Pub Date : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.010
Chih-Yao Chung , Kritarth Singh , Brigida R. Pinho , Jorge M.A. Oliveira , Michael R. Duchen
Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in Science,1 Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.
{"title":"Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease","authors":"Chih-Yao Chung , Kritarth Singh , Brigida R. Pinho , Jorge M.A. Oliveira , Michael R. Duchen","doi":"10.1016/j.chembiol.2025.11.010","DOIUrl":"10.1016/j.chembiol.2025.11.010","url":null,"abstract":"<div><div>Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in <em>Science</em>,<span><span><sup>1</sup></span></span> Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1439-1441"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771268","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.009
Jingwei Liu , Xiaoyu Song , Liu Cao
PARP1 detects DNA damage and catalyzes PARylation of proteins to promote DNA damage response. In a study recently published by Nature Chemical Biology, Zhu et al.1 identify a new function for PARP1 in transcriptional restart by PARylation and stabilization of AFF1, which expands PARP1’s role to transcriptional recovery.
PARP1检测DNA损伤并催化蛋白质的PARylation以促进DNA损伤反应。在Nature Chemical Biology最近发表的一项研究中，Zhu等人1通过对AFF1的PARylation和稳定化发现了PARP1在转录重启中的新功能，这将PARP1的作用扩展到转录恢复。
{"title":"Transcriptional restart: A new role for PARylation in overcoming DNA damage","authors":"Jingwei Liu , Xiaoyu Song , Liu Cao","doi":"10.1016/j.chembiol.2025.11.009","DOIUrl":"10.1016/j.chembiol.2025.11.009","url":null,"abstract":"<div><div>PARP1 detects DNA damage and catalyzes PARylation of proteins to promote DNA damage response. In a study recently published by <em>Nature Chemical Biology</em>, Zhu et al.<span><span><sup>1</sup></span></span> identify a new function for PARP1 in transcriptional restart by PARylation and stabilization of AFF1, which expands PARP1’s role to transcriptional recovery.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1436-1438"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771743","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.001
Min Zhou , Ning Shi , Pilong Li
Multimerization and phase separation represent two paradigms for organizing receptor tyrosine kinases (RTKs). However, their functional distinctions from the perspective of biomolecular organization remain unclear. Here, we present CORdensate, a light-controllable condensation system combining two synergistic photoactuators: oligomeric Cry2 and heterodimeric LOVpep/ePDZ. Engineering single-chain photoswitches, we achieve four biomolecular organization patterns ranging from monomerization to phase separation. CORdensate exhibits constant assembly and disassembly kinetics. Applying CORdensate to mimic pathogenic RTK granules establishes the role of phase separation in activating ALK and RET. Moreover, assembling ALK and RET through varying organization patterns, we highlight the superior organizational ability of phase separation over multimerization. Additionally, CORdensate-based RTK granules suggest that phase separation broadly and robustly activates RTKs. This study introduces a optogenetic tool for investigating biomolecular condensation.
{"title":"Optogenetic control of biomolecular organization reveals distinct roles of phase separation in RTK signaling","authors":"Min Zhou , Ning Shi , Pilong Li","doi":"10.1016/j.chembiol.2025.11.001","DOIUrl":"10.1016/j.chembiol.2025.11.001","url":null,"abstract":"<div><div>Multimerization and phase separation represent two paradigms for organizing receptor tyrosine kinases (RTKs). However, their functional distinctions from the perspective of biomolecular organization remain unclear. Here, we present CORdensate, a light-controllable condensation system combining two synergistic photoactuators: oligomeric Cry2 and heterodimeric LOVpep/ePDZ. Engineering single-chain photoswitches, we achieve four biomolecular organization patterns ranging from monomerization to phase separation. CORdensate exhibits constant assembly and disassembly kinetics. Applying CORdensate to mimic pathogenic RTK granules establishes the role of phase separation in activating ALK and RET. Moreover, assembling ALK and RET through varying organization patterns, we highlight the superior organizational ability of phase separation over multimerization. Additionally, CORdensate-based RTK granules suggest that phase separation broadly and robustly activates RTKs. This study introduces a optogenetic tool for investigating biomolecular condensation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1503-1516.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657865","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.004
Manijeh Khanmohammadi , Yasmin Mirzaalikhan , Sara Baratchi
The ability of innate immune cells to sense and respond to their physical environment is essential for regulating immune function. Macrophages, key players in inflammation, pathogen defense, and tissue repair, are influenced not only by biochemical cues but also by the mechanical properties of their microenvironment, including extracellular matrix stiffness, shear stress, and cyclic stretch. While the effects of soluble factors, such as cytokines on macrophage behavior are well characterized, the mechanisms underlying macrophage mechanotransduction remain poorly understood. This review synthesizes current understanding of how distinct mechanical forces shape macrophage activation, migration, polarization, and cytokine production. We also explore emerging insights into the roles of mechanosensitive ion channels (e.g., Piezo1, TRPV4), integrins, and cytoskeletal dynamics in transducing mechanical signals into pro- or anti-inflammatory responses. A deeper understanding of these pathways may uncover new therapeutic targets for treating cardiovascular diseases, including atherosclerosis.
