Cell Chemical Biology最新文献

{"title":"A STING inhibitor suppresses ferroptosis through radical-trapping antioxidant activity","authors":"Songlin Yin,Yan Li,Ting Mei,Jiayao Li,Xueting Wang,Xiaoxiao Li,Liguo Yang,Junhong Lin,Weijie Ye,Fujia Lu,Weimin Wang","doi":"10.1016/j.chembiol.2026.09.004","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.09.004","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"98 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993806","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":"Dual-function PROTAC suppresses ferroptosis and restores neuronal function via brain-targeted delivery","authors":"Tianyu Ma, Tianli Luo, Ming Wang","doi":"10.1016/j.chembiol.2026.06.010","DOIUrl":"10.1016/j.chembiol.2026.06.010","url":null,"abstract":"<div><ul><li><span>•</span><span><div>Dual-function dACSL4 concurrently degrades ACSL4 and activates PPARγ signaling</div></span></li><li><span>•</span><span><div>DACSL4 suppresses ferroptosis via PUFA remodeling and PPARγ-GPX4 axis activation</div></span></li><li><span>•</span><span><div>Brain-targeted dACSL4 delivery suppresses ferroptosis and restores motor function</div></span></li></ul></div><div>Targeted protein degradation (TPD) offers a transformative approach for drug discovery, yet its application in the central nervous system (CNS) is hindered by the blood-brain barrier and the need for multi-pathway modulation in complex neurodegenerative diseases. This study introduces a dual-function PROTAC, <strong>dACSL4</strong>, which achieves synergistic ferroptosis suppression by simultaneously degrading the pro-ferroptotic enzyme ACSL4 and activating the neuroprotective PPARγ pathway. Beyond simple protein degradation, we demonstrate that precise linker optimization can leverage geometric constraints to divert the fate of PROTAC from proteolysis to functional activation, providing a modular strategy for designing “degrader-plus-agonist” bifunctional molecules. To overcome the challenges of CNS delivery, we developed ROS-responsive, biodegradable lipid nanoparticles (BAmP-TK12) for intranasal administration, enabling brain-preferred protein degradation and robust therapeutic efficacy in a Parkinson’s disease model. By designing dual-function PROTAC and brain-preferred delivery, this study provides a non-invasive strategy for regulating ferroptosis and restoring neuronal function for treating neurodegenerative disorders.</div><div><div>Targeted protein degradation (TPD) via proteolysis-targeting chimeras (PROTACs) offers a promising strategy for modulating disease-associated proteins, yet effective brain-preferred protein degradation remains challenging. Herein, we report a dual-function PROTAC, <strong>dACSL4,</strong> and its nose-to-brain delivery for brain-preferred protein degradation and therapeutic suppression of ferroptosis in neurodegeneration. <strong>dACSL4</strong> selectively degrades acyl-CoA synthetase long-chain family member 4 (ACSL4) while concurrently activating peroxisome proliferator-activated receptor γ (PPARγ), thereby coordinating lipid metabolism and oxidative stress to suppress neuronal ferroptosis. <strong>dACSL4</strong> achieved up to 30-fold greater protection against neuronal ferroptosis compared to conventional ferroptosis inhibitors. Intranasal delivery of <strong>dACSL4</strong> using biodegradable lipid nanoparticles (BAmP-TK12) enabled brain-preferred ACSL4 degradation and PPARγ activation, reducing lipid peroxidation and preserving dopaminergic neurons in a Parkinson’s disease model, ultimately improving motor function. Our findings establish a modular strategy for brain-preferred protein degradation and highlight the therapeutic potential of dual-function degraders for ferroptosis suppression in neurodegene","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1270-1283.e8"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547319","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":"Oncogene activation mechanism determines the limits of targeted protein degradation","authors":"Evelina Gudauskaitė, Brianda Hernández-Morán, Gillian C.A. Taylor, Andrew J. Wood","doi":"10.1016/j.chembiol.2026.08.006","DOIUrl":"10.1016/j.chembiol.2026.08.006","url":null,"abstract":"<div><ul><li><span>•</span><span><div>The mechanism of oncogene activation shapes degrader response and resistance</div></span></li><li><span>•</span><span><div>Stabilizing mutations do not limit the minimum protein level degraders achieve</div></span></li><li><span>•</span><span><div>Increased target synthesis limits the extent of protein depletion</div></span></li></ul></div><div>This study provides an important