Cell DiscoveryPub Date : 2026-10-20DOI: 10.1038/s41421-026-00927-z
Yan Bian, Ye Gao, Xin Chang, Bo Tian, Qianqian Meng, Lei Xin, Han Lin, Wei Wang, Zhaoshen Li, Luowei Wang
{"title":"FAM50A promotes esophageal squamous cell carcinoma progression via splicing-dependent oncogenic circSDK1- and DUSP22-mediated MAPK/FAK activation.","authors":"Yan Bian, Ye Gao, Xin Chang, Bo Tian, Qianqian Meng, Lei Xin, Han Lin, Wei Wang, Zhaoshen Li, Luowei Wang","doi":"10.1038/s41421-026-00927-z","DOIUrl":"https://doi.org/10.1038/s41421-026-00927-z","url":null,"abstract":"<p><p>Dysregulated splicing factors play critical roles in tumor progression. Here, we identify family with sequence similarity 50 member A (FAM50A) as a pivotal oncogenic splicing factor involved in esophageal squamous cell carcinoma (ESCC). Multi-omics and multi-cohort analyses revealed that FAM50A is upregulated in ESCC and correlates with a poor prognosis. Functional studies demonstrated that FAM50A promotes ESCC proliferation and migration both in vitro and in vivo, primarily through the activation of mitogen-activated protein kinases (MAPKs) and focal adhesion kinase (FAK). We further characterized the FAM50A-binding RNA motif and established its transcriptome-wide splicing landscape. Notably, we identified a novel FAM50A-dependent backsplicing event that generates circSDK1, which originates from exons 2-4 of the sidekick cell adhesion molecule 1 (SDK1) pre-mRNA. Mechanistically, circSDK1 binds to dual-specificity phosphatase 22 (DUSP22) and occupies its phosphatase domain, inhibiting the DUSP22-mediated dephosphorylation of MAPKs and FAK and thereby sustaining their activation. Furthermore, the transcription factor TFAP2C increased FAM50A expression. Finally, we identified rifabutin as a small-molecule inhibitor of FAM50A and confirmed its anti-tumor efficacy in cell-derived xenograft, patient-derived organoid, and patient-derived xenograft models. In summary, FAM50A promotes ESCC progression via the FAM50A/circSDK1/DUSP22 axis, leading to MAPKs and FAK activation. Genetic or pharmacological targeting of FAM50A with rifabutin represents a promising therapeutic strategy for ESCC.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223393","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 DiscoveryPub Date : 2026-10-13DOI: 10.1038/s41421-026-00929-x
Mengna Zhang, Yongxia Wang, Yun Huang, Yaqi Liang, Pengxiao Chen, Zheng Ji, Minghu Song, He Chen, Chunyu Wang, Can Cao
{"title":"Structural insights into the ligand modulation of MRGPRX4 conformational plasticity.","authors":"Mengna Zhang, Yongxia Wang, Yun Huang, Yaqi Liang, Pengxiao Chen, Zheng Ji, Minghu Song, He Chen, Chunyu Wang, Can Cao","doi":"10.1038/s41421-026-00929-x","DOIUrl":"10.1038/s41421-026-00929-x","url":null,"abstract":"<p><p>Chronic pruritus is a debilitating condition with limited treatment options, particularly in cholestatic liver diseases, where bile acid dysregulation is a known trigger. Although Mas-related G protein-coupled receptor X4 (MRGPRX4) has recently been identified as a key mediator of bile acid-induced pruritus, the structural mechanisms underlying its inhibition remain poorly understood, hindering the development of therapeutic antagonists. Here, we report the cryo-electron microscopy structures of MRGPRX4 in three distinct states: agonist-bound state, antagonist-bound state, and apo state. Our structures reveal a previously unrecognized antagonist-binding site that is structurally distinct from those engaged by agonists. Complementary functional assays and molecular dynamics simulations further demonstrate that the extracellular pocket of MRGPRX4 undergoes pronounced ligand-dependent conformational rearrangements upon binding to both the agonist and the antagonist. Collectively, these findings elucidate the conformational plasticity underlying MRGPRX4 activity modulation and establish a structural framework for the rational design of MRGPRX4 antagonists that target chronic pruritus.