{"title":"Immunity in motion: The role of mechanics in macrophage biology","authors":"Manijeh Khanmohammadi , Yasmin Mirzaalikhan , Sara Baratchi","doi":"10.1016/j.chembiol.2025.11.004","DOIUrl":"10.1016/j.chembiol.2025.11.004","url":null,"abstract":"<div><div>The ability of innate immune cells to sense and respond to their physical environment is essential for regulating immune function. Macrophages, key players in inflammation, pathogen defense, and tissue repair, are influenced not only by biochemical cues but also by the mechanical properties of their microenvironment, including extracellular matrix stiffness, shear stress, and cyclic stretch. While the effects of soluble factors, such as cytokines on macrophage behavior are well characterized, the mechanisms underlying macrophage mechanotransduction remain poorly understood. This review synthesizes current understanding of how distinct mechanical forces shape macrophage activation, migration, polarization, and cytokine production. We also explore emerging insights into the roles of mechanosensitive ion channels (e.g., Piezo1, TRPV4), integrins, and cytoskeletal dynamics in transducing mechanical signals into pro- or anti-inflammatory responses. A deeper understanding of these pathways may uncover new therapeutic targets for treating cardiovascular diseases, including atherosclerosis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1442-1457"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704154","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 : 2025-11-20DOI: 10.1016/j.chembiol.2025.10.010
Hannah L. Baillie , Thomas A. Milne
In this issue of Cell Chemical Biology, Zhang et al.1 report the identification of a high-affinity EMBOW-derived inhibitor of WDR5, Ac7, which demonstrates in-cell target engagement and in vivo antileukemic efficacy. The microprotein-inspired inhibitor potently blocks the WDR5-MLL1 interaction, suppressing H3K4 methylation and transcription of target genes in mixed lineage leukemia (MLL)-rearranged leukemia.
{"title":"Small proteins with a big job: An EMBOW-derived microprotein targets WDR5-MLL1 and suppresses transcription in leukemia","authors":"Hannah L. Baillie , Thomas A. Milne","doi":"10.1016/j.chembiol.2025.10.010","DOIUrl":"10.1016/j.chembiol.2025.10.010","url":null,"abstract":"<div><div>In this issue of <em>Cell Chemical Biology</em>, Zhang et al.<span><span><sup>1</sup></span></span> report the identification of a high-affinity EMBOW-derived inhibitor of WDR5, Ac7, which demonstrates in-cell target engagement and <em>in vivo</em> antileukemic efficacy. The microprotein-inspired inhibitor potently blocks the WDR5-MLL1 interaction, suppressing H3K4 methylation and transcription of target genes in mixed lineage leukemia (MLL)-rearranged leukemia.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1305-1307"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554788","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 : 2025-11-20DOI: 10.1016/j.chembiol.2025.10.002
Ming Zhang , Meixia Chen , Peiyan Li , Jinrong Min
WD40 repeat-containing protein 5 (WDR5) is a core component of the SET1/mixed lineage leukemia (MLL) complex that regulates gene expression via H3K4 methylation and plays a key role in maintaining oncogenic gene expression programs, particularly in MLL1-rearranged leukemias. In this study, we leveraged a microprotein, endogenous microprotein binder of WDR5 (EMBOW), to develop peptide-based inhibitors that specifically targeted WDR5. Through comprehensive biophysical analyses and high-resolution structural studies, we revealed that EMBOW mainly bound to the WDR5 interaction (WIN) site of WDR5. Structure-guided optimization led to the development of EMBOW-derived peptides, notably Ac7, which exhibited high affinity for WDR5 (Kd = 9.17 ± 4.01 nM). These peptides effectively inhibited H3K4 methylation, suppressed oncogenic gene expression, and impeded leukemia cell proliferation in vitro. Importantly, in xenograft mouse models, Ac7 demonstrated significant anti-tumor activity with low toxicity. This work offers a promising strategy for targeting epigenetic regulators with peptide-based therapeutics, providing a foundation for innovative treatments in leukemia.