mechanistic perspective on a central question in targeted protein degradation: how the pre-existing homeostatic state of target protein expression influences the efficacy of degrader molecules. Using β-catenin as a clinically relevant model and the dTAG platform as a controlled degradation system, the authors distinguish between two common routes of oncogene activation: increased protein stability and increased protein production, and show that these mechanisms have fundamentally different consequences for degradation outcomes. Notably, cancer-associated β-catenin mutations that prolong protein lifetime markedly elevated baseline abundance yet did not prevent degraders from driving the protein to a common lower steady-state level. In contrast, enhanced transcription created a persistent elevation in target abundance even after degrader treatment, indicating that synthesis rate can set a practical limit on the depth of depletion. These findings move beyond conventional metrics such as Dmax and fractional degradation, emphasizing the importance of considering absolute protein levels and proteostatic context when evaluating degrader performance across different biological contexts. More broadly, the work offers a conceptual framework for understanding variability in degrader responses across genetically diverse tumors, highlights gene amplification and other mechanisms that increase synthesis as potential resistance liabilities, and suggests that oncogenic target proteins activated via stabilizing mutations may remain particularly amenable to degradation-based therapies. As the field advances degrader drugs toward the clinic, this study underscores the need to integrate target production and turnover kinetics into both preclinical models and patient stratification strategies.</div><div><div>Protein degrader drugs such as PROTACs are being advanced as therapeutics targeted against oncogenic proteins. During tumorigenesis, oncogenic proteins can become constitutively activated via mechanisms including gene amplification, which increases protein production, and point mutations, which can extend protein half-life. Few experimental studies have addressed how disease-associated changes in target protein homeostasis influence PROTAC activity. We developed orthogonal methods to increase production or enhance stability of β-catenin, an important oncoprotein and target for degrader therapeutics, and used the dTAG system to evaluate the consequences for PROTAC activity. Stabilizing oncogenic missense mutations increase protein expression up to 5-fold","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1333-1341.e4"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872411","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":"Nitrated fatty acids form membrane biochemical capacitors that restrain inflammation","authors":"Nicole Colussi, Sonia R. Salvatore, Matias M. Vazquez, Maria V. Gutierrez, Scott Hahn, Karina Ricart, Felipe Vendrame, Matias Badino, Agustina L. Schopfer, Dario A. Vitturi, Luis Villacorta, Rakesh P. Patel, Amit Gaggar, Carsten Skarke, Adam C. Straub, Francisco J. Schopfer","doi":"10.1016/j.chembiol.2026.08.002","DOIUrl":"10.1016/j.chembiol.2026.08.002","url":null,"abstract":"<div><ul><li><span>•</span><span><div>Distinct dietary and membrane pathways generate endogenous nitrated fatty acids</div></span></li><li><span>•</span><span><div>Membrane phospholipids store NO<sub>2</sub>-CLA as a mobilizable anti-inflammatory reservoir</div></span></li><li><span>•</span><span><div>NO<sub>2</sub>-CLA release suppresses inflammatory signaling and preserves vascular homeostasis</div></span></li><li><span>•</span><span><div>Depletion of NO<sub>2</sub>-CLA stores during inflammation reveals therapeutic opportunities</div></span></li></ul></div><div>Lipid mediators are central regulators of inflammation, yet current paradigms largely focus on enzymatically derived oxylipins, overlooking a broader landscape of redox-derived bioactive lipids. Among these, nitrated fatty acids (NO<sub>2</sub>-FAs) form by nitration reactions and function as anti-inflammatory signaling lipids. Although their therapeutic potential in inflammatory diseases is well established, integrated NO<sub>2</sub>-FA signaling in the context of endogenous formation remains unexplored. This study identifies endogenous nitro-conjugated linoleic acid (NO<sub>2</sub>-CLA) as a dynamically regulated and physiologically relevant class of anti-inflammatory mediators. We uncover complementary pathways linking dietary intake and membrane lipid nitration to NO<sub>2</sub>-CLA formation, establishing phospholipids as a previously unrecognized