ACS Central Science最新文献

{"title":"Immunomodulatory Nanoparticles Enable Combination Therapies To Enhance Disease Prevention and Flare Control in Rheumatoid Arthritis","authors":"Wade T. Johnson,&nbsp;, ,&nbsp;Elizabeth L. Wilkinson,&nbsp;, ,&nbsp;Neha Iyer,&nbsp;, ,&nbsp;Maksim Dolmat,&nbsp;, ,&nbsp;Miriam Bollmann,&nbsp;, ,&nbsp;Nour Dada,&nbsp;, ,&nbsp;Xiaofu Wei,&nbsp;, ,&nbsp;Shen Yang,&nbsp;, ,&nbsp;Tiffany Zhang,&nbsp;, ,&nbsp;Grace Yoo,&nbsp;, ,&nbsp;Marianne Bernardo,&nbsp;, ,&nbsp;Madison Price,&nbsp;, ,&nbsp;Elizabeth Frame,&nbsp;, ,&nbsp;Mariko Ishimori,&nbsp;, ,&nbsp;Jon T. Giles,&nbsp;, ,&nbsp;Wei Wang,&nbsp;, ,&nbsp;Mattias N.D. Svensson,&nbsp;, ,&nbsp;Nunzio Bottini*,&nbsp;, and ,&nbsp;Nisarg J. Shah*,&nbsp;","doi":"10.1021/acscentsci.5c00723","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00723","url":null,"abstract":"<p >Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. <i>In vitro</i>, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic T_H17 cells. Next generation RNA sequencing of lymph node DC revealed <i>Ctla4</i> upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.</p><p >Agg-CLNP is a disease modifying agent which modulates immune activation and effectively suppresses disease onset and controls flares, providing a potential solution to unmet needs in rheumatoid arthritis.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1581–1597"},"PeriodicalIF":10.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00723","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modern Disposable E-Cigarettes: Small in Size but Big in Toxic Metals","authors":"Pablo Olmedo​,&nbsp; and ,&nbsp;Fernando Gil,&nbsp;","doi":"10.1021/acscentsci.5c01312","DOIUrl":"https://doi.org/10.1021/acscentsci.5c01312","url":null,"abstract":"<p >Safety concerns continue to arise as lead and other potentially toxic metals are found in the aerosols of modern disposable e-cigarettes.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 8","pages":"1272–1274"},"PeriodicalIF":10.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c01312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stereochemistry Drives the Macromolecular Conformation and Biological Activity of Glycopolymers","authors":"Muhammad Waqas Ishaq,&nbsp;, ,&nbsp;Parisa Farzeen,&nbsp;, ,&nbsp;Lindsay R. Vaughn,&nbsp;, ,&nbsp;Daniel J. Stone,&nbsp;, ,&nbsp;Sanket A. Deshmukh,&nbsp;, and ,&nbsp;Cassandra E. Callmann*,&nbsp;","doi":"10.1021/acscentsci.5c00768","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00768","url":null,"abstract":"<p >Chirality plays a fundamental role in biology, where stereochemical information governs how molecules fold, interact, and function. While the effects of stereochemistry are well-established for small molecules and natural biomacromolecules, less is known about how it shapes the properties of synthetic, biomimetic polymers. In this study, we explore how backbone and glycan stereochemistry influences conformation, physical interactions, and biological behavior in water-soluble glycopolymers. Using ring opening metathesis polymerization (ROMP), we synthesized precision glycopolymers (PGPs) from two diastereomeric norbornenyl moieties (<i>endo</i> and <i>exo</i>) and monosaccharides (glucose, galactose, and mannose). Despite having nearly identical molecular and macromolecular compositions, the resulting PGPs displayed major differences in their physical and biological properties. Glycopolymers with β-linkages showed distinct circular dichroism (CD) signals, and <i>exo</i>-derived backbones displayed more hydrophobic local environments, as confirmed by all-atom molecular dynamics simulations and dye interaction studies. These structural differences had clear functional consequences. <i>exo</i>-PGPs bound plant lectins more rapidly and with higher avidity, whereas <i>endo</i>-PGPs showed greater selectivity toward human galectin-3, stronger inhibition of cholera toxin, and enhanced uptake into 4T1 triple-negative breast cancer cells. Together, these findings provide the first demonstration of biological activity in <i>endo</i>-derived glycopolymers and establish backbone stereochemistry as a key design element that encodes macromolecular behavior in biologically relevant contexts.