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179570","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":"Blocking PD1 prevents T-cell-promoted fibrosis in myocardial infarction.","authors":"Xiaoying Chen, Changchen Xiao, Changle Ke, Jiamin Li, Ye Liu, Junhua He, Mo Li, Jing Zhao, Zhiwei Zhong, Qiming Chen, Tingting Hong, Fei Liao, Feimu Zhang, Yu Zhang, Jiayue Cai, Shuyuan Sheng, Qingju Li, Yongjian Chen, Yinghui Xu, Jingyi Wang, Shuhan Zhong, Xianpeng Wu, Peng Shi, Yang Xu, Wei Zhu, Xinyang Hu, Cheng Ni, Jian'an Wang","doi":"10.1038/s41421-026-00924-2","DOIUrl":"10.1038/s41421-026-00924-2","url":null,"abstract":"<p><p>Myocardial fibrosis is a common pathological feature that affects the outcome of various heart diseases, typically in the context of myocardial infarction (MI). The role of T cells in heart failure has been increasingly recognized, but whether programmed cell death protein 1 (PD1<sup>+</sup>) T cells modulate cardiac fibrosis during the post-MI pathological remodeling process remains unclear. Single-cell RNA sequencing and mass cytometry were conducted to determine the proportion of PD1<sup>+</sup> T cells in both human ischemic diseases and a mouse MI model. Bulk RNA sequencing and cytokine arrays were used to investigate the function of PD1<sup>+</sup> T cells. Cardiac function and histology were evaluated in non-human primates and rodents post-MI. We observed significant enrichment of PD1<sup>+</sup> T cells in the heart after MI, which was positively associated with cardiac fibroblast activation and, hence, collagen secretion. Unlike in tumors, PD1<sup>+</sup> T cells in the heart after MI demonstrated activated characteristics. PD1 knockout mice exhibited reduced cardiac fibrosis, resulting in increased cardiac performance following MI. Mechanistically, activated PD1<sup>+</sup> T cells were found to drive fibrosis remodeling by modulating the CXCL9/CXCR3 axis through direct interaction with cardiac fibroblasts - an effect that occurred independently of the PD1/programmed death-ligand 1 (PD-L1) signaling pathway. Notably, anti-PD1 therapy in both mouse and non-human primate MI models effectively attenuated fibrosis and improved cardiac function without eliciting detectable adverse effects in non-cardiac organs. Our findings reveal a distinct PD-L1-independent pro-fibrotic mechanism mediated by PD1<sup>+</sup> T cells during post-MI cardiac remodeling. Therapeutic inhibition of PD1<sup>+</sup> T cells effectively suppressed fibrosis progression, highlighting its potential as an immunotherapeutic target for post-MI cardiac repair.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104521","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}
Cell DiscoveryPub Date : 2026-09-29DOI: 10.1038/s41421-026-00926-0
Kun Hao, Jiahui Chen, Jun Zhao, Renjie Li, Yue Li, Pu Yuan, Qinru Bai, Yanli Dong, Jie Yu, Yan Zhao
{"title":"Structural basis of the transport mechanism of hBGT1.","authors":"Kun Hao, Jiahui Chen, Jun Zhao, Renjie Li, Yue Li, Pu Yuan, Qinru Bai, Yanli Dong, Jie Yu, Yan Zhao","doi":"10.1038/s41421-026-00926-0","DOIUrl":"10.1038/s41421-026-00926-0","url":null,"abstract":"<p><p>In the kidney and liver, the betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT1) transports betaine to maintain the osmotic balance of renal medullary cells and reduce the toxicity of homocysteine accumulation. In the brain, BGT1 reuptakes GABA from the synaptic cleft into glial cells to terminate GABAergic signaling. Despite its importance, the molecular mechanisms of BGT1 substrate recognition and ion coupling remain unknown. Here, we resolved the cryo-electron microscopy structures of BGT1 in complex with two substrates, GABA and betaine, as well as the substrate-free form without any fiducial marker. The substrate-bound complex elucidates the mechanism by which BGT1 recognizes chemically distinct GABA and betaine. These structures are trapped in occluded and inward-open states, elucidating the structural basis for conformational transitions. Furthermore, we proposed a Na3-binding site and investigated the functional role of the Na3 site in limiting reverse transport and promoting substrate accumulation. These insights improve our understanding of substrate recognition, conformational transitions, and ion coupling mechanisms in BGT1, as well as other neurotransmitter transporters.