reservoir that can be rapidly mobilized through phospholipase activation. Once released, NO<sub>2</sub>-CLA acts as a potent electrophilic signaling molecule that suppresses inflammatory pathways. Notably, we demonstrate that this protective lipid pool is rapidly depleted during inflammatory stress in both murine models and human subjects, revealing a temporal dimension to its bioactivity. These findings redefine how NO<sub>2</sub>-FAs are generated and function <em>in vivo</em>. By identifying a transient, endogenous anti-inflammatory lipid reserve that becomes depleted during disease, this work highlights a potential therapeutic opportunity to restore NO<sub>2</sub>-CLA levels and sustain the resolution of inflammation.</div><div><div>Nitrated fatty acids (NO<sub>2</sub>-FAs) are electrophilic lipid mediators that suppress inflammatory signaling, yet the sources, storage mechanisms, and physiological functions of endogenous NO<sub>2</sub>-FAs remain poorly understood. Here, we identify nitro-conjugated linoleic acid (NO<sub>2</sub>-CLA) as a diet-derived anti-inflammatory lipid that accumulates in membrane phospholipids and functions as a mobilizable biochemical reserve. Using cellular, murine, and human models, we show that phospholipids store NO<sub>2</sub>-CLA under basal conditions and rapidly release it during inflammatory stress through phospholipase-dependent remodeling. Mobilized NO<sub>2</sub>-CLA dampens cytokine production, limits inflammatory mediator formation, and preserves vascular homeostasis during endotoxemia. In both ","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1252-1269.e5"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148974229","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":"Signaling of glycoRNAs to Siglec-11 protects neurons by suppressing NF-κB","authors":"Xingwen Wang, Jiahao Huang, Shangjie An, Yue Wang, Xiaodan Jia, Lie Wu, Xiue Jiang","doi":"10.1016/j.chembiol.2026.05.017","DOIUrl":"10.1016/j.chembiol.2026.05.017","url":null,"abstract":"<div><ul><li><span>•</span><span><div>Neuronal glycoRNAs become aberrantly expressed during inflammation</div></span></li><li><span>•</span><span><div>GlycoRNAs mediate contact-dependent intercellular communication</div></span></li><li><span>•</span><span><div>Cell surface glycoRNAs bind Siglec-11 and contribute to neuroimmune signaling</div></span></li><li><span>•</span><span><div>GlycoRNA-Siglec-11 signaling suppresses NF-κB and inflammatory cytokines</div></span></li></ul></div><div>GlycoRNAs are a recently discovered biomolecules that carry both glycan modifications and RNA chains, challenging the traditional view that RNA primarily functions inside cells while glycosylation mainly modifies proteins and lipids. Their existence suggests a neglected set of regulatory signals on the cell surface, making it necessary to investigate the biological functions of glycoRNAs. GlycoRNAs are located on the cell membrane and bear terminal sialic acids; therefore, they possess the potential to interact with immune receptors such as the Siglecs family. Exploring glycoRNA-mediated intercellular immune interactions will bridge glycoRNAs biology and immunology. Neuroinflammation is a key driver of many neurodegenerative disorders, yet current anti-inflammatory strategies targeting immune checkpoints remain very limited. If glycoRNAs participate in regulating neuroimmune responses, they could represent a potential class of therapeutic targets for diseases such as Alzheimer’s and Parkinson’s. In this study, we provide evidence for a glycoRNA-Siglec-11 axis that suppresses NF-κB-driven inflammation and protects neurons, suggesting glycoRNAs may serve as mediators of intercellular signaling with therapeutic potential in neuroinflammation.</div><div><div>Glycosylated RNAs (glycoRNAs), a class of extracellular glycosylated molecules, emerge as key regulators yet with undefined roles in neuroimmune communication. Through neuron-like and glia-like co-culture models, we identify a neuron’s protective mechanism mediated by membrane-associated glycoRNAs. Proinflammatory stimulation markedly enhances glycoRNAs expression on human neuroblastoma (SH-SY5Y) neuronal membranes, with their target depletion disrupting their adhesion and concomitantly attenuating the activity of SH-SY5Y cells. Mechanistic analyses establish that the binding of glycoRNAs on SH-SY5Y cells to sialic acid-binding immunoglobulin-like lectin 11 (Siglec-11) on HMC3 cells activates the canonical Siglec-11 signaling pathway. This signaling cascade suppresses NF-κB-mediated proinflammatory pathways, evidenced by diminished NF-κB activation and reduced secretion of inflammatory mediators (interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)), ultimately promoting SH-SY5Y survival. Our findings establish glycoRNAs as critical mediators of intercellular signaling with therapeutic potential in neuroinflammation.