Pub Date : 2026-01-15Epub Date: 2025-12-31DOI: 10.1016/j.chembiol.2025.12.003
José L. Montaño , Vishnu R. Tejus , Vee Xu , Andrew C. Condon , Andrew K. Ecker , Andreas Langen , Kevin K. Leung , Balyn W. Zaro
The NCI-60 cancer cell line panel is one of the most extensively characterized and publicly accessible resources in cancer research. Here, we expand this platform by generating a comprehensive proteomic and cysteine reactivity atlas using shotgun proteomics and quantitative chemoproteomics. We quantified over 12,000 proteins and identified more than 36,000 reactive cysteines, including over 10,000 hyperreactive sites, across the panel. Our analyses reveal widespread heterogeneity in cysteine reactivity, while conserved hyperreactive cysteines strongly correlate with functional roles. Tissue-specific cysteine reactivity occurred independently of protein abundance, highlighting context-dependent regulation. To enable exploration and integration with existing datasets, we developed an interactive online database that allows users to visualize protein and cysteine coverage and design custom cell line panels. Together, these data and tools illuminate the landscape of cysteine reactivity in cancer and provide a foundational resource to advance future studies in protein function, redox biology, and covalent drug discovery.
{"title":"An interactive resource mapping the proteome and reactive cysteine landscape across the NCI-60 reveals cell and tissue-specific profiles","authors":"José L. Montaño , Vishnu R. Tejus , Vee Xu , Andrew C. Condon , Andrew K. Ecker , Andreas Langen , Kevin K. Leung , Balyn W. Zaro","doi":"10.1016/j.chembiol.2025.12.003","DOIUrl":"10.1016/j.chembiol.2025.12.003","url":null,"abstract":"<div><div>The NCI-60 cancer cell line panel is one of the most extensively characterized and publicly accessible resources in cancer research. Here, we expand this platform by generating a comprehensive proteomic and cysteine reactivity atlas using shotgun proteomics and quantitative chemoproteomics. We quantified over 12,000 proteins and identified more than 36,000 reactive cysteines, including over 10,000 hyperreactive sites, across the panel. Our analyses reveal widespread heterogeneity in cysteine reactivity, while conserved hyperreactive cysteines strongly correlate with functional roles. Tissue-specific cysteine reactivity occurred independently of protein abundance, highlighting context-dependent regulation. To enable exploration and integration with existing datasets, we developed an interactive online database that allows users to visualize protein and cysteine coverage and design custom cell line panels. Together, these data and tools illuminate the landscape of cysteine reactivity in cancer and provide a foundational resource to advance future studies in protein function, redox biology, and covalent drug discovery.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 117-131.e5"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888179","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 : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.004
Jürg Gertsch
In this issue of Cell Chemical Biology, Tufail et al.1 demonstrate that the peripheral diacylglycerol lipase α/β inhibitor A1480LS exerts potent anti-inflammatory and analgesic effects by blocking 2-arachidonoylglycerol synthesis and reducing arachidonate-derived eicosanoid production. However, potential risks from altered protein kinase C signaling due to elevated diacylglycerols warrant further evaluation in future therapeutic applications.
{"title":"Targeting the endocannabinoid-eicosanoid axis to treat pain: Promise and pitfalls","authors":"Jürg Gertsch","doi":"10.1016/j.chembiol.2025.12.004","DOIUrl":"10.1016/j.chembiol.2025.12.004","url":null,"abstract":"<div><div>In this issue of <em>Cell Chemical Biology</em>, Tufail et al.<span><span><sup>1</sup></span></span> demonstrate that the peripheral diacylglycerol lipase α/β inhibitor A1480LS exerts potent anti-inflammatory and analgesic effects by blocking 2-arachidonoylglycerol synthesis and reducing arachidonate-derived eicosanoid production. However, potential risks from altered protein kinase C signaling due to elevated diacylglycerols warrant further evaluation in future therapeutic applications.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 4-6"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975814","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 : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.011
Lukas M. Braun , Robert Zeiser
In this issue of Cell Chemical Biology, Uible et al.1 uncover a previously unknown non-proteolytic role for caspase-1 (CASP1) in leukemia. CASP1 sustains leukemic growth by coordinating mTORC1-NF-κB signaling as scaffold for RPTOR, rather than regulating IL-1β and pyroptosis. CASP1’s scaffolding function was found as a therapeutic vulnerability in leukemia.