</p><p >Subtle changes in polymer stereochemistry drive major differences in macromolecular conformation and biological function, revealing stereochemistry as a key element in glycomaterial design.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1573–1580"},"PeriodicalIF":10.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00768","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unmasking the Molecules Behind our Emotions","authors":"Marta Zaraska,&nbsp;","doi":"10.1021/acscentsci.5c01268","DOIUrl":"https://doi.org/10.1021/acscentsci.5c01268","url":null,"abstract":"<p >Scientists are identifying the chemicals we emit when we emote─and learning how they affect the behavior of people around us.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 8","pages":"1261–1265"},"PeriodicalIF":10.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c01268","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper-Catalyzed Asymmetric Cyclizative Sulfinamidation: Forging Indole-Based Stereogenic Sulfur(IV) Centers and Atropisomeric Chirality","authors":"Xiaowu Fang,&nbsp;, ,&nbsp;Fengrui Xiang,&nbsp;, ,&nbsp;Yue Zhao,&nbsp;, and ,&nbsp;Zhuangzhi Shi*,&nbsp;","doi":"10.1021/acscentsci.5c00909","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00909","url":null,"abstract":"<p >The structural prominence of indole-based sulfur-containing compounds in pharmacologically relevant substances stems from their versatile biofunctional capabilities. Despite their significance, the stereogenic elements embedded in these structures have frequently been overlooked in drug discovery endeavors primarily due to the absence of efficient synthetic methodologies. Here, we introduce a groundbreaking strategy for the enantioselective synthesis of indole-based sulfinamides via a copper-catalyzed asymmetric nucleophilic cyclization and sulfinamidation reaction. Utilizing <i>ortho</i>-alkynylanilines and sulfinylamines, this method achieves a broad spectrum of sulfinamides with complete atom economy, establishing a new paradigm in synthetic efficiency. Our approach not only facilitates the formation of S-chirogenic sulfinamides but also concurrently constructs products featuring both stereogenic sulfur and atropisomeric chirality. Comprehensive mechanistic investigations, complemented by density functional theory (DFT) calculations, provide deep insights into the reaction mechanism, particularly in elucidating the S-stereogenic and atropisomeric control during the cyclization and sulfinamidation processes.</p><p >A copper-catalyzed cyclizative sulfinamidation strategy enables facile synthesis of indole-based sulfinamides with simultaneous control of stereogenic sulfur and atropisomeric chirality.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1762–1772"},"PeriodicalIF":10.