</div></div><div>Glycosylated RNAs (glycoRNAs), a class of extracellula","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1223-1236.e8"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262611","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":"Mechanistic dissection of SMARCA2/4 molecular glues reveals programmable switching between DCAF16 and FBXO22","authors":"Milad Rouhimoghadam, Christie J. Kang, Jackson A. Gartman, Sameera Senaweera, Ioanna Zoi, Alex Y. Jiu, Judith A. Ronau, Andrea G. Shergalis, Hua Tang, Shaun M. McLoughlin, Panga Jaipal Reddy, Qi Sun, Loren M. Lasko, Tiffany A. Thibaudeau, Xiaoli Huang, Violeta L. Marin, Elyse C. Freiberger, Ashish Thakur, Zhaozhong J. Jia, Daniel T. Ladror, Xiaoyu Lin","doi":"10.1016/j.chembiol.2026.05.019","DOIUrl":"10.1016/j.chembiol.2026.05.019","url":null,"abstract":"<div><ul><li><span>•</span><span><div>Single-atom edits switch ligase preference between DCAF16 and FBXO22</div></span></li><li><span>•</span><span><div>Compound <strong>1</strong> degrades SMARCA2/4 exclusively via DCAF16 Cys173</div></span></li><li><span>•</span><span><div>FBXO22 Cys228 and Cys326 enable productive degradation by analogs</div></span></li><li><span>•</span><span><div>Productive ternary geometry, not binding alone, determines degradation</div></span></li></ul></div><div>The ability to precisely control E3 ligase engagement represents a critical frontier in advancing molecular glue degraders (MGDs) and redefining the limits of targeted protein degradation. The observation that single-atom chemical modifications can rewire ligase preference between DCAF16 and FBXO22 reveals an extraordinary and previously underappreciated sensitivity of degradation mechanisms to minimal structural perturbations, establishing a high level of chemical precision in dictating E3 selection. The identification of Cys173 as a covalent engagement site in DCAF16 further expands the actionable landscape of E3 ligases, highlighting the potential of ligandable cysteines as programmable anchors for degrader design. Critically, these findings redefine a central mechanistic principle of the field: ternary complex formation alone is insufficient, and only specific, productive assemblies translate into effective degradation. This insight resolves a disconnect between binding and functional outcomes, providing a conceptual framework for predictive, mechanism-informed design. The ability to toggle or combine ligase engagement through minimal chemical edits introduces a transformative strategy to overcome resistance, exploit context-dependent ligase biology, and expand the scope of degradable targets. In the context of SMARCA2/4, key oncogenic drivers within switch/sucrose non-fermentable (SWI/SNF)-dependent cancers, such tunability enables precise control over degradation outcomes. Collectively, these advances elevate molecular glues into a new paradigm of chemically encoded, mechanism-defined, and therapeutically adaptable modalities.</div><div><div>Molecular glue degraders (MGDs) represent a powerful strategy for targeted protein degradation, yet the rules governing ligase selectivity remain elusive. Here, we characterize a class of SMARCA2/4 MGDs with tunable E3 ligase engagement. Compound <strong>1</strong> degraded SMARCA2/4 exclusively via DCAF16, driven by covalent capture of Cys173. Strikingly, 1-carbon analogs rewired ligase preferences: compounds <strong>2</strong> and <strong>3</strong> recruited both DCAF16 and FBXO22, whereas compound <strong>4</strong> remained strictly DCAF16 dependent despite weak FBXO22 binding, although all compounds shared an alkynyl pyridine moiety essential for covalent attachment. Mutational analysis further pinpointed Cys228 and Cys326 in FBXO22 as indispensable for degradation. These findings reveal that subtle scaffold modifi","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1300-1309.e11"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374340","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":"A designer saxitoxin-engineered sodium channel pair as a general tool for subtype-selective inhibition","authors":"Elizabeth R. Park, Nicholas Denomme, Holly S. Hajare, J. Du Bois","doi":"10.1016/j.chembiol.2026.05.016","DOIUrl":"10.1016/j.chembiol.2026.05.016","url":null,"abstract":"<div><ul><li><span>•</span><span><div>A designer saxitoxin targets a mutant Na<sub>V</sub> with ca. 