Pub Date : 2026-02-19DOI: 10.1016/j.chembiol.2026.01.010
Jiajia Wei , Chao Xu
Ubiquitin-conjugating enzyme BIRC6 displays high specificity toward ubiquitin-activating enzyme UBA6. In a study recently published by Nature Structural & Molecular Biology,1 Riechmann et al. unveiled the mechanism underlying UBA6-BIRC6 specificity and its mediated thioester switch, which broadened the understanding of the E1-orchestrated E2 hierarchy.
{"title":"Decoding E1-E2 specificity: How UBA6 prioritizes BIRC6 for ubiquitin conjugation","authors":"Jiajia Wei , Chao Xu","doi":"10.1016/j.chembiol.2026.01.010","DOIUrl":"10.1016/j.chembiol.2026.01.010","url":null,"abstract":"<div><div>Ubiquitin-conjugating enzyme BIRC6 displays high specificity toward ubiquitin-activating enzyme UBA6. In a study recently published by <em>Nature Structural & Molecular Biology</em>,<span><span><sup>1</sup></span></span> Riechmann et al. unveiled the mechanism underlying UBA6-BIRC6 specificity and its mediated thioester switch, which broadened the understanding of the E1-orchestrated E2 hierarchy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 150-152"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256887","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}
Pub Date : 2026-02-19Epub Date: 2026-01-13DOI: 10.1016/j.chembiol.2025.12.010
Garrett L. Lindsey , Thomas K. Hockley , Alejandro Villa Gomez , Andrew C. Marshall , William R. Brothers , Colin T. Finney , Jacob Gross , Archa H. Fox , Gene W. Yeo , Bruno Melillo , Charles S. Bond , Benjamin F. Cravatt
RNA-binding proteins (RBPs) play important roles in mRNA transcription, processing, and translation. Chemical tools are lacking for RBPs, which has hindered efforts to perturb and understand RBP function in cells. We previously described a chloroacetamide compound (R)-SKBG-1 that covalently binds the RBP NONO and stabilizes its interactions with mRNAs, leading to transcriptional remodeling and suppression of cancer cell growth. Here, we report the crystal structure of an (R)-SKBG-1:NONO complex, which confirms covalent modification of cysteine-145 at a pocket proximal to the RNA-binding interface of the protein. We show that this pocket can also be targeted by a lower reactivity chlorofluoroacetamide analog (R, R)-GL-373, which retains the pharmacological properties of (R)-SKBG-1, including blockade of estrogen receptor expression in breast cancer cells, while displaying much greater proteome-wide selectivity. Our findings thus show that NONO can be targeted by covalent ligands with high specificity to pharmacologically suppress pro-tumorigenic gene products in cancer cells.
{"title":"Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO","authors":"Garrett L. Lindsey , Thomas K. Hockley , Alejandro Villa Gomez , Andrew C. Marshall , William R. Brothers , Colin T. Finney , Jacob Gross , Archa H. Fox , Gene W. Yeo , Bruno Melillo , Charles S. Bond , Benjamin F. Cravatt","doi":"10.1016/j.chembiol.2025.12.010","DOIUrl":"10.1016/j.chembiol.2025.12.010","url":null,"abstract":"<div><div>RNA-binding proteins (RBPs) play important roles in mRNA transcription, processing, and translation. Chemical tools are lacking for RBPs, which has hindered efforts to perturb and understand RBP function in cells. We previously described a chloroacetamide compound (<em>R</em>)-SKBG-1 that covalently binds the RBP NONO and stabilizes its interactions with mRNAs, leading to transcriptional remodeling and suppression of cancer cell growth. Here, we report the crystal structure of an (<em>R</em>)-SKBG-1:NONO complex, which confirms covalent modification of cysteine-145 at a pocket proximal to the RNA-binding interface of the protein. We show that this pocket can also be targeted by a lower reactivity chlorofluoroacetamide analog (<em>R</em>, <em>R</em>)-GL-373, which retains the pharmacological properties of (<em>R</em>)-SKBG-1, including blockade of estrogen receptor expression in breast cancer cells, while displaying much greater proteome-wide selectivity. Our findings thus show that NONO can be targeted by covalent ligands with high specificity to pharmacologically suppress pro-tumorigenic gene products in cancer cells.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 256-267.e11"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962144","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}
Pub Date : 2026-02-19DOI: 10.1016/j.chembiol.2026.01.012
Joseph P. Dillard
Pattern recognition receptors detect peptidoglycan and trigger inflammatory responses promoting bacterial clearance. So, how do our gut bacteria survive? In this issue of Cell Chemical Biology, Liang et al.1 determine the structures of peptidoglycan fragments released by beneficial bacteria that mediate a NOD2-dependent reduction in inflammatory responses to bacterial products.
