Cell Chemical Biology最新文献_第2页

Allosteric rewiring of mitochondrial stress signaling through Miro1 线粒体应激信号通过mir1的变构重布线

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 DOI: 10.1016/j.chembiol.2026.07.011

Layla Drwesh, Julia C. Fitzgerald

引用次数: 0

An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies 用于可编程基因和mRNA治疗的内质网应激性RNA变阻器。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-08-05 DOI: 10.1016/j.chembiol.2026.07.006

Roza Ogurlu, Eliya B. Sanchez, Joshua A. Hull, Sophia M. Fergione, Vivian Yudistyra, Gabriela M. Webb, Helen L. Wu, Cleiton T. Pessoa, Matthew C. Humkey, Sofia K. Potter, Alan Rosales, Heather A. Vincent, Jonah B. Sacha, Aravind Asokan

{"title":"An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies","authors":"Roza Ogurlu, Eliya B. Sanchez, Joshua A. Hull, Sophia M. Fergione, Vivian Yudistyra, Gabriela M. Webb, Helen L. Wu, Cleiton T. Pessoa, Matthew C. Humkey, Sofia K. Potter, Alan Rosales, Heather A. Vincent, Jonah B. Sacha, Aravind Asokan","doi":"10.1016/j.chembiol.2026.07.006","DOIUrl":"10.1016/j.chembiol.2026.07.006","url":null,"abstract":"<div><div>Therapeutic protein overexpression can overwhelm endoplasmic reticulum (ER) folding capacity, trigger unfolded protein response (UPR) signaling, and compromise the safety of gene and mRNA therapies. Here, we engineer stress-responsive RNA rheostats that couple transgene expression to endogenous ER stress sensing. Short RNA elements derived from X-box-binding protein 1 (<em>XBP1</em>) mRNA undergo inositol-requiring enzyme 1α (IRE1α)-dependent splicing under ER stress, inducing a frameshift that attenuates downstream protein expression. XBP1 switches function across DNA and mRNA delivery platforms and regulate the expression of fluorescent reporters, coagulation factor VIII, and Leronlimab, a therapeutic anti-CCR5 monoclonal antibody. Switch activation reduces ER stress markers while preserving expression under homeostatic conditions. We further demonstrate the regulation of Leronlimab expression <em>in vivo</em> using recombinant adeno-associated virus vectors. Together, these findings establish programmable RNA feedback control as a strategy for linking cellular proteostasis to therapeutic protein expression and improving the safety of gene and mRNA therapies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1179-1192.e6"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676592","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}

引用次数: 0

Metabolic danger signals: TCA cycle metabolites regulate immunity and disease 代谢危险信号：TCA循环代谢产物调节免疫和疾病

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-08-04 DOI: 10.1016/j.chembiol.2026.07.004

Tristram A.J. Ryan, Ivan Zanoni

{"title":"Metabolic danger signals: TCA cycle metabolites regulate immunity and disease","authors":"Tristram A.J. Ryan, Ivan Zanoni","doi":"10.1016/j.chembiol.2026.07.004","DOIUrl":"10.1016/j.chembiol.2026.07.004","url":null,"abstract":"<div><div>Mitochondrial tricarboxylic acid (TCA) cycle metabolites have emerged as critical regulators of immunity and inflammation beyond their canonical metabolic functions. During inflammatory responses, these metabolites accumulate to millimolar concentrations in immune cells and act as endogenous damage-associated molecular patterns (DAMPs), linking metabolic state to immune regulation through receptor-dependent and receptor-independent mechanisms. Here, we characterize the inflammatory roles of TCA cycle metabolites as immunometabolites in infections, inflammatory and autoimmune diseases, and cancers. We discuss how their anti-microbial functions must be balanced against their capacity to drive and sustain inflammation. To capture the pleiotropic functions of immunometabolites, we introduce the concept of metabolic DAMPs (metaDAMPs), a class of metabolically derived danger signals that orchestrate immune responses. We highlight key metaDAMPs, including itaconate, succinate, and fumarate, and emerging immunometabolites such as malate and oxaloacetate. Finally, we highlight technological advances redefining our understanding of metabolite signaling and consider how targeting immunometabolite signaling may enable therapeutic intervention.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1077-1103"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666036","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}

