Cell Death & Disease最新文献

{"title":"PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.","authors":"José Manuel Rodríguez-Vargas, Jerónimo Borrego-Pérez, Vanesa Cabeza-Fernández, Esteban Zamudio-Martínez, Francisco Javier Ríos-Sola, David Martín-Oliva, Francisco Abadía-Molina, Françoise Dantzer, F Javier Oliver","doi":"10.1038/s41419-026-09079-0","DOIUrl":"https://doi.org/10.1038/s41419-026-09079-0","url":null,"abstract":"<p><p>Hypoxia, or low oxygen availability, is one of the main factors that determine tumor growth and metastatic survival. The hypoxic response is orchestrated by HIF transcription factors, which activate genetic and metabolic programs that promote angiogenesis, metabolic reprogramming, migration, and ultimately a clinically aggressive phenotype. Mitochondria play a central role in this process, as they are not only the main consumers of oxygen but also undergo morphological and biochemical adaptations that shape how tumor cells respond to a hostile microenvironment. Because the contribution of ADP ribosylation to these mitochondrial adaptations remains unclear, we aimed to define how PARP inhibition influences mitochondrial behavior during hypoxia. To address this question, we first examined how PARP inhibitors affect mitochondrial structure and function under oxygen deprivation. We found that PARP inhibition drives a shift toward a small, globular mitochondrial phenotype characterized by membrane depolarization (ΔΨm) and enhanced fission. Given that mitochondrial morphology is tightly linked to metabolic state, we next investigated whether these structural changes altered hypoxia induced metabolic reprogramming. PARP inhibition prevented the typical shift toward anaerobic glycolysis, forcing tumor cells to activate the AMPk/mitophagy axis as an alternative survival pathway. Finally, to determine the functional consequences of this adaptive response, we assessed tumor cell fitness when mitophagy was impaired. Blocking mitophagy markedly reduced the proliferative and malignant potential of hypoxic tumor cells, thereby increasing their sensitivity to PARP inhibition. Collectively, our results uncover a previously unrecognized pathway of mitochondrial adaptation to hypoxia and reveal a therapeutically relevant crosstalk between mitochondrial dynamics and ADP ribosylation that may be exploited in future anticancer strategies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419034","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":"ATP7A-mediated copper ion efflux reprogrammes tumour immunity and promotes cisplatin resistance in cervical cancer.","authors":"Shuangjia Pan, Qianqian Wu, Hejing Liu, Yujia Zhou, Jiayi Ruan, Yuqing Jin, Lingxiao Huang, Jian'an Zhang, Huihui Ji, Xueqiong Zhu","doi":"10.1038/s41419-026-09082-5","DOIUrl":"10.1038/s41419-026-09082-5","url":null,"abstract":"<p><p>Cisplatin resistance is a major obstacle to effective chemotherapy in patients with cervical cancer and is associated with an immunosuppressive tumour microenvironment. Copper ions are essential trace elements that regulate redox and immune balance. However, the connections among copper ions, cisplatin resistance and immune regulation remain unclear. Here, higher serum copper levels correlated with increased pan-cancer mortality. Integrative transcriptomic and single-cell RNA sequencing analyses revealed lower copper-related transcriptional activity in CD8⁺ T cells from cervical cancer tissues. Multiomics analysis revealed that ATPase copper transporting alpha (ATP7A) expression was upregulated in cisplatin-resistant patients compared with sensitive patients and correlated with poor survival. ATP7A knockdown increased sensitivity to cisplatin and promoted cuproptosis, whereas ATP7A overexpression increased cisplatin resistance and impaired CD8⁺ T cells through copper ion efflux. Furthermore, excess copper ions directly bind to the lymphocyte-specific protein tyrosine kinase (LCK) activation loop (Tyr394), impairing T-cell receptor (TCR) signalling in CD8⁺ T cells. Sex-determining region Y-box 21 (SOX21) directly binds two conserved motifs within