{"title":"What’s the good word? Lactobacilli produce peptidoglycan fragments with the right structure to induce tolerance during colitis","authors":"Joseph P. Dillard","doi":"10.1016/j.chembiol.2026.01.012","DOIUrl":"10.1016/j.chembiol.2026.01.012","url":null,"abstract":"<div><div>Pattern recognition receptors detect peptidoglycan and trigger inflammatory responses promoting bacterial clearance. So, how do our gut bacteria survive? In this issue of <em>Cell Chemical Biology</em>, Liang et al.<span><span><sup>1</sup></span></span> determine the structures of peptidoglycan fragments released by beneficial bacteria that mediate a NOD2-dependent reduction in inflammatory responses to bacterial products.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 145-146"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256820","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}
Pub Date : 2026-02-19DOI: 10.1016/j.chembiol.2026.01.009
Jinyao Chen , Ming Zhang , Yeji Wang , Zhiyu Xie , Fei Yang , Hongjun Yu , Di Zhang , Min Fang , Xiaoyi Luan , Xueyang Jin , Xue Wang , Yanan Qiao , Shicun Zheng , Xiuyun Li , Wenqiang Chang , Hongxiang Lou
The overexpression of drug exporters is a well-known mechanism driving antifungal drug resistance. Here, we investigate that converting the exporter to function as a drug importer provides an alternative approach to combat drug resistance. Using high-throughput screening, we identified quaternary ammonium compounds exhibiting hypersensitivity in Candida albicans strains overexpressing MDR1. Further experiments involving CRISPR-Cas9-mediated deletion in C. albicans, heterologous expression of CaMdr1 in Saccharomyces cerevisiae and construction of CaMdr1-containing proteoliposomes confirmed Mdr1 acts as an importer of MKT-077, a potent cyanine derivative highly selective against MDR1-overexpressing strains. By combining computational simulations and the site-directed mutagenesis, critical residues within the transmembrane domains of CaMdr1 involved in MKT-077 import were further identified. Moreover, MKT-077 exhibited therapeutic efficacy in Galleria mellonella infected with Mdr1-overexpressing C. albicans. This work opens an avenue to convert drug resistance into drug sensitivity-a paradigm-shifting strategy in antifungal drug discovery.