引用次数: 0

RNA-dependent SFPQ condensates coordinate multidimensional regulation of extra-long neuronal genes rna依赖的SFPQ凝聚体协调超长神经元基因的多维调控。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-07-09 DOI: 10.1016/j.chembiol.2026.06.004

Motoyasu Hosokawa, Ryosuke Kawakami, Koshi Imami, Ryo Kurosawa, Takuya Yoshizawa, Yasushi Ishihama, Takeshi Imamura, Masatoshi Hagiwara, Akihide Takeuchi

{"title":"RNA-dependent SFPQ condensates coordinate multidimensional regulation of extra-long neuronal genes","authors":"Motoyasu Hosokawa, Ryosuke Kawakami, Koshi Imami, Ryo Kurosawa, Takuya Yoshizawa, Yasushi Ishihama, Takeshi Imamura, Masatoshi Hagiwara, Akihide Takeuchi","doi":"10.1016/j.chembiol.2026.06.004","DOIUrl":"10.1016/j.chembiol.2026.06.004","url":null,"abstract":"<div><div>The mammalian brain uniquely expresses a large repertoire of extra-long genes critical for neuronal development and function, yet these transcripts are particularly vulnerable to dysregulation linked to neurological disorders, such as autism spectrum disorder and amyotrophic lateral sclerosis. The molecular mechanisms that ensure their stable expression remain poorly understood. Here, we show that the RNA-binding protein SFPQ forms meshwork-like biomolecular condensates that scaffold a multidimensional gene regulatory complex essential for long-gene expression. Super-resolution microscopy and functional perturbation assays demonstrate that disruption of SFPQ condensates impairs both extra-long gene expression and splicing. Proximity-dependent biotin labeling combined with mass spectrometry (BioID-MS) reveals that SFPQ condensates recruit transcriptional elongation factors, splicing regulators, and chromatin remodelers. Notably, many of these interactors overlap with autism-associated genes, suggesting direct disease relevance. These findings define a higher-order nuclear architecture organized by SFPQ and provide mechanistic insight into long-gene transcriptopathies underlying neurological disorders.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1146-1164.e9"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417436","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}

引用次数: 0

Making zombies to kill cancer 制造僵尸来杀死癌症

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 DOI: 10.1016/j.chembiol.2026.07.012

Tudor Moldoveanu

引用次数: 0

Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer’s disease brain 神经炎症途径的氧化还原调节有助于阿尔茨海默病脑损伤

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-04-23 DOI: 10.1016/j.chembiol.2026.03.017

Lauren N. Carnevale, Piu Banerjee, Xu Zhang, Jazmin Navarro, Charlene K Raspur, Parth Patel, Tomohiro Nakamura, Emily Schahrer, Henry Scott, Nhi Lang, Jolene K. Diedrich, Amanda J. Roberts, John R. Yates III, Stuart A. Lipton

{"title":"Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer’s disease brain","authors":"Lauren N. Carnevale, Piu Banerjee, Xu Zhang, Jazmin Navarro, Charlene K Raspur, Parth Patel, Tomohiro Nakamura, Emily Schahrer, Henry Scott, Nhi Lang, Jolene K. Diedrich, Amanda J. Roberts, John R. Yates III, Stuart A. Lipton","doi":"10.1016/j.chembiol.2026.03.017","DOIUrl":"10.1016/j.chembiol.2026.03.017","url":null,"abstract":"<div><div>Aberrant activation of innate immune signaling is known to contribute to neuroinflammation in age-related neurological disorders, but the mechanisms underlying this activation remain unclear. Here, we discovered that protein <em>S</em>-nitrosylation, a redox-based posttranslational modification, regulates the stimulator of interferon genes (STING) protein in Alzheimer’s disease (AD). Using a combination of redox chemical biology and mass spectrometry, we identified <em>S</em>-nitrosylation at cysteine 148 as a critical modification facilitating STING oligomerization and triggering excessive type I interferon signaling in a causal fashion. This modification was observed in human AD postmortem brain tissue, in human induced pluripotent stem cell (hiPSC)-derived innate immune cells exposed to AD-related protein aggregates, and in a transgenic AD mouse model. Our findings reveal a novel molecular link between nitrosative stress and dysregulated innate immunity that drives neuroinflammation and synaptic loss in AD. Targeting this redox-sensitive cysteine presents a promising therapeutic strategy to modulate neuroinflammation and potentially slow disease progression.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1104-1116.e8"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147752914","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}