{"title":"Cutting without cleaving: How caspase-1 shapes leukemia beyond enzymatic activity","authors":"Lukas M. Braun , Robert Zeiser","doi":"10.1016/j.chembiol.2025.12.011","DOIUrl":"10.1016/j.chembiol.2025.12.011","url":null,"abstract":"<div><div>In this issue of <em>Cell Chemical Biology</em>, Uible et al.<span><span><sup>1</sup></span></span> uncover a previously unknown non-proteolytic role for caspase-1 (CASP1) in leukemia. CASP1 sustains leukemic growth by coordinating mTORC1-NF-κB signaling as scaffold for RPTOR, rather than regulating IL-1β and pyroptosis. CASP1’s scaffolding function was found as a therapeutic vulnerability in leukemia.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 1-3"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972629","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 : 2026-01-15Epub Date: 2026-01-06DOI: 10.1016/j.chembiol.2025.12.002
Emma E. Uible , Issac Choi , Courtnee A. Clough , Aishlin Hassan , Annabelle J. Anandappa , Julianna Fisher , Bibek Karki , Kathleen Hueneman , Kwangmin Choi , Eric J. Vick , William Seibel , Kenneth D. Greis , Lynn Lee , Courtney Jones , Timothy M. Chlon , Jorge Henao-Mejia , Chandrashekhar Pasare , John T. Cunningham , Andrew G. Volk , Daniel T. Starczynowski
Caspase-1 (CASP1) is best known for regulating IL-1β processing and pyroptosis; however, its role in leukemia has not been clearly defined. Here, we show that loss of CASP1 impairs leukemic cell growth, drives differentiation, and reduces leukemic burden in vivo, independent of its CASP1 protease activity. Instead, CASP1 functions as a scaffolding hub, controlling nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling via its interaction with raptor (RPTOR), a component of mTORC1. Deletion of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell function. We further developed a proteolysis-targeting chimera (PROTAC) degrader that selectively depletes Pro-CASP1 and suppresses leukemic cells. These findings reveal CASP1 as a regulator of mTORC1-NF-κB signaling in leukemia and highlight its scaffolding activity as a therapeutic vulnerability.
{"title":"Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia","authors":"Emma E. Uible , Issac Choi , Courtnee A. Clough , Aishlin Hassan , Annabelle J. Anandappa , Julianna Fisher , Bibek Karki , Kathleen Hueneman , Kwangmin Choi , Eric J. Vick , William Seibel , Kenneth D. Greis , Lynn Lee , Courtney Jones , Timothy M. Chlon , Jorge Henao-Mejia , Chandrashekhar Pasare , John T. Cunningham , Andrew G. Volk , Daniel T. Starczynowski","doi":"10.1016/j.chembiol.2025.12.002","DOIUrl":"10.1016/j.chembiol.2025.12.002","url":null,"abstract":"<div><div>Caspase-1 (CASP1) is best known for regulating IL-1β processing and pyroptosis; however, its role in leukemia has not been clearly defined. Here, we show that loss of CASP1 impairs leukemic cell growth, drives differentiation, and reduces leukemic burden <em>in vivo</em>, independent of its CASP1 protease activity. Instead, CASP1 functions as a scaffolding hub, controlling nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling via its interaction with raptor (RPTOR), a component of mTORC1. Deletion of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell function. We further developed a proteolysis-targeting chimera (PROTAC) degrader that selectively depletes Pro-CASP1 and suppresses leukemic cells. These findings reveal CASP1 as a regulator of mTORC1-NF-κB signaling in leukemia and highlight its scaffolding activity as a therapeutic vulnerability.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 59-73.e10"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903111","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 : 2026-01-15Epub Date: 2025-12-30DOI: 10.1016/j.chembiol.2025.12.001
Wen-Chao Yu , Yan-Lei Yu , Bing-Cheng Dong , Ze-Yu Wang , Au-Qi Du , Song-Wei Li , Buddha Bahadur Basnet , Xiao-Ze Bao , Xuan-Rong Sun , Xing-Nuo Li , Qi Xuan , Qihao Wu , Hong Wang , Bin Wei
Natural products embedded within complex metabolomes are valuable sources of drug leads. Untargeted metabolomics using cosine-based MS2 comparisons is widely used for discovering bioactive molecules. To improve annotation accuracy and resolution, alternative algorithms have been developed to complement cosine-based MS2 comparison. Here, we present MSanalyst, a user-friendly platform that integrates 46 distinct mass spectral similarity algorithms. Benchmarking with microbial metabolite datasets and over three million MS2 spectral pairs demonstrated that complementary algorithms substantially enhance the detection of metabolite-metabolite spectral connections. Applying MSanalyst to Kutzneria viridogrisea DSM 43850 led to the discovery of a class of aromatic glycosides, the kutznaposides. Biological assays and multi-omics analyses revealed that kutznaposides C–F arise from a previously unrecognized menaquinone shunt pathway, enabling the host to mitigate oxidative stress and avoid self-toxicity. Collectively, these findings highlight the potential of MSanalyst to uncover hidden metabolites, metabolic pathways, and their biological functions.