{"title":"Exporter Mdr1 as an importer is an achilles’ heel for combating drug-resistant Candida","authors":"Jinyao Chen , Ming Zhang , Yeji Wang , Zhiyu Xie , Fei Yang , Hongjun Yu , Di Zhang , Min Fang , Xiaoyi Luan , Xueyang Jin , Xue Wang , Yanan Qiao , Shicun Zheng , Xiuyun Li , Wenqiang Chang , Hongxiang Lou","doi":"10.1016/j.chembiol.2026.01.009","DOIUrl":"10.1016/j.chembiol.2026.01.009","url":null,"abstract":"<div><div>The overexpression of drug exporters is a well-known mechanism driving antifungal drug resistance. Here, we investigate that converting the exporter to function as a drug importer provides an alternative approach to combat drug resistance. Using high-throughput screening, we identified quaternary ammonium compounds exhibiting hypersensitivity in <em>Candida albicans</em> strains overexpressing <em>MDR1</em>. Further experiments involving CRISPR-Cas9-mediated deletion in <em>C. albicans</em>, heterologous expression of <em>Ca</em>Mdr1 in <em>Saccharomyces cerevisiae</em> and construction of <em>Ca</em>Mdr1-containing proteoliposomes confirmed Mdr1 acts as an importer of MKT-077, a potent cyanine derivative highly selective against <em>MDR1</em>-overexpressing strains. By combining computational simulations and the site-directed mutagenesis, critical residues within the transmembrane domains of <em>Ca</em>Mdr1 involved in MKT-077 import were further identified. Moreover, MKT-077 exhibited therapeutic efficacy in <em>Galleria mellonella</em> infected with Mdr1-overexpressing <em>C. albicans</em>. This work opens an avenue to convert drug resistance into drug sensitivity-a paradigm-shifting strategy in antifungal drug discovery.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 227-240.e6"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256817","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}
Pub Date : 2026-02-19Epub Date: 2026-01-12DOI: 10.1016/j.chembiol.2025.12.012
Dong-Ting Ke , Zilong Zhan , Wenliang Zhang , Zhenyi Hu , Po-Han Chen
Phosphorylation dynamics are delicately balanced by kinases and phosphatases, and abnormal protein phosphorylation events may disrupt normal cellular physiology and thus lead to diseases. Recent developments in phosphorylation targeting tools—mostly the small-molecule kinase inhibitors—have changed the treatments for cancers and other diseases. Alternatively, the use of bifunctional modalities offers another approach through an “event-driven model” with distinct advantages. Here, we highlight advances in bifunctional modalities that modulate protein phosphorylation, including PhosTACs, DEPTACs, PhoRCs, PHICS, and related approaches. Starting with an overview of both kinases and phosphates, we describe recent applications of phosphorylation-targeting therapeutics, with a discussion about the advantages and limitations of current tools, and alternative solutions using bifunctional systems. In addition, the modes of action of various bifunctional modalities and the interplay among protein substrates, kinases, and phosphatases are also discussed, offering an insight into the advancements of phosphorylation targeting strategies against human diseases.
{"title":"Deciphering phosphorylation TACtics: Advances in phosphorylation targeting strategies and bifunctional modalities","authors":"Dong-Ting Ke , Zilong Zhan , Wenliang Zhang , Zhenyi Hu , Po-Han Chen","doi":"10.1016/j.chembiol.2025.12.012","DOIUrl":"10.1016/j.chembiol.2025.12.012","url":null,"abstract":"<div><div>Phosphorylation dynamics are delicately balanced by kinases and phosphatases, and abnormal protein phosphorylation events may disrupt normal cellular physiology and thus lead to diseases. Recent developments in phosphorylation targeting tools—mostly the small-molecule kinase inhibitors—have changed the treatments for cancers and other diseases. Alternatively, the use of bifunctional modalities offers another approach through an “event-driven model” with distinct advantages. Here, we highlight advances in bifunctional modalities that modulate protein phosphorylation, including PhosTACs, DEPTACs, PhoRCs, PHICS, and related approaches. Starting with an overview of both kinases and phosphates, we describe recent applications of phosphorylation-targeting therapeutics, with a discussion about the advantages and limitations of current tools, and alternative solutions using bifunctional systems. In addition, the modes of action of various bifunctional modalities and the interplay among protein substrates, kinases, and phosphatases are also discussed, offering an insight into the advancements of phosphorylation targeting strategies against human diseases.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 153-168"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949877","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}
Pub Date : 2026-02-19Epub Date: 2026-02-03DOI: 10.1016/j.chembiol.2026.01.002
Hangchao Zhang , Jian Fu , Yan Guo , Shijie Liu , Xuehua Mei , Xiu Zeng , Wenkai Ren
Inflammatory macrophages (M1 macrophages) and interleukin-1β (IL-1β) serve as critical mediators of inflammatory response and antimicrobial defense in the immune system. Our preliminary investigation identified the HEAT repeat protein (maestro heat-like repeat family member 7, MROH7) as a potential regulator of IL-1β; however, its function in macrophages remains unexplored. In this study, we demonstrated that MROH7 inhibits IL-1β production in M1 macrophages. Mechanistically, MROH7 facilitates the acetylation of lipopolysaccharide-binding protein (LBP) through accumulating intracellular arachidonic acid (AA), thereby promoting its degradation and inhibiting the nuclear factor κB (NF-κB) signaling pathway. Additionally, mice with the myeloid depletion of Mroh7 exhibit an aggravated inflammatory response in lipopolysaccharide (LPS)-induced systemic inflammation. In summary, our study establishes MROH7 as a regulator in macrophage-mediated inflammation, providing critical insights into potential therapeutic targets for inflammatory disorders.