引用次数: 0

XPO1 inhibition induces NCOR1-Dependent oxidative stress to suppress hepatocellular carcinoma XPO1抑制诱导ncor1依赖性氧化应激抑制肝细胞癌。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-07-07 DOI: 10.1016/j.chembiol.2026.06.001

Wei Wang, Linmeng Zhang, Qiaozhu Zuo, Xuhui Ma, Ying Cao, Lili Zhu, Shuyi Ji, Wenxin Qin, Hui Wang, Shengxian Yuan, René Bernards, Cun Wang

{"title":"XPO1 inhibition induces NCOR1-Dependent oxidative stress to suppress hepatocellular carcinoma","authors":"Wei Wang, Linmeng Zhang, Qiaozhu Zuo, Xuhui Ma, Ying Cao, Lili Zhu, Shuyi Ji, Wenxin Qin, Hui Wang, Shengxian Yuan, René Bernards, Cun Wang","doi":"10.1016/j.chembiol.2026.06.001","DOIUrl":"10.1016/j.chembiol.2026.06.001","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to the limited efficacy of current systemic therapies. To identify potential therapeutic approaches, computational analysis of HCC datasets and drug screening were integrated, leading to the repurposing of hematological malignancy drug selinexor (an XPO1 inhibitor) for HCC treatment. Functional studies revealed that XPO1 inhibition triggers oxidative stress and cell cycle arrest in HCC cells through nuclear sequestration of NCOR1, disrupting redox homeostasis through FOXK1-dependent transcriptional activation of genes associated with reactive oxygen species (ROS). A genome-wide CRISPR-Cas9 screen further identified the KEAP1-NRF2 axis as a key determinant of sensitivity to XPO1 inhibition. Furthermore, high-throughput compound screening demonstrated that disulfiram, a clinically used aldehyde dehydrogenase inhibitor, synergizes with XPO1 inhibitor through exacerbation of ROS accumulation. Collectively, these findings demonstrate the therapeutic repurposing of selinexor for HCC while uncovering its mechanism of action, establishing a predictive biomarker, and proposing an immediately translatable combination therapy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1205-1216.e6"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403009","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}

引用次数: 0

A protective human antibody reveals a quaternary epitope on the Epstein-Barr virus fusion apparatus 一种保护性的人抗体揭示了爱泼斯坦-巴尔病毒融合装置上的一个四级表位。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-07-28 DOI: 10.1016/j.chembiol.2026.06.017

Ge-Xin Zhao (赵舸昕), Xin-Yan Fang (房昕燕), Ting Li (李婷), Guo-Long Bu (卜国龙), Jing Wang (王静), Wen-Ting Du (杜文婷), Pei-Huang Wu (吴培煌), Hang Zhou (周杭), Guo-Kai Feng (冯国开), Sen-Fang Sui (隋森芳), Cong Sun (孙聪), Zheng Liu (刘铮), Mu-Sheng Zeng (曾木圣)