the ATP7A promoter (-372 bp and -245 bp) and enhances its transcriptional activity. These results revealed a SOX21/ATP7A/copper ion axis connecting copper ion efflux with immune suppression and cisplatin resistance. Targeting ATP7A or copper ion efflux may restore CD8⁺T-cell activity and enhance the efficacy of cisplatin for the treatment of cervical cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SUMOylation activates ECHS1 for adaptive catabolism in lung cancer.","authors":"Yalan Chen, Hui Mao, Lili Cai, Qianyu Li, Juan Song, Mingming Zhang, Shanshan Chen, Ziqi Ai, Qiangqiang Xiong, Kexin Liu, Xin Lin, Hongsheng Tan, Tianshi Wang, Qiuju Fan, Yong Zuo, Jianli He, Jinke Cheng, Jun Tu","doi":"10.1038/s41419-026-09078-1","DOIUrl":"10.1038/s41419-026-09078-1","url":null,"abstract":"<p><p>Cellular metabolism dynamically adapts to nutrient fluctuations, yet the regulatory mechanisms underlying this plasticity remain incompletely understood. In particular, the adaptive activation mechanism of enoyl-CoA hydratase short-chain 1 (ECHS1), a key mitochondrial enzyme for fatty acid and amino acid catabolism, is poorly characterized. Herein, we identify SUMO1 modification at lysine 128 of ECHS1 as an essential activation switch that drives mitochondrial catabolism and restricts growth of lung cancer cells. Nutrients generating crotonyl-CoA (fatty acids, lysine, tryptophan) stimulate this modification, accelerating crotonyl-CoA oxidation to acetyl-CoA. This metabolic adaptation decreases crotonyl-CoA pools, thereby reducing histone crotonylation (e.g., H2BK20cr and H3K27cr). Conversely, SUMOylation deficiency impairs formation of the catalytic ECHS1 homohexamer, increasing crotonyl-CoA accumulation and histone crotonylation. This epigenetically suppresses oxidative phosphorylation and associated ROS generation while activating PI3K-Akt signaling, promoting lung cancer growth in vitro and in vivo. In lung adenocarcinoma patients, H2BK20cr and H3K27cr levels are elevated in tumor tissues and predict poor survival, highlighting their clinical prognostic significance. Collectively, these findings establish ECHS1 SUMOylation as a nutrient-sensitive activation mechanism for adaptive catabolism and reveal mitochondrial SUMOylation as a critical regulator of nuclear epigenetic reprogramming, defining a metabolite-driven paradigm in cancer epigenetics.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLC22A3 regulates ferroptosis in the mesenchymal subtype of triple-negative breast cancer by modulating histone H3K4 serotonylation.","authors":"Dongsheng Zhai, Wang Li, Guo Chen, Wenli Zhang, Yue Hu, Lele Deng, Dengguo Li, Han Cheng, Jixiang Zhou, Mingkai Li, Li Wang, Lu Zifan","doi":"10.1038/s41419-026-09057-6","DOIUrl":"10.1038/s41419-026-09057-6","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) remains a challenging and clinically aggressive subtype due to its heterogeneity and high mortality rate. Recent molecular subtyping has identified distinct TNBC subgroups with varying therapeutic responses, highlighting the need for targeted therapeutic strategies. The mesenchymal (MES) subtype is characterized by low immune cell infiltration, cancer stem cell-like features, and resistance to multiple drugs. Ferroptosis, a form of iron-dependent cell death, has emerged as a promising therapeutic strategy in TNBC due to the abundance of iron and lipids in tumor cells. However, ferroptosis sensitivity varies across different TNBC subtypes. Notably, the MES subtype exhibits resistance to ferroptosis despite elevated iron levels, due to impaired ferroptosis-executing mechanisms. This study investigates the role of SLC22A3, an organic cation transporter, which is enriched in MES tumors and positively correlates with markers of tumor stem cells. High SLC22A3 expression in MES-TNBC cells modulates serotonin uptake and metabolism, conferring ferroptosis resistance through two pathways. First, 5-HT(serotonin) acts as a radical-trapping antioxidant, eliminating lipid peroxides and inhibiting ferroptosis. Second, 5-HT induces histone serotonylation, which enhances histone