炎性巨噬细胞（M1巨噬细胞）和白细胞介素-1β (IL-1β)在免疫系统中作为炎症反应和抗菌防御的重要介质。我们的初步研究发现HEAT重复蛋白（maestro HEAT -like repeat family member 7, MROH7）是IL-1β的潜在调节因子；然而，其在巨噬细胞中的功能尚不清楚。在这项研究中，我们证明了MROH7抑制M1巨噬细胞中IL-1β的产生。在机制上，MROH7通过细胞内花生四烯酸（AA）的积累，促进脂多糖结合蛋白（LBP）的乙酰化，从而促进其降解，抑制核因子κB （NF-κB）信号通路。此外，髓系Mroh7缺失的小鼠在脂多糖（LPS）诱导的全身炎症反应中表现出加重的炎症反应。总之，我们的研究确立了MROH7在巨噬细胞介导的炎症中的调节作用，为炎性疾病的潜在治疗靶点提供了重要的见解。
{"title":"The HEAT repeat protein MROH7 regulates the inflammatory macrophage response via LBP acetylation","authors":"Hangchao Zhang , Jian Fu , Yan Guo , Shijie Liu , Xuehua Mei , Xiu Zeng , Wenkai Ren","doi":"10.1016/j.chembiol.2026.01.002","DOIUrl":"10.1016/j.chembiol.2026.01.002","url":null,"abstract":"<div><div>Inflammatory macrophages (M1 macrophages) and interleukin-1β (IL-1β) serve as critical mediators of inflammatory response and antimicrobial defense in the immune system. Our preliminary investigation identified the HEAT repeat protein (maestro heat-like repeat family member 7, MROH7) as a potential regulator of IL-1β; however, its function in macrophages remains unexplored. In this study, we demonstrated that MROH7 inhibits IL-1β production in M1 macrophages. Mechanistically, MROH7 facilitates the acetylation of lipopolysaccharide-binding protein (LBP) through accumulating intracellular arachidonic acid (AA), thereby promoting its degradation and inhibiting the nuclear factor κB (NF-κB) signaling pathway. Additionally, mice with the myeloid depletion of <em>Mroh7</em> exhibit an aggravated inflammatory response in lipopolysaccharide (LPS)-induced systemic inflammation. In summary, our study establishes MROH7 as a regulator in macrophage-mediated inflammation, providing critical insights into potential therapeutic targets for inflammatory disorders.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 169-182.e5"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110974","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}
Pub Date : 2026-02-19Epub Date: 2026-02-09DOI: 10.1016/j.chembiol.2026.01.005
Yaquan Liang , Christopher Adamson , Chenyu Li , Evan Wei Long Ng , Yujie Li , Yuan Qiao
Gut bacteria-derived peptidoglycan fragments (PGNs) are key signaling molecules in mammalian hosts. However, the production and functional roles of soluble PGNs secreted by individual gut bacterial species have not been systematically explored. Herein, we used a targeted LC-MS/MS approach to profile PGNs released by bacteria, identifying Lactobacillaceae as the predominant producers of disaccharide PGNs in culture supernatants. We then chemically synthesized such disaccharide PGNs and confirmed their activation of the mammalian sensor NOD2. Notably, priming murine macrophages with disaccharide PGNs induced tolerance to subsequent stimulation by TLR2/4 ligands, suggesting that sustained exposure to bioactive PGNs in the gut may shape host immune responses. Consistently, the administration of the disaccharide PGN, GM-AQK, effectively alleviated gut inflammation in a DSS-induced colitis mouse model. Together, these findings deepen our understanding of PGN-mediated gut microbiota-host crosstalk and position natural disaccharide PGNs as promising postbiotic candidates for the therapeutic modulation of intestinal inflammation.