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073274","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":"Eggerthella lenta disrupts the gut vascular barrier to drive colorectal cancer liver metastasis.","authors":"Cheng Kong, Yutao Jin, Guang Liu, Yangyang Guo, Fanying Guo, Yanlei Ma","doi":"10.1038/s41421-026-00922-4","DOIUrl":"10.1038/s41421-026-00922-4","url":null,"abstract":"<p><p>Distant metastasis is the leading cause of death in colorectal cancer (CRC), and the gut vascular barrier (GVB) is the first obstacle to hematogenous spread. To investigate whether GVB function is directly influenced by metastasis-associated bacteria, we analyzed two cohorts comprising 20 healthy controls, 82 non-metastatic CRC patients, and 65 patients with liver or lung metastases. Multi-omics approaches (metagenomic sequencing and single-cell RNA sequencing) and gnotobiotic mouse models were employed to examine gut microbes that are linked to GVB disruption and metastasis. Patients with CRC liver metastasis exhibited impaired GVB and bacterial colonization at metastatic sites. Eggerthella lenta was enriched in patients with elevated expression of plasmalemmal vesicle-associated protein-1 (PV-1), a GVB injury marker, and its abundance was correlated with metastasis and recurrence. In vitro and in vivo, E. lenta compromised endothelial tight junction and GVB integrity, enhancing CRC cell migration and liver metastasis. Mechanistically, E. lenta adhered to endothelial cells and activated endoplasmic reticulum (ER) stress via a TLR4-dependent pathway, promoting autophagy and apoptosis. The knockdown of PERK attenuated ER stress, prevented autophagy and apoptosis, and downregulated the expression of ZO-1 and Claudin-5 induced by E. lenta. These findings highlight the clinical potential of microbiota-targeted strategies and PERK inhibition in the treatment of E. lenta-associated CRC metastasis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015582","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}
Cell DiscoveryPub Date : 2026-09-15DOI: 10.1038/s41421-026-00918-0
Liang Guo, Baoying Huang, Hanzhi Yu, Yi Xu, Lei Wei, Jijie Zheng, Yuanzhe Li, Di Wu, Peng Zhao, Changcheng Wu, Wenjie Tan, Yichang Jia
{"title":"The accessory protein ORF3a hijacks the CLCC1 chloride channel to disrupt ER homeostasis in betacoronavirus pathogenesis.","authors":"Liang Guo, Baoying Huang, Hanzhi Yu, Yi Xu, Lei Wei, Jijie Zheng, Yuanzhe Li, Di Wu, Peng Zhao, Changcheng Wu, Wenjie Tan, Yichang Jia","doi":"10.1038/s41421-026-00918-0","DOIUrl":"10.1038/s41421-026-00918-0","url":null,"abstract":"<p><p>Beta-coronavirus infection disrupts endoplasmic reticulum (ER) homeostasis; however, the mechanisms by which viral proteins manipulate ER-resident factors remain unclear. Here, we report that the SARS-CoV-2 accessory protein ORF3a binds to the ER chloride channel CLCC1, thereby impairing ER ion homeostasis, activating the unfolded protein response, and inducing endomembrane remodeling. Using newly developed ratiometric reporters, we showed that this interaction exacerbated the basal levels of ER-phagy and nucleophagy. Importantly, CLCC1 counteracted ORF3a by sequestering it within the ER, attenuating its toxicity and suppressing viral replication, which established CLCC1 as a host restriction factor. We further elucidated a spatiotemporal mechanism: during early infection, ORF3a accumulates in the ER, co-assembles with CLCC1 into puncta, and disrupts ER homeostasis; at the later stage, ORF3a overload enables its escape from CLCC1-mediated ER retention and subsequent translocation to lysosomes, facilitating viral egress. This ER-centric function is conserved across diverse beta-coronaviruses, including SARS-CoV-1 and bat- or pangolin-derived strains, revealing a unified pathogenic strategy. Furthermore, in mouse brains, the ORF3a-CLCC1 axis recapitulates key neuropathological features, including ER stress, autophagic dysfunction, neuronal death, and neuroinflammation, providing a mechanistic link to COVID-19-associated neurological symptoms. Our findings identify CLCC1 as an essential host defense protein and establish a conceptual framework to guide future research on antiviral responses at the organelle level and related disease mechanisms.