Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115685
Alexandra G Bardon, Jesus J Ballesteros, Scott L Brincat, Jefferson E Roy, Meredith K Mahnke, Yumiko Ishizawa, Emery N Brown, Earl K Miller
{"title":"Convergent effects of different anesthetics on changes in phase alignment of cortical oscillations.","authors":"Alexandra G Bardon, Jesus J Ballesteros, Scott L Brincat, Jefferson E Roy, Meredith K Mahnke, Yumiko Ishizawa, Emery N Brown, Earl K Miller","doi":"10.1016/j.celrep.2025.115685","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115685","url":null,"abstract":"<p><p>Many anesthetics cause loss of consciousness despite having diverse underlying molecular and circuit actions. To explore the convergent effects of these drugs, we examine how anesthetic doses of ketamine and dexmedetomidine affect bilateral oscillations in the prefrontal cortex of nonhuman primates. Both anesthetics increase phase locking in the ventrolateral and dorsolateral prefrontal cortex, within and across hemispheres. However, the nature of the phase locking varies. Neighboring prefrontal subregions within a hemisphere show decreased phase alignment with both drugs. Local analyses within a region suggest that this finding could be explained by broad cortical distance-based effects, such as large traveling waves. In contrast, homologous areas across hemispheres become more aligned in phase. Our results suggest that both anesthetics induce strong patterns of cortical phase alignment that are markedly different from those during waking and that these patterns may be a common feature driving loss of responsiveness from different anesthetic drugs.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115685"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115677
Leyao Yu, Patricia Dugan, Werner Doyle, Orrin Devinsky, Daniel Friedman, Adeen Flinker
{"title":"A left-lateralized dorsolateral prefrontal network for naming.","authors":"Leyao Yu, Patricia Dugan, Werner Doyle, Orrin Devinsky, Daniel Friedman, Adeen Flinker","doi":"10.1016/j.celrep.2025.115677","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115677","url":null,"abstract":"<p><p>The ability to connect the form and meaning of a concept, known as word retrieval, is fundamental to human communication. While various input modalities could lead to identical word retrieval, the exact neural dynamics supporting this process relevant to daily auditory discourse remain poorly understood. Here, we recorded neurosurgical electrocorticography (ECoG) data from 48 patients and dissociated two key language networks that highly overlap in time and space, critical for word retrieval. Using unsupervised temporal clustering techniques, we found a semantic processing network located in the middle and inferior frontal gyri. This network was distinct from an articulatory planning network in the inferior frontal and precentral gyri, which was invariant to input modalities. Functionally, we confirmed that the semantic processing network encodes word surprisal during sentence perception. These findings elucidate neurophysiological mechanisms underlying the processing of semantic auditory inputs ranging from passive language comprehension to conversational speech.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115677"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115647
Saar Krell, Amit Hamburg, Ofer Gover, Kfir Molakandov, Gil Leibowitz, Kfir Sharabi, Michael D Walker, Aharon Helman
{"title":"Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling.","authors":"Saar Krell, Amit Hamburg, Ofer Gover, Kfir Molakandov, Gil Leibowitz, Kfir Sharabi, Michael D Walker, Aharon Helman","doi":"10.1016/j.celrep.2025.115647","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115647","url":null,"abstract":"<p><p>Precise regulation of insulin secretion by pancreatic β cells is essential to prevent excessive insulin release. Here, we show that the nutrient sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) is rapidly activated by glucose in β cells via the insulin secretion machinery, positioning mTORC1 as a sensor of β cell activity. Acute pharmacological inhibition of mTORC1 during glucose stimulation enhances insulin release, suggesting that mTORC1 