{"title":"Discovery of bioactive peptidoglycan fragments from Lactobacillaceae that confer intestinal protection in hosts","authors":"Yaquan Liang , Christopher Adamson , Chenyu Li , Evan Wei Long Ng , Yujie Li , Yuan Qiao","doi":"10.1016/j.chembiol.2026.01.005","DOIUrl":"10.1016/j.chembiol.2026.01.005","url":null,"abstract":"<div><div>Gut bacteria-derived peptidoglycan fragments (PGNs) are key signaling molecules in mammalian hosts. However, the production and functional roles of soluble PGNs secreted by individual gut bacterial species have not been systematically explored. Herein, we used a targeted LC-MS/MS approach to profile PGNs released by bacteria, identifying <em>Lactobacillaceae</em> as the predominant producers of disaccharide PGNs in culture supernatants. We then chemically synthesized such disaccharide PGNs and confirmed their activation of the mammalian sensor NOD2. Notably, priming murine macrophages with disaccharide PGNs induced tolerance to subsequent stimulation by TLR2/4 ligands, suggesting that sustained exposure to bioactive PGNs in the gut may shape host immune responses. Consistently, the administration of the disaccharide PGN, GM-AQK, effectively alleviated gut inflammation in a DSS-induced colitis mouse model. Together, these findings deepen our understanding of PGN-mediated gut microbiota-host crosstalk and position natural disaccharide PGNs as promising postbiotic candidates for the therapeutic modulation of intestinal inflammation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 198-212.e11"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138825","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}
Pub Date : 2026-02-19DOI: 10.1016/j.chembiol.2026.01.011
Zhijun He , Peng Jiang
The von Hippel-Lindau (VHL) protein is known for degrading hydroxylated proteins in normoxia, but its role under hypoxia remains unclear. In a recent report in Cell Metabolism Li et al.1 demonstrate that mitochondrial VHL remodels amino acid metabolism under chronic hypoxia to support cell growth, independent of hydroxylated protein degradation.
von Hippel-Lindau （VHL）蛋白在常氧条件下降解羟基化蛋白，但其在缺氧条件下的作用尚不清楚。在Cell Metabolism最近的一篇报道中，Li等人1证明了线粒体VHL在慢性缺氧下重塑氨基酸代谢以支持细胞生长，而不依赖于羟基化蛋白的降解。
{"title":"Beyond a degrader: VHL reprograms hypoxic metabolism","authors":"Zhijun He , Peng Jiang","doi":"10.1016/j.chembiol.2026.01.011","DOIUrl":"10.1016/j.chembiol.2026.01.011","url":null,"abstract":"<div><div>The von Hippel-Lindau (VHL) protein is known for degrading hydroxylated proteins in normoxia, but its role under hypoxia remains unclear. In a recent report in <em>Cell Metabolism</em> Li et al.<span><span><sup>1</sup></span></span> demonstrate that mitochondrial VHL remodels amino acid metabolism under chronic hypoxia to support cell growth, independent of hydroxylated protein degradation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 147-149"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256880","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}
Targeted protein degradation (TPD) has emerged as a powerful therapeutic paradigm by enabling the selective elimination of disease-associated proteins beyond the reach of conventional inhibition strategies. Among TPD approaches, lysosome-targeting chimeras (LYTACs) uniquely enable the degradation of extracellular and membrane-associated proteins through receptor-mediated endocytosis and lysosomal delivery. This Review provides a mechanistic and conceptual overview of LYTAC technology, emphasizing molecular classification based on ligand architecture, lysosome-targeting receptor engagement, and endocytic trafficking pathways. We discuss how receptors such as the cation-independent mannose-6-phosphate receptor and asialoglycoprotein receptor dictate internalization efficiency and degradation outcomes, and highlight key biochemical and cellular determinants governing target recognition, intracellular routing, and lysosomal processing. Finally, we examine major translational challenges, including tissue selectivity, pharmacokinetics, immunogenicity, and manufacturing constraints, and outline emerging design strategies such as ligand and linker engineering, modular scaffold optimization, and synthetic receptor recruitment that may enable next-generation LYTAC therapeutics with improved precision and clinical potential.