{"title":"Targeted discovery of aromatic glycosides with dual detoxification effects via a highly customized molecular networking platform","authors":"Wen-Chao Yu , Yan-Lei Yu , Bing-Cheng Dong , Ze-Yu Wang , Au-Qi Du , Song-Wei Li , Buddha Bahadur Basnet , Xiao-Ze Bao , Xuan-Rong Sun , Xing-Nuo Li , Qi Xuan , Qihao Wu , Hong Wang , Bin Wei","doi":"10.1016/j.chembiol.2025.12.001","DOIUrl":"10.1016/j.chembiol.2025.12.001","url":null,"abstract":"<div><div>Natural products embedded within complex metabolomes are valuable sources of drug leads. Untargeted metabolomics using cosine-based MS<sup>2</sup> comparisons is widely used for discovering bioactive molecules. To improve annotation accuracy and resolution, alternative algorithms have been developed to complement cosine-based MS<sup>2</sup> comparison. Here, we present MSanalyst, a user-friendly platform that integrates 46 distinct mass spectral similarity algorithms. Benchmarking with microbial metabolite datasets and over three million MS<sup>2</sup> spectral pairs demonstrated that complementary algorithms substantially enhance the detection of metabolite-metabolite spectral connections. Applying MSanalyst to <em>Kutzneria viridogrisea</em> DSM 43850 led to the discovery of a class of aromatic glycosides, the kutznaposides. Biological assays and multi-omics analyses revealed that kutznaposides C–F arise from a previously unrecognized menaquinone shunt pathway, enabling the host to mitigate oxidative stress and avoid self-toxicity. Collectively, these findings highlight the potential of MSanalyst to uncover hidden metabolites, metabolic pathways, and their biological functions.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 132-144.e9"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877252","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 : 2026-01-15Epub Date: 2026-01-05DOI: 10.1016/j.chembiol.2025.10.013
Wenjin Wan , Xin Ji , Haozhi Song , Zhongxuan Zhang , Chun Kit Kwok , Xiaohong Fang , Xing Li
Spatiotemporal imaging of genomic DNA dynamics in live mammalian cells is essential for elucidating eukaryotic organization and processes relevant to health and disease. CRISPR systems greatly facilitate the development of live cell DNA imaging tools. However, conventional CRISPR imaging tools typically utilize constitutively fluorescent proteins, resulting in high background noise, nonspecific nucleolar signals, and low signal-to-noise ratios. To address this, fluorogenic CRISPR-based imaging tools have been developed. These tools remain non-fluorescent until they bind to the target DNA, thus significantly reducing the background and enhancing the sensitivity. This review summarizes four fluorogenic CRISPR strategies, each utilizing different fluorogenic reporters, including fluorogenic proteins, fluorogenic RNA aptamers, split fluorescent proteins, and molecular beacons. These fluorogenic CRISPR approaches successfully monitored the subnucleus gene loci localization, dynamics, and DNA breaks and repairs. We anticipate that this review can inspire researchers to expand the fluorogenic CRISPR for cellular DNA imaging and diverse bioapplications.