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00909","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Synthetic Lectin for Glucuronate","authors":"Canjia Zhai,&nbsp;, ,&nbsp;Chengkai Xu,&nbsp;, ,&nbsp;Yunpeng Cui,&nbsp;, ,&nbsp;Lukasz Wojtas,&nbsp;, ,&nbsp;Jianfeng Cai,&nbsp;, and ,&nbsp;Wenqi Liu*,&nbsp;","doi":"10.1021/acscentsci.5c00951","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00951","url":null,"abstract":"<p >The selective recognition of hydrophilic carbohydrates in water remains a longstanding challenge in supramolecular chemistry due to solvent competition and the lack of a strong driving force comparable to the hydrophobic effect. Herein, we report the design, synthesis, and characterization of a water-soluble tetralactam macrocycle, MPNT²⁺·2Cl^–, as a highly effective synthetic lectin for glucuronate. MPNT²⁺·2Cl^– features two dimethylnaphthalene panels, pyridinium spacers, and morpholine side chains, forming a rigid, preorganized cavity with convergent hydrogen bond donors, polarized C–H donors, and complementary electrostatic interactions. The receptor achieves a binding affinity of 103,000 M^–1 for glucuronate in water, over 19-fold higher than previous synthetic systems, along with excellent selectivity over structurally similar carbohydrates. Single-crystal X-ray analysis, DFT calculation, and IGMH analysis reveal a dense network of [N–H···O], [C–H···O], and [C–H···π] interactions, highlighting the role of stereoelectronic complementarity in complex formation. Moreover, MPNT²⁺·2Cl^– acts as a chiroptical sensor, producing binding-induced circular dichroism signals that enable sensitive detection of glucuronic acid at physiologically relevant concentrations. This work presents a generalizable strategy for designing synthetic lectins that recognize carbohydrates in aqueous solutions and opens up new possibilities for developing molecular sensors and diagnostic tools for biologically important anionic sugars.</p><p >A synthetic macrocyclic lectin recognizes glucuronate in water, enabling strong, selective binding and chiroptical sensing of a biologically important sugar.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1753–1761"},"PeriodicalIF":10.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00951","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Martini 3 Lipidome: Expanded and Refined Parameters Improve Lipid Phase Behavior","authors":"Kasper B. Pedersen,&nbsp;, ,&nbsp;Helgi I. Ingólfsson,&nbsp;, ,&nbsp;Daniel P. Ramirez-Echemendia,&nbsp;, ,&nbsp;Luís Borges-Araújo,&nbsp;, ,&nbsp;Mikkel D. Andreasen,&nbsp;, ,&nbsp;Charly Empereur-mot,&nbsp;, ,&nbsp;Josef Melcr,&nbsp;, ,&nbsp;Tugba N. Ozturk,&nbsp;, ,&nbsp;W. F. Drew Bennett,&nbsp;, ,&nbsp;Lisbeth R. Kjølbye,&nbsp;, ,&nbsp;Christopher Brasnett,&nbsp;, ,&nbsp;Valentina Corradi,&nbsp;, ,&nbsp;Hanif M. Khan,&nbsp;, ,&nbsp;Elio A. Cino,&nbsp;, ,&nbsp;Jackson Crowley,&nbsp;, ,&nbsp;Hyuntae Kim,&nbsp;, ,&nbsp;Balázs Fábián,&nbsp;, ,&nbsp;Ana C. Borges-Araújo,&nbsp;, ,&nbsp;Giovanni M. Pavan,&nbsp;, ,&nbsp;Guillaume Launay,&nbsp;, ,&nbsp;Fabio Lolicato,&nbsp;, ,&nbsp;Tsjerk A. Wassenaar,&nbsp;, ,&nbsp;Manuel N. Melo,&nbsp;, ,&nbsp;Sebastian Thallmair,&nbsp;, ,&nbsp;Timothy S. Carpenter,&nbsp;, ,&nbsp;Luca Monticelli,&nbsp;, ,&nbsp;D. Peter Tieleman,&nbsp;, ,&nbsp;Birgit Schiøtt,&nbsp;, ,&nbsp;Paulo C. T. Souza*,&nbsp;, and ,&nbsp;Siewert J. Marrink*,&nbsp;","doi":"10.1021/acscentsci.5c00755","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00755","url":null,"abstract":"<p >Lipid membranes are central to cellular life. Complementing experiments, computational modeling has been essential in unraveling complex lipid-biomolecule interactions, crucial in both academia and industry. The Martini model, a coarse-grained force field for efficient molecular dynamics simulations, is widely used to study membrane phenomena but has faced limitations, particularly in capturing realistic lipid phase behavior. Here, we present refined Martini 3 lipid models with a mapping scheme that distinguishes lipid tails that differ by just two carbon atoms, enhancing the structural resolution and thermodynamic accuracy of model membrane systems including ternary mixtures. The expanded Martini lipid library includes thousands of models, enabling simulations of complex and biologically relevant systems. These advancements establish Martini as a robust platform for lipid-based simulations across diverse fields.