100:1 selectivity over WT channels</div></span></li><li><span>•</span><span><div>Block of ion conduction in mutant channels occurs rapidly (seconds) and reversibly</div></span></li><li><span>•</span><span><div>APs in native neurons and CNS tissue are unaffected at operative ligand concentrations</div></span></li><li><span>•</span><span><div>Applicable for studies of any one of multiple Na<sub>V</sub> subtypes, Na<sub>V</sub>1.1–1.4, 1.6, 1.7</div></span></li></ul></div><div>Neuronal excitability relies on the tightly regulated expression and discrete subcellular localization of voltage-gated sodium channels (Na<sub>V</sub>s), large membrane protein complexes responsible for initiating and propagating action potentials. Channel malfunction underlies multiple human pathologies (e.g., epilepsy, pain, arrhythmia, and musculoskeletal disorders), clinical findings that drive considerable interest in Na<sub>V</sub>s as drug targets and that motivate research to better understand channel physiology. To investigate Na<sub>V</sub> function in health and disease, pharmacological tools that enable rapid and reversible manipulation of individual Na<sub>V</sub> isoforms are needed along with methods for differentiating between the same Na<sub>V</sub> isoform present in two or more cell types (e.g., Na<sub>V</sub>1.6 in neurons vs. glia). The latter is currently not possible even with the availability of potent, subtype-selective Na<sub>V</sub> ligands. Accordingly, we have capitalized on chemical design and protein engineering to address these challenges by developing a general technology for interrogating Na<sub>V</sub>1.1, 1.2, 1.3, 1.4, 1.6, or 1.7 physiology. A synthetic derivative of the bis-guanidinium toxin, saxitoxin (STX), is paired with two discrete outer pore-forming amino acid mutations to achieve ca. 100:1 selectivity for the engineered channel over all wild-type isoforms. The designer ligand is nanomolar potent against the mutant channel and acts within seconds to block sodium ion conduction; washout occurs rapidly and completely to restore channel function. The advent of a unique pharmacological inhibitor of a genetically encoded Na<sub>V</sub> subtype will unlock new studies of Na<sub>V</sub> physiology and afford precise control of action potential signaling given the requisite role of Na<sub>V</sub>s in electrogenesis.</div><div><div>We have used small molecule chemical design and protein engineering to fashion an orthogonal ligand-channel pair that enables acute and selective inhibition of a genetically encoded voltage-gated sodium channel (Na<sub>V</sub>). A modified ligand based on the nerve toxin, saxitoxin (STX), binds potently and reversibly to a Na<sub>V</sub> bearing two unique amino acid mutations in the outer mouth of the channel (Site 1). The same ligand is ineffective at blocking wild-type Na<sub>V</sub>s and does not disrupt action","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1322-1332.e7"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872433","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":"Cell-surface glycoRNAs put the brakes on neuroinflammation","authors":"Junchen Chen,&nbsp;Sheng Zhong","doi":"10.1016/j.chembiol.2026.07.014","DOIUrl":"10.1016/j.chembiol.2026.07.014","url":null,"abstract":"<div><div>Cell-surface glycoRNAs are emerging as neuroimmune signals. In this issue of <em>Cell Chemical Biology</em>, Wang et al. showed in co-culture that neuronal glycoRNAs engaged microglial Siglec-11, increased SHP1 phosphorylation, suppressed NF-κB-dependent cytokine production, and improved neuronal-cell survival, establishing signaling direction, downstream mechanism, and protective function for a glycoRNA-Siglec pathway.<span><span>¹</span></span></div></div><div>Cell-surface glycoRNAs are emerging as neuroimmune signals. In this issue of <em>Cell Chemical Biology</em>, Wang et al. showed in co-culture that neuronal glycoRNAs engaged microglial Siglec-11, increased SHP1 phosphorylation, suppressed NF-κB-dependent cytokine production, and improved neuronal-cell survival, establishing signaling direction, downstream mechanism, and protective function for a glycoRNA-Siglec pathway.<span><span>¹</span></span></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1217-1219"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148974452","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":"NAT10 promotes keratinocyte-neutrophil crosstalk in atopic dermatitis","authors":"Jia-nan Wang,&nbsp;Xiao-ming Meng","doi":"10.1016/j.chembiol.2026.08.007","DOIUrl":"10.1016/j.chembiol.2026.08.007","url":null,"abstract":"<div><div>Atopic dermatitis (AD) is driven by complex interactions between keratinocytes and immune cells. In this issue of <em>Cell Chemical Biology</em>, Shao et al.