{"title":"Fluorogenic CRISPR for DNA imaging in live mammalian cells","authors":"Wenjin Wan , Xin Ji , Haozhi Song , Zhongxuan Zhang , Chun Kit Kwok , Xiaohong Fang , Xing Li","doi":"10.1016/j.chembiol.2025.10.013","DOIUrl":"10.1016/j.chembiol.2025.10.013","url":null,"abstract":"<div><div>Spatiotemporal imaging of genomic DNA dynamics in live mammalian cells is essential for elucidating eukaryotic organization and processes relevant to health and disease. CRISPR systems greatly facilitate the development of live cell DNA imaging tools. However, conventional CRISPR imaging tools typically utilize constitutively fluorescent proteins, resulting in high background noise, nonspecific nucleolar signals, and low signal-to-noise ratios. To address this, fluorogenic CRISPR-based imaging tools have been developed. These tools remain non-fluorescent until they bind to the target DNA, thus significantly reducing the background and enhancing the sensitivity. This review summarizes four fluorogenic CRISPR strategies, each utilizing different fluorogenic reporters, including fluorogenic proteins, fluorogenic RNA aptamers, split fluorescent proteins, and molecular beacons. These fluorogenic CRISPR approaches successfully monitored the subnucleus gene loci localization, dynamics, and DNA breaks and repairs. We anticipate that this review can inspire researchers to expand the fluorogenic CRISPR for cellular DNA imaging and diverse bioapplications.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 33-44"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897817","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 : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.008
Yusuf Z. Tufail , Carlos Guijas , David A. Kummer , Cassandra L. Henry , Jeanne V. Moody , Taylor Andalis , Bryan Boyd , Jacob Gil , Jacquelyn Ha , Dylan M. Herbst , Rachel A. Herbst-Graham , Clayton Hutton , Ellen M. Kozina , Micah J. Niphakis , Nhi Ngo , Gary P. O’Neill , Holly T. Reardon , Michael Shaghafi , Olesya A. Ulanovskaya , Nicholas Raffaele , Jason R. Clapper
Diacylglycerol lipase (DAGL) produces 2-arachidonoylglycerol (2-AG) and other proinflammatory lipids. Inactivation of DAGLs reduces the production of 2-AG, arachidonic acid (AA) and eicosanoids and elicits antinociceptive and anti-(neuro)inflammatory effects in rodents. However, inhibitors that enter the brain can cause significant central nervous system (CNS) side effects. Using activity-based protein profiling (ABPP), we report the discovery of A1480LS, a potent, in vivo active, small molecule dual inhibitor of DAGLα/β that is functionally biased to the periphery. We demonstrate that A1480LS reduces pain behaviors and nociceptor activity in animal models. Moreover, A1480LS accomplishes this by reducing 2-AG and other lipids in peripheral tissues without causing adverse CNS effects. Overall, we show that inhibiting DAG metabolism in the periphery elicits antinociceptive effects that can be functionally dissected from adverse central effects and provide preclinical validation for a non-narcotic strategy to treat pain.
{"title":"Suppression of pain transmission and behavior by inhibition of peripheral diacylglycerol metabolism","authors":"Yusuf Z. Tufail , Carlos Guijas , David A. Kummer , Cassandra L. Henry , Jeanne V. Moody , Taylor Andalis , Bryan Boyd , Jacob Gil , Jacquelyn Ha , Dylan M. Herbst , Rachel A. Herbst-Graham , Clayton Hutton , Ellen M. Kozina , Micah J. Niphakis , Nhi Ngo , Gary P. O’Neill , Holly T. Reardon , Michael Shaghafi , Olesya A. Ulanovskaya , Nicholas Raffaele , Jason R. Clapper","doi":"10.1016/j.chembiol.2025.12.008","DOIUrl":"10.1016/j.chembiol.2025.12.008","url":null,"abstract":"<div><div>Diacylglycerol lipase (DAGL) produces 2-arachidonoylglycerol (2-AG) and other proinflammatory lipids. Inactivation of DAGLs reduces the production of 2-AG, arachidonic acid (AA) and eicosanoids and elicits antinociceptive and anti-(neuro)inflammatory effects in rodents. However, inhibitors that enter the brain can cause significant central nervous system (CNS) side effects. Using activity-based protein profiling (ABPP), we report the discovery of A1480LS, a potent, <em>in vivo</em> active, small molecule dual inhibitor of DAGLα/β that is functionally biased to the periphery. We demonstrate that A1480LS reduces pain behaviors and nociceptor activity in animal models. Moreover, A1480LS accomplishes this by reducing 2-AG and other lipids in peripheral tissues without causing adverse CNS effects. Overall, we show that inhibiting DAG metabolism in the periphery elicits antinociceptive effects that can be functionally dissected from adverse central effects and provide preclinical validation for a non-narcotic strategy to treat pain.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 74-90.e19"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976316","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 : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.014
Ana M. Sebastião
In a study recently published in Nature, Yue et al.1 provide a causal relationship between mitochondrial metabolism, adenosine receptor signaling, and the mechanism of action for novel antidepressants. Their findings identify adenosine as a key driver of rapid-acting antidepressant effects and as a therapeutic target for major depressive disorder.
