Cell Discovery最新文献

{"title":"Manganese: biology, physiology and role in disease.","authors":"Zhidan Xia, Xinran Li, Rui Liu, Karin Tuschl, Junxia Min, Fudi Wang","doi":"10.1038/s41421-026-00894-5","DOIUrl":"10.1038/s41421-026-00894-5","url":null,"abstract":"<p><p>Manganese (Mn) has lingered in the shadows as a mere enzymatic cofactor, with its profound role in regulating the most fundamental life processes largely overlooked. This review heralds a \"manganese renaissance\" - a paradigm shift that elevates Mn from a passive trace element to a dynamic architect of metabolic homeostasis and a critical driver of disease. We synthesize breakthroughs that redefine its biological significance. In addition to enabling reactions for enzymes such as MnSOD, Mn actively governs lipid trafficking via the modulation of the COPII complex, facilitates cGAS/STING signaling for host immune responses, and precisely activates ion transporters and sensors to maintain cellular homeostasis. Dysregulated Mn homeostasis - whether stemming from genetic defects in key transporters (SLC30A10, SLC39A8, SLC39A11, and SLC39A14) or environmentally induced overload - fuels a spectrum of pathologies, including metabolic syndrome, Parkinsonism-like neurodegeneration, hepatic dysfunction, cardiovascular disease, and immune dysfunction. This disruption underscores the irreplaceable role of Mn as a biological linchpin, as its balance is not merely supportive but also central to sustaining health. In the future, we outline translational frontiers - from dietary Mn modulation and transporter-specific therapies for genetic Mn disorders to the elucidation of Mn signaling and the development of exposure guidelines to safeguard public health. This synthesis reaffirms that Mn is far more important than simply functioning as a nutrient. Research into Mn functions has been conducted across biology, environmental science, and medicine, and Mn acts as a master regulator whose emerging mechanisms will reshape our understanding of metabolic health and disease pathogenesis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263365","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":"Top-down medial prefrontal cortex-to-hypothalamic paraventricular nucleus circuit regulates social avoidance and conditioned fear in male mice.","authors":"Yu Wang, Xiang-Yu Pan, Bo Wu, Dan-Yang Li, Shuo-Wen Wang, Xin-Ya Qin, Qing-Hong Shan, Peng Chen, Pu Hu, Hao Wang, Rong-Yu Liu, Hui Gong, Jiang-Ning Zhou","doi":"10.1038/s41421-026-00893-6","DOIUrl":"10.1038/s41421-026-00893-6","url":null,"abstract":"<p><p>Compromised cortical inhibition during threat processing contributes to individual vulnerability to stress-related psychiatric disorders. However, the precise underlying neurobiological circuits remain elusive. Here, by combining monosynaptic viral tracing, electrophysiology, in vivo calcium imaging, and functional manipulations in mice, we elucidated a functionally specialized monosynaptic pathway originating from glutamatergic pyramidal neurons in the ventromedial prefrontal cortex (vmPFC^Glu) to corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN^CRH). We found that activating medial prefrontal cortex (mPFC)-driven CRH \"pacemaker\" cells propagated calcium signals within the local CRH network of the PVN. Hyperactivity of this vmPFC^Glu-PVN^CRH circuit promoted persistent social avoidance, consolidated threat memory, facilitated auditory-cued fear acquisition, and impaired extinction. Conversely, inhibition of this circuit selectively reduced social stress‑induced avoidance. Our findings define a novel top-down circuit that specifically controls psychosocial stress responses and amplifies susceptibility to conditioned fear.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13250170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148210314","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":"Trans-ethnic estimation and implications of genetic impact on continuous glycemic profiles.","authors":"Evan Yi-Wen Yu, Hui-Ying Ren, Xinxiu Liang, Yue Xi, Menglei Shuai, Zelei Miao, Fengzhe Xu, Ke Zhang, Luqi Shen, Hui Xia, Miranda T Schram, Marleen van Greevenbroek, Bastiaan E de Galan, Carla J H van der Kallen, David E J Linden, Gabriëlla A M Blokland, Ilja C W Arts, Tos T J M Berendschot, Yan Yan, Yuanqing Fu, Anke Wesselius, Yuming Chen, Ju-Sheng Zheng","doi":"10.1038/s41421-026-00897-2","DOIUrl":"10.1038/s41421-026-00897-2","url":null,"abstract":"<p><p>The genetic architecture of glycemic dynamic metrics derived from continuous-glucose monitoring (CGM) across different populations remains poorly understood. Here, we conducted a trans-ethnic genome-wide association study (GWAS) meta-analysis of 20 CGM-derived glycemic traits, building upon a previously established European-ancestry CGM dataset and extending it through the inclusion of additional cohorts, in up to 9677 individuals originating from 2051 Chinese, 901 Dutch, and 6725 Israelis. Across 20 glycemic traits, we identified 18 genome-wide significant associations, of which 9 met study-wide significance, and three variants were novel. These variants indicated a shared genetic basis for continuous glycemic regulation and exhibited consistent patterns with those of