. Kulkarni ,&nbsp;Dana R. Julian ,&nbsp;Zariel I. Johnson ,&nbsp;Brandon L. Lantonio ,&nbsp;Nahed Ismail ,&nbsp;Cecelia C. Yates ,&nbsp;Bryan N. Brown","doi":"10.1016/j.ajpath.2025.04.002","DOIUrl":"10.1016/j.ajpath.2025.04.002","url":null,"abstract":"<div><div>Systemic and organ-specific fibrotic disorders are a leading cause of death worldwide. Crosstalk between fibroblasts and macrophages has been suggested as a key event leading to either resolution or aberrant remodeling and fibrosis. This study sought to identify the impacts of the timing and effects of exposure to quiescent (basal) and transforming growth factor-β–stimulated (activated) fibroblast-secreted products on macrophage polarization and function. Naïve (M0 macrophages), lipopolysaccharide/interferon-γ–stimulated (M1 macrophages), and IL-4–stimulated (M2 macrophages) macrophages were exposed to basal or activated fibroblast conditioned media (FBCM) for 24 hours before, after, or during macrophage polarization. Macrophage function and polarization were quantified by phagocytosis, nitric oxide, and arginase activity assays and by cytokine array. FBCM from activated fibroblasts led to a pronounced up-regulation of arginase-1 compared with that from quiescent fibroblasts in M0 macrophages. Moreover, treatment with FBCM from activated fibroblasts resulted in significant increases in arginase-1 immunoexpression as well as urea production in M2 macrophages when applied antecedent, concurrent, or subsequent to M2 macrophage polarizing cytokines. Activated FBCM enhanced several proinflammatory cytokines, such as IL-1β and IL-6, in all macrophage subsets while only increasing tumor necrosis factor-α in M1 macrophages. This study elucidates multiple proinflammatory and profibrotic effects of fibroblasts on M1 and M2 macrophages, providing insights into the complex orchestration of macrophage-fibroblast crosstalk in fibrosis and the critical role of fibroblasts in the inflammatory response to injury.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1264-1278"},"PeriodicalIF":4.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955879","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":"Collagen VII Is Associated with Airway Remodeling, Honeycombing, and Fibroblast Foci in Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis","authors":"Barbora Svobodová ,&nbsp;Anna Löfdahl ,&nbsp;Måns Kadefors ,&nbsp;Salad Mohamed Ali ,&nbsp;Oskar Rosmark ,&nbsp;Pavan Prabhala ,&nbsp;Mattias Magnusson ,&nbsp;Hans Brunnström ,&nbsp;Sofia Lundin ,&nbsp;Göran Dellgren ,&nbsp;Catharina Müller ,&nbsp;Linda Elowsson ,&nbsp;Gunilla Westergren-Thorsson","doi":"10.1016/j.ajpath.2025.03.013","DOIUrl":"10.1016/j.ajpath.2025.03.013","url":null,"abstract":"<div><div>Collagen VII is an essential anchoring protein in the basement membrane zone, maintaining the attachment of stratified and pseudostratified epithelia to the underlying interstitial matrix. However, collagen VII is largely unexplored in normal lungs and idiopathic pulmonary fibrosis (IPF), a disease characterized by excessive accumulation of extracellular matrix and aberrant re-epithelialization of fibrotic lung parenchyma. Analysis of collagen VII protein and mRNA encoded by <em>COL7A1</em> gene in IPF distal lungs demonstrated elevated levels compared with those in normal lungs. To investigate its cellular source and spatial distribution in lung tissue, immunohistochemistry, RNAscope <em>in situ</em> hybridization, and cell culture experiments, in combination with analysis of public transcriptomic data sets were performed. In the IPF lungs, collagen VII was abundant in pathologically remodeled airways and honeycomb cysts, associated with increased basal cell populations. In contrast, in the control lungs, collagen VII was mainly localized in larger airways. RNA sequencing data revealed that epithelial basal cells and KRT5^–/KRT17⁺ aberrant basaloid cells are the primary sources of COL7A1 mRNA expression. Furthermore, COL7A1 mRNA was observed in mesenchymal subsets, and both COL7A1 mRNA and the protein were observed in fibroblast foci, another histopathologic feature of IPF. <em>In vitro</em>, COL7A1 mRNA expression was increased in normal human lung fibroblasts treated with transforming growth factor-β1. These findings suggest that collagen VII could be involved in the process of abnormal re-epithelialization in lung fibrosis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1467-1483"},"PeriodicalIF":4.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963504","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":"Transcription Factor YY2 Inhibits Tumor Cell Glutamine Catabolism by Regulating GLS1 RNA Splicing Isoform GAC","authors":"Jingyi Liu ,&nbsp;Juan Li ,&nbsp;Yanjun Li ,&nbsp;Mankun Wei ,&nbsp;Debing Xiang ,&nbsp;Hezhao Zhao ,&nbsp;Makoto Miyagishi ,&nbsp;Vivi Kasim ,&nbsp;Shourong Wu","doi":"10.1016/j.ajpath.2025.04.003","DOIUrl":"10.1016/j.ajpath.2025.04.003","url":null,"abstract":"<div><div>The metabolic reprogramming of amino acids is critical for tumorigenesis. Alterations in amino acid metabolism are frequently observed in tumors and are crucial for fulfilling the demand for macromolecular biosynthesis, redox balance, and energy production in tumor cells. Despite its importance, the mechanism regulating amino acid metabolic reprogramming in tumor cells has not been completely elucidated. Herein, colorectal cancer and hepatocarcinoma cells were used to show that Yin yang 2 (YY2) significantly reduced the transcriptional activity of glutaminase 1 (<em>GLS1</em>), which hydrolyzes glutamine to glutamate, by decreasing the expression of glutaminase C, a splicing isoform of GLS1. This, in turn, promoted glutamine accumulation while decreasing that of glutamate, leading to a drop in DNA and <em>de novo</em> glutathione synthesis, followed by a reduction in tumor cell proliferation and antioxidant capacity. Subsequently, YY2/GLS1–mediated inhibition of glutamine catabolism significantly suppressed tumorigenic potential <em>in vivo</em>. Critically, mutant YY2, often found in clinical tumor samples, failed to exert this effect. Together, these results identified YY2/glutaminase C as a negative regulator of glutamine catabolism in tumor cells and revealed a novel molecular mechanism underlying the tumor-suppressive effect of YY2. Moreover, these findings suggest that YY2 could serve as an antitumor therapeutic agent by targeting glutamine metabolism.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1340-1357"},"PeriodicalIF":4.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958053","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":"Blowing Dust Off the Archives","authors":"Richard N. Mitchell","doi":"10.1016/j.ajpath.2024.08.016","DOIUrl":"10.1016/j.ajpath.2024.08.016","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 5","pages":"Pages 812-813"},"PeriodicalIF":4.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860411","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}