</p><p >Expanded and reparameterized Martini 3 lipidome with refined mapping improves lipid phase behavior and enables accurate simulations of complex and biologically relevant membrane systems.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1598–1610"},"PeriodicalIF":10.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Synthetic Phage-Peptide Conjugate as a Potent Antibacterial Agent for Pseudomonas aeruginosa Infections","authors":"Yanxi Yang,&nbsp;, ,&nbsp;Shelby Vexler,&nbsp;, ,&nbsp;Maria C. Jordan,&nbsp;, ,&nbsp;Serena Abbondante,&nbsp;, ,&nbsp;Dayeon Kang,&nbsp;, ,&nbsp;Huan Peng,&nbsp;, ,&nbsp;Michaela Marshall,&nbsp;, ,&nbsp;Bita V. Naini,&nbsp;, ,&nbsp;Saumya Jain,&nbsp;, ,&nbsp;Yei-Chen Lai,&nbsp;, ,&nbsp;Nasim Annabi,&nbsp;, ,&nbsp;Kenneth P. Roos,&nbsp;, ,&nbsp;Eric Pearlman,&nbsp;, and ,&nbsp;Irene A. Chen*,&nbsp;","doi":"10.1021/acscentsci.5c00562","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00562","url":null,"abstract":"<p >Antibiotic resistance among Gram-negative organisms is a major challenge. Some molecules, including antimicrobial peptides such as polymyxin B (PMB), are antibacterial but toxic due to low specificity, causing poor clinical utility. Drug delivery to bacterial cells using a biocompatible nanomaterial is a possible approach to securing such drugs. We engineered a nonlytic phage to recognize the lipopolysaccharide of Gram-negative bacteria and cross-linked thousands of peptides per virion, making “PMB-M13^αLPS”. PMB-M13^αLPS reduced the minimum inhibitory concentration <i>in vitro</i> by ∼2 orders of magnitude across multiple pathogen strains. Immunocompetent mice with multidrug-resistant <i>P. aeruginosa</i> pneumonia or corneal infection were effectively treated by PMB-M13^αLPS, which showed potency ∼2 orders of magnitude greater <i>in vivo</i> compared to that of PMB. PMB-M13^αLPS was well-tolerated, with no toxic effects. Conjugates of antimicrobial peptides and synthetic phages combine engineerable targeting with large payload capacity, improving potency and therapeutic index for otherwise toxic molecules.</p><p >A phage-peptide conjugate delivers an effective but toxic peptide specifically to bacterial cells. The conjugate treated mouse models of infection safely, showing how to increase clinical utility.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1715–1735"},"PeriodicalIF":10.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precise and In Vivo-Compatible Spatial Proteomics via Bioluminescence-Triggered Photocatalytic Proximity Labeling","authors":"Xuege Sun,&nbsp;, ,&nbsp;Yanling Zhang,&nbsp;, ,&nbsp;Wenjie Lu,&nbsp;, ,&nbsp;Hongyang Guo,&nbsp;, ,&nbsp;Guodong He,&nbsp;, ,&nbsp;Siyuan Luo,&nbsp;, ,&nbsp;Haodong Guo,&nbsp;, ,&nbsp;Zijuan Zhang,&nbsp;, ,&nbsp;Wenjing Wang,&nbsp;, ,&nbsp;Ling Chu,&nbsp;, ,&nbsp;Xiangyu Liu,&nbsp;, and ,&nbsp;Wei Qin*,&nbsp;","doi":"10.1021/acscentsci.5c00520","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00520","url":null,"abstract":"<p >Protein function is closely tied to its localization and interactions, which can be mapped using proximity labeling (PL). Traditional PL methods, such as peroxidases and biotin ligases, suffer from toxicity or high background. While visible-light-triggered photocatalytic labeling offers great potential, it is limited by light-induced background and restricted <i>in vivo</i> applications. Here we present BRET-ID, an <i>in vivo</i>-compatible PL technology for precise mapping of membraneless organelles and transient protein–protein interactions with subminute temporal resolution. BRET-ID combines a genetically