Cell Chemical Biology最新文献_第6页

Localized covalent targeting of NMDA receptors reprograms behavior NMDA受体的局部共价靶向重编程行为

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2026-08-24 DOI: 10.1016/j.chembiol.2026.08.001

Daniel Bátora,Máté Varga,Sharad Kumar Suthar,András Málnási-Csizmadia

{"title":"Localized covalent targeting of NMDA receptors reprograms behavior","authors":"Daniel Bátora,Máté Varga,Sharad Kumar Suthar,András Málnási-Csizmadia","doi":"10.1016/j.chembiol.2026.08.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.08.001","url":null,"abstract":"Spatiotemporal control of neuronal activity has largely relied on genetically defined cell populations, limiting the ability to interrogate native biomolecules within intact circuits. Pharmacological approaches with high spatial precision are therefore needed to preserve physiological network architecture. Here, we demonstrate confined neuromodulation through two-photon molecular tattooing (sequential localized photocrosslinking). We introduce AL-701, an aryl azide derivatized photoreactive NMDA receptor antagonist that covalently binds receptors upon two-photon laser irradiation. In zebrafish larvae, molecular tattooing enabled spatially restricted inhibition of NMDA receptors in a hindbrain subregion regulating the acoustic startle reflex. This localized inhibition led to persistent suppression of NMDA receptor-dependent habituation, demonstrating that regionally restricted modulation of receptor function can alter behavior. Our results show the proof-of-concept for localized photocrosslinking within cell clusters in a vertebrate nervous system and thereby establish molecular tattooing as a robust chemical biology tool for circuit modulation and optically controlled reprogramming of behavior in vivo.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"14 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805870","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

The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence BAX/BAK凋亡检查点调控治疗诱导的衰老

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-08-03 DOI: 10.1016/j.chembiol.2026.07.002

Aislinn Gallagher Aldave, Vaishnavi Venugopalan, Gokhan Gunay, Seren Hamsici, Ronaldo Rodrigues Ribeiro, Aoife Costigan, Anna Gabrielyan, Hande Efe-Cicek, Seamus J. Martin

{"title":"The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence","authors":"Aislinn Gallagher Aldave, Vaishnavi Venugopalan, Gokhan Gunay, Seren Hamsici, Ronaldo Rodrigues Ribeiro, Aoife Costigan, Anna Gabrielyan, Hande Efe-Cicek, Seamus J. Martin","doi":"10.1016/j.chembiol.2026.07.002","DOIUrl":"10.1016/j.chembiol.2026.07.002","url":null,"abstract":"<div><div>Cytotoxic chemotherapy is intended to eliminate transformed cells but can also provoke therapy-induced senescence, a persistent and pro-inflammatory cell state that can promote tumor progression. The molecular mechanisms that govern the apoptosis-senescence fate decision remain incompletely understood. Here, we show that the mitochondrial pore-forming proteins BAX and BAK function as a critical checkpoint that restricts entry to therapy-induced senescence. Genetic ablation of BAX and BAK markedly enhanced entry to senescence in response to multiple DNA-damaging agents, whereas loss of the BAX/BAK antagonists Bcl-xL or Mcl-1 suppressed entry to senescence and promoted cell death. Mechanistically, genotoxic stress induced BH3-only proteins, including Noxa, Bid, and Puma, creating a dependence on Bcl-xL and Mcl-1 to restrain BAX/BAK activation and maintain survival. These findings identify the Bcl-2 family network as a central regulator of entry to therapy-induced senescence, a pro-inflammatory cell state that goes beyond the mere avoidance of apoptosis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1117-1134.e6"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666052","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

The degrader gets degraded as cysteine fluctuates 随着半胱氨酸的波动，降解剂被降解

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 DOI: 10.1016/j.chembiol.2026.07.010

Junyi Chen, Haopeng Xiao

引用次数: 0

STINGing the brain: S-nitrosylation drives neuroinflammation in Alzheimer’s disease 刺痛大脑：s -亚硝基化引发阿尔茨海默病的神经炎症

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 DOI: 10.1016/j.chembiol.2026.07.003

Andrew A. Pieper, Emiko Miller, Oleh Khalimonchuk, Bindu D. Paul

引用次数: 0

Aptamer targeting HMGB1 attenuates inflammatory disease via domain-specific antagonism 靶向HMGB1的适体通过结构域特异性拮抗减轻炎性疾病。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-07-20 DOI: 10.1016/j.chembiol.2026.06.011

Hui Zhang, Lele Ma, Shaoju Gan, Mengyuan Jiang, Zheng Zhang, Weidi Sun, Wanlin Xie, Peiyu Xi, Fengli Qu, Weihong Tan

{"title":"Aptamer targeting HMGB1 attenuates inflammatory disease via domain-specific antagonism","authors":"Hui Zhang, Lele Ma, Shaoju Gan, Mengyuan Jiang, Zheng Zhang, Weidi Sun, Wanlin Xie, Peiyu Xi, Fengli Qu, Weihong Tan","doi":"10.1016/j.chembiol.2026.06.011","DOIUrl":"10.1016/j.chembiol.2026.06.011","url":null,"abstract":"<div><div>Damage-associated molecular patterns (DAMPs) are key mediators of inflammatory disease, among which HMGB1 is a prototypical extracellular alarmin and an attractive therapeutic target. Here, we report ZH-1a, a high-affinity DNA aptamer (Kd = 2.1 nM) identified through SELEX and sequence optimization, that preferentially recognizes the proinflammatory B-box region of HMGB1. ZH-1a functions as an extracellular HMGB1-neutralizing aptamer and suppresses HMGB1-induced inflammatory signaling, including cytokine secretion and NF-κB activation in macrophages. <em>In vivo</em>, ZH-1a reduced late-phase systemic inflammation and multiorgan injury in LPS-induced endotoxemia, improved survival in polymicrobial sepsis, and attenuated inflammatory responses and organ damage in an HMGB1-challenge model. In addition, ZH-1a alleviated joint inflammation and structural damage in collagen-induced arthritis, and further enhanced the therapeutic efficacy of methotrexate. Together, these findings establish ZH-1a as a promising anti-inflammatory aptamer targeting HMGB1 and support aptamer-based neutralization of pathogenic extracellular HMGB1 as a therapeutic strategy for inflammatory disease.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1165-1178.e5"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534781","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

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

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