acts as an intrinsic feedback regulator that restrains insulin secretion. Phosphoproteomic profiling reveals that mTORC1 modulates the phosphorylation of proteins involved in actin remodeling and vesicle trafficking, with a prominent role in the RhoA-GTPase pathway. Mechanistically, mTORC1 promotes RhoA activation and F-actin polymerization, limiting vesicle movement and dampening the second phase of insulin secretion. These findings identify a glucose-mTORC1-RhoA signaling axis that forms an autonomous feedback loop to constrain insulin exocytosis, providing insight into how β cells prevent excessive insulin release and maintain metabolic balance.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115647"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-08DOI: 10.1016/j.celrep.2025.115512
Jamal Fahoum, Maria Billan, Julia K Varga, Dan Padawer, Yelena Britan-Rosich, Maya Elgrably-Weiss, Pallabi Basu, Miri Stolovich-Rain, Leah Baraz, Einav Cohen-Kfir, Sujata Kumari, Esther Oiknine-Djian, Manoj Kumar, Orly Zelig, Guy Mayer, Michail N Isupov, Dana G Wolf, Shoshy Altuvia, Reuven Wiener, Ora Schueler-Furman, Alexander Rouvinski
{"title":"Transfer of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition.","authors":"Jamal Fahoum, Maria Billan, Julia K Varga, Dan Padawer, Yelena Britan-Rosich, Maya Elgrably-Weiss, Pallabi Basu, Miri Stolovich-Rain, Leah Baraz, Einav Cohen-Kfir, Sujata Kumari, Esther Oiknine-Djian, Manoj Kumar, Orly Zelig, Guy Mayer, Michail N Isupov, Dana G Wolf, Shoshy Altuvia, Reuven Wiener, Ora Schueler-Furman, Alexander Rouvinski","doi":"10.1016/j.celrep.2025.115512","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115512","url":null,"abstract":"<p><p>SARS-CoV-2 infection triggers a strong antibody response toward nucleocapsid protein (NP), suggesting its extracellular presence beyond intravirion RNA binding. Our co-culture experiments show NP decorates infected and proximal uninfected cell surfaces. We propose a mechanism whereby extracellular NP on uninfected cells contributes to COVID-19 pathogenicity. We show that NP binds to cell-surface sulfated glycosaminoglycans using its RNA-binding sites, facilitated by the flexible, positively charged linker. Coating uninfected lung-derived cells with NP attracted anti-NP IgG from lung fluids and sera of COVID-19 patients. Immune recognition was significantly higher in moderate versus mild COVID-19. Binding of anti-NP IgG in sera generated clusters, triggering C3b deposition via the classical complement pathway on SARS-CoV-2 non-susceptible cells co-cultured with infected cells. The heparin analog enoxaparin outcompeted NP binding, rescuing cells from anti-NP IgG-mediated complement deposition. Our findings reveal how extracellular NP may exacerbate COVID-19 damage and suggest preventative therapy avenues.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115512"},"PeriodicalIF":7.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115679
Zhuo Wang, Wendong Guo, Xiaowen Zhang, Yufei Wei, Wanying Zhang, Ning Du, Chunlu Li, Xuan Wu, Fei Yi, Tingting Zhou, Xiang Dong, Qiqiang Guo, Hongde Xu, Erli Wang, Na Li, Rong Cheng, Ziwei Li, Xiaoyu Song, Yingxian Sun, Xun Sun, Liu Cao
{"title":"Tumor microenvironment-associated oxidative stress impairs SIRT1 secretion to suppress anti-tumor immune response.","authors":"Zhuo Wang, Wendong Guo, Xiaowen Zhang, Yufei Wei, Wanying Zhang, Ning Du, Chunlu Li, Xuan Wu, Fei Yi, Tingting Zhou, Xiang Dong, Qiqiang Guo, Hongde Xu, Erli Wang, Na Li, Rong Cheng, Ziwei Li, Xiaoyu Song, Yingxian Sun, Xun Sun, Liu Cao","doi":"10.1016/j.celrep.2025.115679","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115679","url":null,"abstract":"<p><p>Sirtuin-1 (SIRT1) is a classical histone deacetylase well known for its roles in intracellular pathways such as energy metabolism, DNA damage response, and genome stability maintenance. We report that SIRT1 can be secreted into the tumor microenvironment (TME) through an unconventional protein secretion pathway, effectively inhibiting tumor growth. However, under the stressful conditions of the TME, SIRT1 undergoes increased methylation, which impedes its secretion. Consequently, tumor-infiltrating M2 macrophages are unable to acquire sufficient