靶向蛋白降解（Targeted protein degradation， TPD）已经成为一种强大的治疗模式，它能够选择性地消除疾病相关蛋白，而不是传统的抑制策略。在TPD方法中，溶酶体靶向嵌合体（LYTACs）通过受体介导的内吞作用和溶酶体递送独特地实现了细胞外蛋白和膜相关蛋白的降解。这篇综述提供了LYTAC技术的机制和概念概述，强调基于配体结构的分子分类，溶酶体靶向受体的参与，以及内吞运输途径。我们讨论了诸如不依赖阳离子的甘露糖-6-磷酸受体和asialal糖蛋白受体等受体如何决定内化效率和降解结果，并强调了控制靶标识别、细胞内路径和溶酶体处理的关键生化和细胞决定因素。最后，我们研究了主要的翻译挑战，包括组织选择性、药代动力学、免疫原性和制造限制，并概述了新兴的设计策略，如配体和连接体工程、模块化支架优化和合成受体招募，这些策略可能使下一代LYTAC治疗药物具有更高的精度和临床潜力。
{"title":"Lysosome-targeting chimeras enable targeted protein degradation.","authors":"Bozhao Li, Yanyan Li, Jian Zhang, Siren Badama, Xian Zhao, Liping Wang, Tian Zhang, Xueting Wang, Xiaoqing Yi, Guo-Bin Ding, Xudong Wang, Guangjun Nie","doi":"10.1016/j.chembiol.2026.01.008","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.01.008","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) has emerged as a powerful therapeutic paradigm by enabling the selective elimination of disease-associated proteins beyond the reach of conventional inhibition strategies. Among TPD approaches, lysosome-targeting chimeras (LYTACs) uniquely enable the degradation of extracellular and membrane-associated proteins through receptor-mediated endocytosis and lysosomal delivery. This Review provides a mechanistic and conceptual overview of LYTAC technology, emphasizing molecular classification based on ligand architecture, lysosome-targeting receptor engagement, and endocytic trafficking pathways. We discuss how receptors such as the cation-independent mannose-6-phosphate receptor and asialoglycoprotein receptor dictate internalization efficiency and degradation outcomes, and highlight key biochemical and cellular determinants governing target recognition, intracellular routing, and lysosomal processing. Finally, we examine major translational challenges, including tissue selectivity, pharmacokinetics, immunogenicity, and manufacturing constraints, and outline emerging design strategies such as ligand and linker engineering, modular scaffold optimization, and synthetic receptor recruitment that may enable next-generation LYTAC therapeutics with improved precision and clinical potential.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224817","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}
Pub Date : 2026-02-02DOI: 10.1016/j.chembiol.2026.01.001
Alexander R. Ziegler, Nichollas E. Scott, Laura E. Edgington-Mitchell
{"title":"Advances in degradomics technologies to assess proteolytic cleavage events","authors":"Alexander R. Ziegler, Nichollas E. Scott, Laura E. Edgington-Mitchell","doi":"10.1016/j.chembiol.2026.01.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.01.001","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"59 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110975","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}
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