sequential fingerstick glucose tests. Our findings further demonstrated that the identified genetic variants were enriched in pathways related to the nervous system. These findings were further supported by observed associations with brain magnetic resonance imaging (MRI) metrics, high CGM-related gene expression and co-regulation of quantitative trait loci in brain tissues. Additionally, we observed a positive relationship between genetic liability for the coefficient of variation (CV) and total cholesterol and a bi-directional putative causal relationship between hyperglycemia and type 1 diabetes across trans-ethnic populations. Moreover, we established a polygenic risk score (PRS) for additional participants and reported that certain glycemic traits were significantly associated with the risk of diabetes or pre-diabetes. These variants constituting the PRS demonstrated high transferability across general populations and pregnant women. Overall, our study yields unique insights into the high trans-ethnic and generalizable genetic architecture of CGM-derived glycemic profiles, supporting improved characterization of interindividual differences in glycemic dynamics and underscoring the potential for more personalized glucose management.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13237324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148162010","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":"Structural basis for a central permeation pathway in the P2X1 receptor.","authors":"Heng Zhang, Pengpeng Wu, Zhiyong Gu, Youwei Xu, Wen Hu, Qingning Yuan, Bingqing Xia, H Eric Xu, Zhaobing Gao","doi":"10.1038/s41421-026-00881-w","DOIUrl":"10.1038/s41421-026-00881-w","url":null,"abstract":"<p><p>The ion permeation pathway is a critical determinant of ion channel function and selectivity; however, the structural basis for ion permeation in the P2X1 receptor, an ATP-gated ion channel crucial for platelet activation, thrombosis, and male infertility, remains incompletely understood. Here, we present high-resolution cryo-electron microscopy (cryo-EM) structures of the P2X1 receptor, which reveal a central ion permeation pathway spanning the entire extracellular domain, complementing the existing paradigms of ion channel architecture for the P2X receptor family. Within this pathway, we identify specific sites that coordinate hydrated calcium ions, including an aspartate ring that acts as a selectivity filter at the apex of the central vestibule. We also discover that a small molecule, 3,5-bis(trifluoromethyl)aniline, binds at the top of the central vestibule and potently inhibits cation flux through this central permeation pathway. Our findings reveal a new inhibitor-binding site in the P2X1 receptor. These insights provide a structural framework for the rational design of subtype-specific P2X receptor inhibitors targeting the central vestibule.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13237026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161991","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":"A spatiotemporal gating hypothesis for psilocybin plasticity: reconciling the 5-HT₂A-TrkB mechanistic paradox.","authors":"Gang Pei","doi":"10.1038/s41421-026-00906-4","DOIUrl":"10.1038/s41421-026-00906-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13221458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052976","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":"Selective cellular localization of UHRF1 safeguards mammalian zygotic genome activation and early embryonic development.","authors":"Rui Yan, Xin Cheng, Xin Long, Yating Zhu, Qiancheng Zhang, Fengyuan Sun, Fan Zhang, Mengyue Wang, Ruifeng Zhang, Tianzi Guo, Xinling Hou, Dongmei Ji, Yunxia Cao, Fei Gao, Dan Liang, Fan Guo","doi":"10.1038/s41421-026-00896-3","DOIUrl":"10.1038/s41421-026-00896-3","url":null,"abstract":"<p><p>Zygotic genome activation (ZGA) is essential for initiating the developmental gene expression program in early embryos. However, whether a gating mechanism orchestrated by a limited number of factors exists in mammals remains debated. In this study, by utilizing an Nlrp14-deficient model that intriguingly disrupts the zygotic localization of UHRF1 and DNMT1, and in combination with comprehensive genetic approaches, we demonstrated that the nuclear exclusion of UHRF1 is essential for mouse ZGA and subsequent developmental progression. Mechanistically, the failure to exclude UHRF1 and DNMT1 from the nucleus in zygotes would impede DNA demethylation in LINE1 elements, promote UHRF1 binding to silence their expression, thereby reducing global chromatin accessibility and inhibiting ZGA. This effect was rescued in Uhrf1/Nlrp14 double knockout (DKO) embryos, which still exhibited heavy DNA methylation, highlighting a dispensable role of UHRF1 in the maintenance of genome-wide DNA methylation after fertilization. Furthermore, reducing DNA methylation through Dnmt1/Nlrp14 DKO or inhibiting the DNA methylation-binding domains of UHRF1 mitigated the adverse effects of nuclear-localized UHRF1 and reactivated the ZGA genes. Finally, we demonstrated that the residual nuclear UHRF1 in normal embryos binds to and facilitates the transcriptional inactivation of specific LTR subtypes that evade DNA demethylation during the genome-wide epigenetic reprogramming. Our findings not only highlight the biological significance of UHRF1 and DNMT1 nuclear exclusion but also elucidate the potentially conserved mechanism that regulates ZGA during mammalian preimplantation development.