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966333","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":"HMMR<sup>+</sup> stromal cells drive human uterine development.","authors":"Jiahui Qi, Xiaoqiang Sheng, Shiyuan Li, Peipei Jiang, Huiyan Wang, Lingxi Li, Jidong Zhou, Yifan Li, Huidan Zhang, Miaomiao Wang, Yang Zhang, Guangfeng Zhao, Guijun Yan, Bruno Péault, Yali Hu, Haixiang Sun, Lijun Ding","doi":"10.1038/s41421-026-00921-5","DOIUrl":"10.1038/s41421-026-00921-5","url":null,"abstract":"<p><p>Early uterine development in humans is a critical determinant of reproductive health and disease susceptibility during adolescence. While single-cell analyses have extensively characterized the adult uterus, the developmental origins of this organ remain poorly understood. In this study, single-cell RNA sequencing and spatial transcriptomics of the human uterus from gestational week 12 (GW12) to GW24 and from adolescents revealed a population of hyaluronan-mediated motility receptor-expressing (HMMR<sup>+</sup>) stromal cells essential for uterine endometrial and myometrial development. These HMMR<sup>+</sup> stromal cells were highly proliferative and differentiated into stromal- and muscle-like lineages upon in vitro induction. Following xenotransplantation into immunodeficient mice, they engrafted and formed mesenchymal-like tissue expressing both stromal and smooth muscle markers. We determined that HMMR<sup>+</sup> stromal cells promote epithelial cell differentiation and development through pleiotrophin signaling. Notably, these HMMR<sup>+</sup> stromal cells were significantly reduced in the thin endometrium. Collectively, our findings define the cellular ontogeny of the human uterus and identify a pivotal stromal progenitor-like population with implications for developmental disorders and endometrial pathologies.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905279","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":"Cross-protective human antibodies against the Mpox virus discovered through structure-guided screening.","authors":"Dongdong Sun, Zihan Jia, Hongyu Han, Nan Zhang, Yiying Guo, Ruitian Hou, Wenli Zhao, Haiyan Yu, Lulu Wang, Yuhui Wang, Jun Dai, Hang Shang, Yamin Liu, Ding Li, Wenhui Tao, Zixian Sun, Ying Li, Zhiyu Ni, Wei Zheng, Haisheng Yu, Yu Guo","doi":"10.1038/s41421-026-00916-2","DOIUrl":"10.1038/s41421-026-00916-2","url":null,"abstract":"<p><p>Mpox virus (MPXV) poses an increasing global health threat, as underscored by two World Health Organization declarations of Public Health Emergencies of International Concern, particularly after the emergence of a novel Clade Ib strain that exhibited high human-to-human transmissibility in the Democratic Republic of the Congo. However, the treatment options for MPXV infection remain extremely limited. To address this unmet need, we established an integrated platform combining single-cell transcriptomics and deep learning-based structural prediction to discover effective human monoclonal antibodies against MPXV. By integrating computational prediction with experimental validation, we identified five neutralizing antibodies targeting the following distinct viral forms: BA345, MA42, and MA49, which engage the extracellular enveloped virus-associated A35R glycoprotein; BAL31, which binds intracellular mature virus (IMV) protein A29L; and HB05, which targets IMV antigen H3L. Importantly, the elite monoclonal antibody BA345 conferred effective protection against MPXV and vaccinia virus both in vitro and in vivo. Combined in silico structure prediction and X-ray crystallography revealed a highly conserved epitope shared across orthopoxviruses. Surface plasmon resonance measurements revealed nanomolar equilibrium dissociation constants of BA345 for A35R homologs, corroborating its cross-reactive, broad-spectrum neutralizing activity against orthopoxviruses. Moreover, the BA345/BAL31 and MA49/BAL31 antibody cocktails developed in this study conferred robust therapeutic protection in MPXV-infected animals, substantially reducing disease severity and viral load. Our findings not only establish a practical paradigm for antibody discovery through the integration of deep learning-driven structure prediction with single-cell multiomics but also inform next-generation biodefense countermeasures against MPXV and related orthopoxviruses.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13534486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872884","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}
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