{"title":"Adenosine signaling as a hub for the action of novel antidepressant strategies","authors":"Ana M. Sebastião","doi":"10.1016/j.chembiol.2025.12.014","DOIUrl":"10.1016/j.chembiol.2025.12.014","url":null,"abstract":"<div><div>In a study recently published in <em>Nature</em>, Yue et al.<span><span><sup>1</sup></span></span> provide a causal relationship between mitochondrial metabolism, adenosine receptor signaling, and the mechanism of action for novel antidepressants. Their findings identify adenosine as a key driver of rapid-acting antidepressant effects and as a therapeutic target for major depressive disorder.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 7-9"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972947","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}
Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer’s disease) and alpha-synuclein in Parkinson’s disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.
{"title":"The interplay between autophagy and unconventional secretion in neurodegeneration","authors":"Maurizio Renna , Raffaella Bonavita , Grace Dixon , Luigi Vittorio Verdicchio , Angeleen Fleming","doi":"10.1016/j.chembiol.2025.12.007","DOIUrl":"10.1016/j.chembiol.2025.12.007","url":null,"abstract":"<div><div>Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer’s disease) and alpha-synuclein in Parkinson’s disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 10-32"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976438","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 : 2026-01-15Epub Date: 2026-01-02DOI: 10.1016/j.chembiol.2025.12.005
Kirk W. Donovan , Eric Stefan , Bekim Bajrami , Melissa Bennion , Sarah Huff , Darsheed N. Mustafa , Mei-Ju Su , Sofya Dragan , Simone Sciabola , Yi-Ying Chou , Jude Prah , Xiaofeng Li , Douglas S. Johnson , Dominic M. Walsh , James S. Harvey
We report the discovery of a chemical series that enhances ApoE secretion from human astrocytes through mechanisms independent of LXR agonism. Target deconvolution of hits from a phenotypic screen in astrocytoma cells employed chemoproteomics, photoaffinity probes, in vitro KINOMEscan analysis, and targeted siRNA knockdown experiments. Photoaffinity labeling coupled with quantitative chemical proteomics identified aryl hydrocarbon receptor (AhR), a transcription factor not previously associated with ApoE secretion, as the primary target. A diverse panel of AhR agonists and antagonists together with genetic knockdown confirmed that ApoE secretion increases when AhR activity is reduced. Using a luciferase reporter assay, we demonstrated that active series analogs exhibit AhR antagonism while inactive compounds do not. Since deletion of AhR has severe peripheral effects, chronic inhibition of AhR is not an attractive therapeutic approach for Alzheimer’s disease; nevertheless, these results position AhR as a modulator of ApoE secretion and a biological pathway worth exploring.
{"title":"Identification of aryl hydrocarbon receptor as a functional target that enhances astrocytic ApoE secretion","authors":"Kirk W. Donovan , Eric Stefan , Bekim Bajrami , Melissa Bennion , Sarah Huff , Darsheed N. Mustafa , Mei-Ju Su , Sofya Dragan , Simone Sciabola , Yi-Ying Chou , Jude Prah , Xiaofeng Li , Douglas S. Johnson , Dominic M. Walsh , James S. Harvey","doi":"10.1016/j.chembiol.2025.12.005","DOIUrl":"10.1016/j.chembiol.2025.12.005","url":null,"abstract":"<div><div>We report the discovery of a chemical series that enhances ApoE secretion from human astrocytes through mechanisms independent of LXR agonism. Target deconvolution of hits from a phenotypic screen in astrocytoma cells employed chemoproteomics, photoaffinity probes, <em>in vitro</em> KINOMEscan analysis, and targeted siRNA knockdown experiments. Photoaffinity labeling coupled with quantitative chemical proteomics identified aryl hydrocarbon receptor (AhR), a transcription factor not previously associated with ApoE secretion, as the primary target. A diverse panel of AhR agonists and antagonists together with genetic knockdown confirmed that ApoE secretion increases when AhR activity is reduced. Using a luciferase reporter assay, we demonstrated that active series analogs exhibit AhR antagonism while inactive compounds do not. Since deletion of AhR has severe peripheral effects, chronic inhibition of AhR is not an attractive therapeutic approach for Alzheimer’s disease; nevertheless, these results position AhR as a modulator of ApoE secretion and a biological pathway worth exploring.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 91-101.e12"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895379","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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