{"title":"Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression","authors":"Ming Zhang , Meixia Chen , Peiyan Li , Jinrong Min","doi":"10.1016/j.chembiol.2025.10.002","DOIUrl":"10.1016/j.chembiol.2025.10.002","url":null,"abstract":"<div><div>WD40 repeat-containing protein 5 (WDR5) is a core component of the SET1/mixed lineage leukemia (MLL) complex that regulates gene expression via H3K4 methylation and plays a key role in maintaining oncogenic gene expression programs, particularly in <em>MLL1</em>-rearranged leukemias. In this study, we leveraged a microprotein, endogenous microprotein binder of WDR5 (EMBOW), to develop peptide-based inhibitors that specifically targeted WDR5. Through comprehensive biophysical analyses and high-resolution structural studies, we revealed that EMBOW mainly bound to the WDR5 interaction (WIN) site of WDR5. Structure-guided optimization led to the development of EMBOW-derived peptides, notably Ac7, which exhibited high affinity for WDR5 (<em>K</em><sub>d</sub> = 9.17 ± 4.01 nM). These peptides effectively inhibited H3K4 methylation, suppressed oncogenic gene expression, and impeded leukemia cell proliferation <em>in vitro</em>. Importantly, in xenograft mouse models, Ac7 demonstrated significant anti-tumor activity with low toxicity. This work offers a promising strategy for targeting epigenetic regulators with peptide-based therapeutics, providing a foundation for innovative treatments in leukemia.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1353-1366.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367183","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 : 2025-11-20DOI: 10.1016/j.chembiol.2025.10.011
Yi Yuan, Yaoyang Zhang
In an interview with Dr. Mishtu Dey, the editor-in-chief of Cell Chemical Biology, the authors of the research article entitled “TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics” share insights about their work and reflect on their scientific field and their journeys as researchers.
{"title":"Meet the authors: Yi Yuan and Yaoyang Zhang","authors":"Yi Yuan, Yaoyang Zhang","doi":"10.1016/j.chembiol.2025.10.011","DOIUrl":"10.1016/j.chembiol.2025.10.011","url":null,"abstract":"<div><div>In an interview with Dr. Mishtu Dey, the editor-in-chief of <em>Cell Chemical Biology</em>, the authors of the research article entitled “TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics” share insights about their work and reflect on their scientific field and their journeys as researchers.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1303-1304"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554787","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 : 2025-11-20DOI: 10.1016/j.chembiol.2025.10.007
Yan Li , Lamei Xue , Feijie Wang , Yu Wang , Yujie Sun , Zhoumin Niu , Shengnan Liu , Ying Yan , Siyi Shen , Kuiliang Zhang , Chenzhipeng Nie , Mingcong Fan , Mei Ma , Yuting Wu , Binrui Yang , Jun Du , Ben Zhou , Duo Zhang , Billy K.C. Chow , Li Zhang , Li Wang
Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte lactate dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired autophagy. Our mechanistic study demonstrates that lactate enhances autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.
{"title":"Lactylation of mTOR enhances autophagy in skeletal muscle during exercise","authors":"Yan Li , Lamei Xue , Feijie Wang , Yu Wang , Yujie Sun , Zhoumin Niu , Shengnan Liu , Ying Yan , Siyi Shen , Kuiliang Zhang , Chenzhipeng Nie , Mingcong Fan , Mei Ma , Yuting Wu , Binrui Yang , Jun Du , Ben Zhou , Duo Zhang , Billy K.C. Chow , Li Zhang , Li Wang","doi":"10.1016/j.chembiol.2025.10.007","DOIUrl":"10.1016/j.chembiol.2025.10.007","url":null,"abstract":"<div><div>Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte lactate dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired autophagy. Our mechanistic study demonstrates that lactate enhances autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1367-1380.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485748","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 : 2025-11-20DOI: 10.1016/j.chembiol.2025.10.008
Fabien Vincent , Davide Gianni
Phenotypic screens carried out with functional genomics or small molecules have led to novel biological insights, revealed previously unknown targets for drug discovery programs, and provided starting points for the development of first-in-class therapies. Despite being valuable research tools, genetic and compound screening also have significant limitations. This perspective aims to shed a light on those limitations and provide mitigation strategies when available, with a goal of helping phenotypic screening practitioners gain an understanding of how and when to best utilize either approach.