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13212597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027423","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":"WAT-to-BAT communication facilitates the sustained activation of BAT thermogenesis during cold exposure.","authors":"Jieyuan Xue, Ding Chen, Chenfeng Wang, Jue Wang, Jiayu Zhou, Wenyan Li, Junxi Qian, Yuanji Huang, Liang Fang, Hongyong Song, Ben He, Xu-Yun Zhao","doi":"10.1038/s41421-026-00891-8","DOIUrl":"10.1038/s41421-026-00891-8","url":null,"abstract":"<p><p>The activation of brown adipose tissue (BAT) for thermogenesis represents a crucial physiological mechanism that helps maintain body temperature during cold exposure. Nevertheless, the exact mechanisms underlying the sustained activation of BAT under cold conditions remain incompletely understood. In this study, we reveal that soluble ST2 (sST2) mediates a white adipose tissue (WAT)-to-BAT endocrine mechanism that is essential for the continuous activation of BAT during cold exposure. Specific depletion of sST2 blocks alternative thermogenesis following BAT denervation and renders mice sensitive to cold during prolonged cold exposure. Mechanistically, sST2 is induced and secreted from epididymal white adipose tissue (eWAT) upon the activation of Creb1, which is driven by β1 and β2 adrenergic receptor signaling. Secreted sST2 directly binds to the β3 adrenergic receptor in BAT and, in synergy with norepinephrine, induces BAT thermogenesis independent of IL33. Additionally, supplementation with sST2 promotes beige fat formation. Therefore, our study illustrates a novel mechanism through which the adipokine sST2 derived from eWAT mediates sustained BAT activation during cold exposure through the integration of neural and humoral signals. More importantly, sST2 exerts a synergistic effect on BAT activation when combined with β3-adrenergic receptor agonists.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13212969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148026678","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":"Exosomal ORF3a mediates lung-liver axis to dysregulate hepatic lipid metabolism in mild COVID-19.","authors":"Yafei Qu, Jinglin Zhou, Xinjia Wang, Shupeng Dong, Jingjiao Li, Lingxi Qiu, Lu Bian, Weiming Yuan, Qing Xie, Jieming Qu, Zhen Zhao, Xianfang Wu, Qiming Liang","doi":"10.1038/s41421-026-00901-9","DOIUrl":"10.1038/s41421-026-00901-9","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13198539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004841","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":"Spatial single-cell landscape of tumor-associated macrophages and their crosstalk with the tumor microenvironment.","authors":"Rui-Chao Nie, Guo-Sheng Hu, Shi-Qiang Cao, An Wang, Du-Chuang Wang, Wen Liu","doi":"10.1038/s41421-026-00888-3","DOIUrl":"10.1038/s41421-026-00888-3","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) constitute a critical immune cell population within the tumor microenvironment (TME) and exhibit high functional heterogeneity. In this study, a pan-cancer atlas comprising 28 TAM subtypes was systematically constructed by integrating single-cell transcriptomic and spatial transcriptomic data from 291 human samples across 16 cancer types. The biological characteristics and spatial distribution patterns of these subtypes within the TME as well as the interaction mechanisms between TAMs and TME components closely associated with tumor progression were elucidated. TAMs localized in the peritumoral or core regions of tumors participate in angiogenesis and metabolic reprogramming, promoting further tumor development. The retention of CD8⁺ T cells by TAMs can induce local inflammation and an immunosuppressive microenvironment. Additionally, cancer-associated fibroblasts (CAFs) play crucial roles in the polarization and survival of TAMs and are involved in their recruitment and activation. TAMs facilitate tumor invasion, metastasis and immune evasion through secreted phosphoprotein 1 (SPP1) and interaction with the integrin family/CD44 axis in CAFs. This study deepens the understanding of the biological characteristics of TAMs and provides new theoretical foundations and potential targets for cancer treatment strategies targeting specific TAM subpopulations.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13187174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970618","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":"Receptor hyper-flexibility of human bitter receptor TAS2R4 revealed by cryo-EM structures in apo and tripeptide-bound states.","authors":"Yuxia Qian, Ming Tan, Zishao Ouyang, Sheng Ye, Jian Wu, Anna Qiao","doi":"10.1038/s41421-026-00895-4","DOIUrl":"10.1038/s41421-026-00895-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13172528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926655","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}