SIRT1 from the TME, resulting in a significant decrease in SIRT1 levels within these cells. This SIRT1 decline leads to elevated expression of programmed cell death ligand 1 (PD-L1) on M2 macrophages, which in turn contributes to CD8<sup>+</sup> T cell exhaustion through the programmed cell death protein 1/PD-L1 interaction pathway. These findings unveil the multifaceted roles and regulatory mechanisms of SIRT1 within the complex TME, providing deeper insights that significantly enhance our understanding of tumor immune-evasion strategies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115679"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115698
Daniel A Skelly, John P Graham, Mingshan Cheng, Mayuko Furuta, Andrew Walter, Thomas A Stoklasek, Hongyuan Yang, Timothy M Stearns, Olivier Poirion, Ji-Gang Zhang, Jessica D S Grassmann, Diane Luo, William F Flynn, Elise T Courtois, Chih-Hao Chang, David V Serreze, Francesca Menghi, Laura G Reinholdt, Edison T Liu
{"title":"Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response.","authors":"Daniel A Skelly, John P Graham, Mingshan Cheng, Mayuko Furuta, Andrew Walter, Thomas A Stoklasek, Hongyuan Yang, Timothy M Stearns, Olivier Poirion, Ji-Gang Zhang, Jessica D S Grassmann, Diane Luo, William F Flynn, Elise T Courtois, Chih-Hao Chang, David V Serreze, Francesca Menghi, Laura G Reinholdt, Edison T Liu","doi":"10.1016/j.celrep.2025.115698","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115698","url":null,"abstract":"<p><p>Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy is experimentally challenging. Our approach, utilizing the Collaborative Cross mouse genetic resource, fixes the tumor genomic configuration while varying host genetics. We find that response to anti-PD-1 (aPD1) immunotherapy is significantly heritable in four distinct murine tumor models (H<sup>2</sup>: 0.18-0.40). For the MC38 colorectal carcinoma system, we map four significant ICI response quantitative trait loci (QTLs) with significant epistatic interactions. The differentially expressed genes within these QTLs that define responder genetics are highly enriched for processes involving antigen processing and presentation, allograft rejection, and graft vs. host disease (all p < 1 × 10<sup>-10</sup>). Functional blockade of two top candidate immune targets, GM-CSF and IL-2RB, completely abrogates the MC38 transcriptional response to aPD1 therapy. Thus, our in vivo experimental platform is a powerful approach for discovery of host genetic factors that establish the tumor immune microenvironment propitious for ICI response.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115698"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Overcoming NK-mediated rejection by anti-3<sup>rd</sup>-party central memory veto CD8 T cells through downregulation of DNAM-1 on alloreactive NK cells.","authors":"Wei-Hsin Liu, Aloukick Kumar Singh, Christa Blagdon, Sandeep Kumar Yadav, Einav Shoshan, Esther Bachar-Lustig, Yair Reisner","doi":"10.1016/j.celrep.2025.115674","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115674","url":null,"abstract":"<p><p>Anti-3<sup>rd</sup>-party central memory veto CD8 T (veto Tcm) cells can overcome T cell-mediated graft rejection under mild conditioning without causing significant graft versus host disease (GVHD). We previously demonstrated that these veto Tcm cells can effectively delete anti-donor T cell clones through a Fas-FasL mechanism, whereas their ability to neutralize alloreactive natural killer (NK) cells and the mechanism of such potential activity remained unknown. Using \"nude\" mice as recipients of allogeneic T cell-depleted hematopoietic stem cell transplantation (HSCT), we demonstrate effective inhibition of NK-mediated rejection by Tcm cells. Ex vivo studies revealed that Tcm cells express high levels of CD155, the ligand of the activating receptor DNAX accessory molecule-1 (DNAM-1). Conjugate formation between alloreactive NK cells and the veto cells induces NK anergy through a unique mechanism mediated by DNAM-1 internalization and degradation. These insights on veto Tcm cells and their impact on alloreactive NK cells offer potential translational approaches for haploidentical bone marrow transplantation and off-the-shelf chimeric antigen receptor (CAR) cell therapies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115674"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115682
Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu
{"title":"Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.","authors":"Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu","doi":"10.1016/j.celrep.2025.115682","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115682","url":null,"abstract":"<p><p>The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115682"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115687
Elizabeth Abraham, Aleksandra Kostina, Brett Volmert, Thomas Roule, Ling Huang, Jingting Yu, April E Williams, Emily Megill, Aidan Douglas, Olivia M Pericak, Alex Morris, Eleonora Stronati, Arantza Larrinaga-Zamanillo, Raquel Fueyo, Mikel Zubillaga, Mark D Andrake, Naiara Akizu, Aitor Aguirre, Conchi Estaras
{"title":"A retinoic acid:YAP1 signaling axis controls atrial lineage commitment.","authors":"Elizabeth Abraham, Aleksandra Kostina, Brett Volmert, Thomas Roule, Ling Huang, Jingting Yu, April E Williams, Emily Megill, Aidan Douglas, Olivia M Pericak, Alex Morris, Eleonora Stronati, Arantza Larrinaga-Zamanillo, Raquel Fueyo, Mikel Zubillaga, Mark D Andrake, Naiara Akizu, Aitor Aguirre, Conchi Estaras","doi":"10.1016/j.celrep.2025.115687","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115687","url":null,"abstract":"<p><p>In cardiac progenitor cells (CPCs), retinoic acid (RA) signaling induces atrial lineage gene expression and acquisition of an atrial cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (i.e., scRNA-seq and snATAC-seq) to untreated and RA-treated human embryonic stem cell (hESC)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP1 and TEAD4 are integrated with the atrial transcription factor enhancer network and that YAP1 activates RA enhancers in CPCs. Furthermore, Yap1 deletion in mouse embryos compromises the expression of RA-induced genes, such as Nr2f2, in the CPCs of the second heart field. Accordingly, in hESC-derived patterned heart organoids, YAP1 regulates the formation of an atrial chamber but is dispensable for the formation of a ventricle. Overall, our findings revealed that YAP1 cooperates with RA signaling to induce atrial lineages during cardiogenesis.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115687"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The m<sup><sup>5</sup></sup>C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.","authors":"Songyu Li, Ya Liu, Xiang Wu, Minjia Pan, Hongxia Zhao, Yunguang Hong, Qinghua Zhang, Shushu Hu, Aorong Ouyang, Guangru Li, Minhui Wu, Shanshan Fan, Zhirong Jia, Shanchao Zhao, Guocai Wu, Xiangwei Gao, Zhigang Yang, Zhanghui Chen","doi":"10.1016/j.celrep.2025.115661","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115661","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is one of the most prevalent heterogeneous hematologic malignancies with a complicated etiology. RNA post-transcriptional modifications have been linked to the incidence and progression of AML, while the detailed mechanism remains to be elucidated. In this study, we find that NOP2/Sun domain family member 2 (NSUN2), a methyltransferase of 5-methylcytosine (m<sup><sup>5</sup></sup>C) RNA methylation, is upregulated in AML and predicts a poor prognosis for patients with AML. Knockdown of NSUN2 in AML cells inhibits proliferation and colony formation and promotes apoptosis. Depletion of NSUN2 in AML mice reduces the tumor burden and prolongs survival. Mechanistically, NSUN2 promotes the expression of phosphoglycerate dehydrogenase (PHGDH) and serine hydroxymethyltransferase 2 (SHMT2), two key enzymes in the serine/glycine biosynthesis pathway, by stabilizing the corresponding mRNAs through regulation of m<sup>5</sup>C modifications. Overall, our findings demonstrate a critical role of NSUN2 in AML development and highlight the therapeutic potential of targeting the NSUN2/m<sup><sup>5</sup></sup>C axis for the treatment of this cancer.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115661"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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