{"title":"The limitations of small molecule and genetic screening in phenotypic drug discovery","authors":"Fabien Vincent , Davide Gianni","doi":"10.1016/j.chembiol.2025.10.008","DOIUrl":"10.1016/j.chembiol.2025.10.008","url":null,"abstract":"<div><div>Phenotypic screens carried out with functional genomics or small molecules have led to novel biological insights, revealed previously unknown targets for drug discovery programs, and provided starting points for the development of first-in-class therapies. Despite being valuable research tools, genetic and compound screening also have significant limitations. This perspective aims to shed a light on those limitations and provide mitigation strategies when available, with a goal of helping phenotypic screening practitioners gain an understanding of how and when to best utilize either approach.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1310-1320"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492443","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 : 2025-11-20DOI: 10.1016/j.chembiol.2025.10.005
Jingyu Feng , Jessica Page , Leeyup Chung , Zhigang He , Kuan Hong Wang
Cannabis-derived compounds, particularly the non-psychoactive cannabidiol (CBD), hold significant potential for pain management. However, CBD’s hydrophobicity limits systemic brain delivery, constraining both its therapeutic efficacy and mechanistic investigation. Here, we present an inclusion-complex-enhanced nano-micelle formulation (CBD-IN) that significantly improves systemic absorption and elevates brain CBD levels. A single dose of CBD-IN fully suppresses allodynia and hyperalgesia in a mouse model of neuropathic pain, without impairing normal sensorimotor or cognitive functions. This rapid and robust analgesic effect enables in-depth investigation of underlying neural mechanisms. Activity-dependent genetic mapping reveals that CBD-IN selectively reduces allodynia-associated neuronal activation across the somatosensory system. Complementary calcium imaging in spinal nociceptive and somatosensory corticospinal neurons further demonstrates pathophysiological state-dependent neural suppression by CBD. These results demonstrate that nano-formulated CBD delivers rapid and effective analgesia by selectively suppressing pathological hyperactivity throughout the somatosensory system, offering a promising therapeutic strategy for neuropathic pain and other disorders involving circuit-level disinhibition.
{"title":"Rapid suppression of neuropathic pain and somatosensory hyperactivity by nano-formulated cannabidiol","authors":"Jingyu Feng , Jessica Page , Leeyup Chung , Zhigang He , Kuan Hong Wang","doi":"10.1016/j.chembiol.2025.10.005","DOIUrl":"10.1016/j.chembiol.2025.10.005","url":null,"abstract":"<div><div>Cannabis-derived compounds, particularly the non-psychoactive cannabidiol (CBD), hold significant potential for pain management. However, CBD’s hydrophobicity limits systemic brain delivery, constraining both its therapeutic efficacy and mechanistic investigation. Here, we present an inclusion-complex-enhanced nano-micelle formulation (CBD-IN) that significantly improves systemic absorption and elevates brain CBD levels. A single dose of CBD-IN fully suppresses allodynia and hyperalgesia in a mouse model of neuropathic pain, without impairing normal sensorimotor or cognitive functions. This rapid and robust analgesic effect enables in-depth investigation of underlying neural mechanisms. Activity-dependent genetic mapping reveals that CBD-IN selectively reduces allodynia-associated neuronal activation across the somatosensory system. Complementary calcium imaging in spinal nociceptive and somatosensory corticospinal neurons further demonstrates pathophysiological state-dependent neural suppression by CBD. These results demonstrate that nano-formulated CBD delivers rapid and effective analgesia by selectively suppressing pathological hyperactivity throughout the somatosensory system, offering a promising therapeutic strategy for neuropathic pain and other disorders involving circuit-level disinhibition.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1412-1428.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454667","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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