{"title":"A protective human antibody reveals a quaternary epitope on the Epstein-Barr virus fusion apparatus","authors":"Ge-Xin Zhao (赵舸昕), Xin-Yan Fang (房昕燕), Ting Li (李婷), Guo-Long Bu (卜国龙), Jing Wang (王静), Wen-Ting Du (杜文婷), Pei-Huang Wu (吴培煌), Hang Zhou (周杭), Guo-Kai Feng (冯国开), Sen-Fang Sui (隋森芳), Cong Sun (孙聪), Zheng Liu (刘铮), Mu-Sheng Zeng (曾木圣)","doi":"10.1016/j.chembiol.2026.06.017","DOIUrl":"10.1016/j.chembiol.2026.06.017","url":null,"abstract":"<div><div>Epstein-Barr virus (EBV) entry into B lymphocytes and epithelial cells requires the conserved fusion machinery gHgL and the tropism-switching glycoprotein gp42. While the individual roles of these proteins have been extensively studied, the functional contribution and antibody accessibility of the assembled gHgL-gp42 complex remain unclear. Here, we describe a human monoclonal antibody, 4G12, that selectively recognizes this complex by binding a quaternary epitope spanning the gHgL DII domain and the gp42 N-terminal interface. 4G12 potently neutralizes EBV infection in both B cells and epithelial cells by blocking viral binding and membrane fusion. A cryogenic electron microscopy (cryo-EM) structure reveals a vulnerable site within the fusion apparatus and defines the molecular basis of inhibition. Importantly, 4G12 confers robust protection against EBV challenge in humanized mice. These findings identify a neutralizing epitope on the gHgL-gp42 fusion complex and establish 4G12 as a mechanistic probe and candidate for EBV prophylaxis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1135-1145.e7"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597180","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}

引用次数: 0

Chemical modulation of Miro1 alleviates cell-type-specific vulnerabilities in Friedreich’s ataxia Miro1的化学调节减轻了弗里德赖希共济失调中细胞类型特异性的脆弱性。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-06-08 DOI: 10.1016/j.chembiol.2026.05.004

Sujyoti Chandra, Chulhwan S. Kwak, Zehui Du, Giuseppe Barisano, Kong T. Nguyen, Vlad Vinogradov, Xinnan Wang

{"title":"Chemical modulation of Miro1 alleviates cell-type-specific vulnerabilities in Friedreich’s ataxia","authors":"Sujyoti Chandra, Chulhwan S. Kwak, Zehui Du, Giuseppe Barisano, Kong T. Nguyen, Vlad Vinogradov, Xinnan Wang","doi":"10.1016/j.chembiol.2026.05.004","DOIUrl":"10.1016/j.chembiol.2026.05.004","url":null,"abstract":"<div><div>Friedreich’s ataxia (FA) is marked by early-onset sensory neurodegeneration and cardiomyopathy. We establish a human dual-cell model of FA by differentiating sensory neurons and cardiomyocytes from the same patients, enabling parallel molecular profiling of disease-relevant cell types. Proteomic analysis reveals distinct, cell-type-specific pathway disruptions in response to frataxin deficiency. Leveraging this platform, we investigate Miro1 reducer 3 (MR3), a selective chemical probe binding Miro1, a mitochondrial outer membrane protein implicated in redox regulation in FA. MR3 treatment modulates molecular signatures in a cell-type-dependent manner, altering pathways related to cardiac contractility in cardiomyocytes and synaptic function in sensory neurons. Mechanistically, MR3 reduces mitochondrial reactive oxygen species and restores membrane potential in FA sensory neurons via potential allosteric reshaping of Miro1 protein. We expand the chemical diversity of this scaffold by conducting ligand-based virtual screening of over 3 billion compounds and identifying previously uncharacterized Miro1 ligands with improved docking and neuroprotective capacity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1193-1204.e12"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203470","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}

引用次数: 0

Small-molecule activation of the tumor suppressor kinase LKB1 via the pseudokinase STRAD 肿瘤抑制激酶LKB1通过假激酶STRAD的小分子活化

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2026-08-18 DOI: 10.1016/j.chembiol.2026.07.013

Lin Song Kretschmer, Dominique C. Mitchell, Jin Liu, Logan Leak, Rigney E. Turnham, LeeAnn Wang, Zheng Wang, Changliang He, Luo Ding, Marc Adler, Timothy Kellett, Aidan Keith, Yeonjoo C. Hwang, Gary K.L. Chan, Robert L.G. Gottschalk, Weicheng Li, Lieza M. Chan, Roopa Ramamoorthi, Sarah Lively, Robert A. Drakas, Vijay Ramani, Tingting Qing, Kliment A. Verba, Trever Bivona, Jonathan M.L. Ostrem, Richard T. Beresis, John D. Gordan

引用次数: 0