encoded photocatalyst and NanoLuc luciferase, locally generating blue light to activate the photocatalyst via bioluminescence resonance energy transfer (BRET). This activation produces singlet oxygen, which oxidizes nearby proteins for analysis with a streamlined chemoproteomic workflow. BRET-ID enables precise mapping of ER membrane proteins, exhibiting high spatial specificity. Leveraging its high temporal resolution, BRET-ID provides 1 min snapshots of dynamic GPCR interactions during ligand-induced endocytosis. Additionally, BRET-ID identifies G3BP1-interacting proteins in arsenite-stressed cells and tumor xenografts, uncovering novel stress granule components, including the mTORC2 subunit RICTOR. BRET-ID serves as a powerful genetically encoded tool for studying protein localization and molecular interactions in living organisms.</p><p >A genetically encoded BRET-activated proximity labeling tool enables high-resolution mapping of protein localizations and interactions in live cells and <i>in vivo</i>.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1611–1626"},"PeriodicalIF":10.4,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00520","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astragaloside IV Alleviates Fructose-Induced Intestinal Metabolic Senescence by Targeting Ketohexokinase Asn261/Ala226 to Preserve Intestinal Stem Cell Homeostasis","authors":"Qifang Wu,&nbsp;, ,&nbsp;Yingna Li,&nbsp;, ,&nbsp;Yunyun Zhao,&nbsp;, ,&nbsp;Ruifen Zhang,&nbsp;, ,&nbsp;Jingyang Tong,&nbsp;, ,&nbsp;Chunlei Ji,&nbsp;, ,&nbsp;Yiming Zhao,&nbsp;, ,&nbsp;Mingjiang Wu,&nbsp;, ,&nbsp;Xiaosheng Jin,&nbsp;, ,&nbsp;Dandan Wang*,&nbsp;, ,&nbsp;Haibin Tong*,&nbsp;, ,&nbsp;Liwei Sun*,&nbsp;, and ,&nbsp;Fangbing Liu*,&nbsp;","doi":"10.1021/acscentsci.5c00726","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00726","url":null,"abstract":"<p >Excessive fructose intake drives intestinal aging and impairs intestinal stem cell (ISC) function, yet effective therapeutic interventions remain elusive. Astragaloside IV (AS-IV), a natural saponin from <i>Astragalus membranaceus</i>, has been widely recognized for its antiaging, anti-inflammatory, and gut-protective properties. Here, we revealed that AS-IV alleviates fructose-induced intestinal metabolic senescence via direct inhibition of ketohexokinase (KHK), the key rate-limiting enzyme in fructose metabolism. Molecular docking and site-directed mutagenesis identified Asn261 and Ala226 as distinct binding sites for AS-IV on KHK, with Asn261 also serving as a critical catalytic residue that is essential for KHK activity. Mutation at Asn261 abolished KHK enzymatic function, reduced the accumulation of fructose-derived metabolites such as palmitic acid and ceramide, and thereby prevented fructose-induced ISC cycle arrest. AS-IV’s therapeutic efficacy was validated across <i>Drosophila</i>, murine intestinal organoids, and mice, where treatment consistently reversed high-fructose-induced intestinal metabolic senescence phenotypes, restored ISC proliferation, and preserved ISC homeostasis. These findings indicate that KHK is a previously unrecognized molecular target of AS-IV and reveal a conserved mechanism by which AS-IV modulates fructose metabolism to interfere with gut aging. Our results highlight its therapeutic potential in treating fructose-driven intestinal aging and associated metabolic disorders.</p><p >We discovered KHK as a novel target of Astragaloside IV, which alleviates fructose-induced intestinal metabolic senescence by binding to Asn261 and Ala226 residues in KHK.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1682–1699"},"PeriodicalIF":10.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00726","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}