<span><span>¹</span></span> identify that NAT10-dependent ac4C modification stabilizes <em>Relb</em> mRNA in keratinocytes, promoting chemokine production, neutrophil recruitment, and dermatitis progression.</div></div><div>Atopic dermatitis (AD) is driven by complex interactions between keratinocytes and immune cells. In this issue of <em>Cell Chemical Biology</em>, Shao et al.<span><span>¹</span></span> identify that NAT10-dependent ac4C modification stabilizes <em>Relb</em> mRNA in keratinocytes, promoting chemokine production, neutrophil recruitment, and dermatitis progression.</div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1220-1222"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148974453","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":"Quantitative profiling of RNA modifications enriched in non-membrane-bound cellular structures using APEX-RNA-MS","authors":"Kyung W. Seo,&nbsp;Dhruv Y. Dhingani,&nbsp;Ralph E. Kleiner","doi":"10.1016/j.chembiol.2026.05.012","DOIUrl":"10.1016/j.chembiol.2026.05.012","url":null,"abstract":"&lt;div&gt;&lt;ul&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;div&gt;APEX-RNA-MS measures the spatial distribution of RNA modifications in cells&lt;/div&gt;&lt;/span&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;div&gt;DNA damage foci are enriched with m&lt;sup&gt;6&lt;/sup&gt;A and m&lt;sup&gt;5&lt;/sup&gt;C&lt;/div&gt;&lt;/span&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;div&gt;Cytosolic tRNAs accumulate in arsenite-induced stress granules&lt;/div&gt;&lt;/span&gt;&lt;/li&gt;&lt;/ul&gt;&lt;/div&gt;&lt;div&gt;RNA modifications serve a dynamic role in regulating RNA functions and behavior across diverse cellular structures and compartments, but characterizing the subcellular distribution and specialized roles of RNA modifications remains a major challenge. In particular, RNA modifications have been associated with the trafficking and accumulation of RNAs in dynamic biomolecular condensates involved in post-transcriptional RNA regulation and implicated in DNA repair processes at DNA damage sites, but we lack general strategies for the direct and multiplexed characterization of RNA modifications in diverse cellular structures. Here, we present APEX-RNA-MS, which is a general workflow combining proximity labeling and nucleoside LC-MS analysis that enable characterization of the complement of RNA modifications in defined protein “neighborhoods.” We apply and validate this approach by characterizing RNA modifications in proximity to three proteins that localize to distinct and dynamic cellular structures recalcitrant to intact biochemical isolation from cells—stress granules, P-bodies, and DNA damage sites. In addition, our study demonstrates that tRNAs are located in proximity to the canonical stress granule-forming protein G3BP1 and accumulate together with G3BP1 upon stress granule formation. Recent work has suggested a function for stress granules in localized and stress-specific translational programs, which would likely involve localized pools of tRNAs. Therefore, our work provides a powerful approach for characterizing the subcellular distribution of modified RNAs and reveals new insights into the composition and function of stress-specific condensates.&lt;/div&gt;&lt;div&gt;&lt;div&gt;The dynamic behavior of RNAs underlies fundamental biological processes. RNA function is controlled by post-transcriptional modifications that are spatiotemporally regulated, but characterizing the distribution of modified RNA transcripts with subcellular resolution is a major challenge. Here, we present APEX-RNA-MS, which combines APEX2 proximity labeling with liquid chromatography-mass spectrometry (LC-MS) quantification of modified ribonucleotides. We use APEX-RNA-MS to characterize RNA modifications proximal to RNA-binding proteins enriched in non-membrane-bound cellular structures. We measure changes in protein-proximal RNA modification levels upon induction of DNA damage foci and stress granules, consistent with previous studies using antibody-based imaging and biochemical fractionation. Further, we show that tRNA-specific modifications are proximal to G3BP1 and use RNA sequencing and RNA fluorescence &lt;em&gt;in situ&lt;/em&gt;","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 9","pages":"Pages 1310-1321.e5"},"PeriodicalIF":9.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13355914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300380","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}