methylation and facilitates the recognition of methylated histones by transcriptional initiation factors. This process activates SIRT1 transcription, inhibiting MAOA transcription mediated by FOXO1, thereby reducing 5-HT degradation and promoting ferroptosis resistance. Moreover, we identified potential SLC22A3 inhibitors and their synergistic combinations with ferroptosis inducers or cisplatin, which suppress tumor growth in both MES-subtype TNBC patient-derived organoids and in vivo, offering a promising strategy for personalized therapy. These findings suggest that targeting SLC22A3, along with ferroptosis inducers, may offer a promising therapeutic strategy for patients with MES-subtype TNBC. SLC22A3 affects serotonin uptake and metabolism in MES-TNBC cells, providing ferroptosis resistance through two mechanisms. 5-HT acts as a radical-trapping antioxidant, eliminating lipid peroxides and inhibiting ferroptosis. In addition, 5-HT induces histone serotonylation, which enhances histone methylation and facilitates the recognition of methylated histones by transcription initiation factors. This process activates SIRT1 transcription, inhibiting MAOA transcription mediated by FOXO1, thereby reducing 5-HT degradation and promoting ferroptosis resistance. TKIs served as SLC22A3 inhibitors and their combinations with RSL3 or cisplatin, which inhibit tumor growth in vivo, offering new personalized treatment options for MES-TNBC patients.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HPC restores mitochondrial homeostasis and ameliorates hypoxic stress through the GSK-3β/β-catenin signaling pathway.","authors":"Wenxin Li, Qian Qu, Xingling Liu, Caixu Guo, Guo Shao, Baohui Ma, Jun Lv, Xiaoqiong Hao, Ruifang Qi","doi":"10.1038/s41419-026-09080-7","DOIUrl":"10.1038/s41419-026-09080-7","url":null,"abstract":"<p><p>Hypoxic preconditioning (HPC) can increase the hypoxia tolerance of the mouse hippocampus both in vivo and in vitro by upregulating ATP levels, which may depend on mitochondrial homeostasis. The GSK-3β/β-catenin signaling pathway is involved in neuroprotection after brain ischemia. The aim of this study was to explore whether HPC can activate GSK-3β/β-catenin to improve the hypoxia tolerance of neuronal cells by enhancing mitochondrial homeostasis. In vitro and in vivo analyses revealed that HPC upregulates the activity of the GSK-3β/β-catenin pathway, maintaining mitochondrial morphological stability. Mechanistically, GSK-3β activity is negatively correlated with mitochondrial homeostasis. Pharmacological inhibition of GSK-3β reduced mitochondrial fission, whereas HPC suppressed GSK-3β expression to attenuate fission and preserve mitochondrial integrity. Conversely, GSK-3β overexpression abrogated HPC-mediated protection and exacerbated mitochondrial dysfunction. These findings elucidate a neuroprotective mechanism whereby HPC stabilizes mitochondrial dynamics via modulation of the GSK-3β/β-catenin pathway, providing novel experimental insights into HPC-mediated neuroprotection.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium influx through T-type calcium channels regulates secondary necrosis and inflammation through recruitment of ATG9A-mediated membrane repair.","authors":"Omar F Audi, Dilara C Ozkocak, Chad Johnson, Bo Shi, Jascinta P Santavanond, Caitlin L Vella, Joanne M Hildebrand, Robyn Sharples, Quan Thinh Le, Lesley Cheng Sim, Amy A Baxter, Mark D Hulett, Ivan K H Poon, Thanh Kha Phan","doi":"10.1038/s41419-026-09070-9","DOIUrl":"10.1038/s41419-026-09070-9","url":null,"abstract":"<p><p>Approximately 200-300 billion cells die daily through apoptosis, a prominent form of programmed cell death, to maintain tissue homoeostasis. If apoptotic cells are not efficiently removed by phagocytes, they progress to secondary necrosis when the plasma membrane (PM) becomes permeabilised and release proinflammatory damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP, which drive inflammation and contribute to autoimmune diseases. Thus, controlling inflammation through maintaining PM integrity is critical, however the molecular mechanisms underpinning this is not well defined. Here, we reveal a calcium-dependent process that delays secondary necrosis by promoting PM repair. Mechanistically, calcium influx through T-type voltage-gated calcium channels mediates the recruitment of the lipid scramblase ATG9A and Golgi components to damaged PM regions, thereby preventing early cellular lysis and DAMP release. Inhibition of calcium influx or loss of ATG9A accelerates PM rupture, increases DAMP secretion, and exacerbates inflammatory cell recruitment in vivo. Taken together, this study establishes a novel role for T-type calcium channels and ATG9A in regulating PM repair during apoptosis and highlights their therapeutic potential for controlling unwanted inflammation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid peroxidation impacts orthoflavivirus infection in a virus-dependent manner.","authors":"Kim Chi Thi Vu, Yvonne F Grande, Laura Bierau, Martin Schauflinger, Emilia Spremberg, Joanne Wei Kay Ku, Julia Hehner, Anja Schöbel, Eva Herker","doi":"10.1038/s41419-026-09071-8","DOIUrl":"10.1038/s41419-026-09071-8","url":null,"abstract":"<p><p>Orthoflavivirus infection is intricately linked to host cell lipid metabolism, yet the function of bioactive lipids as regulators of infection remains to be elucidated. Here, we investigated the role of lipid mediator pathways, namely ALOX/COX enzymes and upstream lipases, in orthoflavivirus replication by comparing dengue virus (DENV), Zika virus (ZIKV), wild-type yellow fever virus (YFV-Asibi), and the live-attenuated vaccine strain YFV-17D. DENV, ZIKV, and YFV-Asibi, but not the vaccine strain, induced COX2 expression in Huh7 hepatoma cells, correlating with prostaglandin E2 (PGE2) levels in culture supernatants. All four viruses replicated more efficiently in COX2-, ALOX15-, and MGLL-deficient cells, indicating a broadly antiviral role for these enzymes. In contrast, DENV and ZIKV specifically induced ALOX12 expression and depended on ALOX12 for efficient viral RNA replication, as demonstrated by reduced genome copy numbers, altered dsRNA replication compartment morphology, and decreased infectious titers in ALOX12-depleted cells. Direct measurement of lipid peroxidation revealed that ZIKV infection markedly elevated lipid peroxide levels through both ALOX12-dependent and -independent mechanisms, whereas DENV infection did not cause detectable lipid peroxide accumulation. Consistent with this, the ferroptosis inhibitor ferrostatin impaired DENV replication, while the ferroptosis inducer erastin enhanced it; this proviral effect of erastin was fully abolished by ALOX12 knockdown, indicating that DENV depends entirely on ALOX12-driven lipid peroxidation. Iron chelation reduced both DENV and ZIKV infection, confirming a requirement for iron-dependent oxidative processes. The proviral role of lipid peroxidation extended beyond hepatoma cells, as ferrostatin treatment significantly reduced DENV and ZIKV infection in human microglia cells. Our results reveal virus-specific exploitation of lipid peroxidation pathways by orthoflaviviruses and identify ALOX12-dependent lipid peroxidation as a novel proviral mechanism that may represent a target for antiviral intervention.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of haploinsufficiency in human neural progenitor cells: insights into early molecular effects of autism-related genes.","authors":"Roni Sarel-Gallily, Assa Sherman, Daniel Pollak, Nissim Benvenisty","doi":"10.1038/s41419-026-09085-2","DOIUrl":"10.1038/s41419-026-09085-2","url":null,"abstract":"<p><p>Haploinsufficiency describes a phenomenon where one functional allele of a gene in a diploid cell or organism is insufficient for a normal phenotype. There are several neurodevelopmental disorders (NDD) affected by the haploinsufficiency phenomenon, and many of them are related to autism spectrum disorder (ASD). Here, we aim to identify genes involved in the early stages of neural differentiation when one of the two alleles is lost. We thus differentiated a genome-wide heterozygous loss-of-function CRISPR library into neural progenitor cells (NPCs) and defined about 250 genes essential for neural differentiation in a haploinsufficient manner. We were able to identify NDD-related dosage-sensitive pathways and pinpoint specific molecular processes affected by ASD-related genes. By comparing the molecular phenotypes of homozygote and heterozygote mutations, we could illuminate overlapping and distinct transcriptional pathways affected in the two mutant models, along with partial chemical rescue of some of these phenotypes. Our work provides a comprehensive framework for exploring dosage-sensitive regulation in early neural development and offers new insights into the embryonic molecular basis of ASD and other NDDs driven by gene dosage imbalance.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E3 ligase FBXO2-mediated protein stability of insulin receptor regulates adipogenesis and metabolic health in obesity.","authors":"Yue Xin, Jiaxin Liu, Zhaoyi Zhai, Haofeng Wu, Muchen Wu, Xueqin Wu, Ruiping Wang, Qi Wang, Xiaowei Jia, Lulu Wang, Hongwei Shang, Xin Lu, Meng Zhou, Tao Lu, Chun Yang, Dongliang Fang, Yan Gao","doi":"10.1038/s41419-026-09096-z","DOIUrl":"10.1038/s41419-026-09096-z","url":null,"abstract":"<p><p>Adipogenesis, a crucial physiological process, serves to safely sequester lipids, thereby preventing lipotoxicity in peripheral organs and preserving metabolic health during obesity. While insulin signaling plays a pivotal role in adipogenesis, regulating factors, especially the braking mechanism governing this process, warrant further investigation. Our study identified proteasome-dependent degradation of the insulin receptor (IR) during the early stages of adipogenesis as a critical event for the mitotic clonal expansion phase of the adipocyte differentiation program. A series of studies confirmed that the ubiquitinated modification of IR is regulated by E3 ligase FBXO2, and this is based on IR phosphorylation. We further elucidated that the FBD domain of FBXO2 is indispensable for its function in catalyzing p-IR ubiquitination. Gain or loss of function of Fbxo2 inhibited or promoted SVF or 3T3L1 cells proliferation and adipogenesis both in vitro and in vivo, which regulated adipose hyperplasia and plasticity of adipose tissue. Moreover, FBXO2 played an important role in regulating the metabolic health of mice when subjected to caloric excess. Collectively, our findings unveil FBXO2 as a negative regulator of adipogenesis by impairing the insulin signaling pathway.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRRC2A-mediated m⁶A modification on NCOA4 promotes thymic epithelial tumor progression through PKM2-induced glycolysis.","authors":"Tao Wang, Lang Xia, Lei Zhang, Yuntao Feng, Haoran E, Jueming Yu, Hongbo Huang, Junqi Wu, Chang Chen, Yue Zhao, Deping Zhao","doi":"10.1038/s41419-026-08883-y","DOIUrl":"10.1038/s41419-026-08883-y","url":null,"abstract":"<p><p>Thymic epithelial tumors (TETs) are heterogeneous neoplasms. While most early-stage cases are curable after resection, advanced or aggressive subtypes have limited treatment options and poor outcomes. The molecular mechanisms underlying their metabolic reprogramming remain poorly understood. Proline-rich Coiled-coil 2a (PRRC2A), a N6-methyladenosine (m⁶A) reader protein, is significantly upregulated in TET tissues and is associated with poor clinical outcomes. Multi-omics analyses and molecular experiments revealed that PRRC2A binds to m⁶A-modified sites within the NCOA4 mRNA, thereby stabilizing NCOA4 transcripts and enhancing its protein expression. Elevated NCOA4 interacts with PKM2, a rate-limiting glycolytic enzyme, resulting in increased glycolysis and promoting TETs progression. In vivo experiments showed that inhibition of PRRC2A suppressed tumor growth and metastasis in TETs, while combined treatment with the PKM2 inhibitor C599 and PRRC2A knockdown produced enhanced antitumor effects. These findings provide novel insights into the glycolytic metabolic regulation of TETs and suggest that the PRRC2A-NCOA4-PKM2 axis represents a promising therapeutic target.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}