Nature Communications最新文献

Cationic-anionic synchronous ring-opening polymerization

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-56953-0

Wenli Wang, Xue Liang, Hengxu Liu, Jiamin Zhang, Yuanzu Zhang, Beibei Zhang, Jianhua Li, Yunqing Zhu, Jianzhong Du

{"title":"Cationic-anionic synchronous ring-opening polymerization","authors":"Wenli Wang, Xue Liang, Hengxu Liu, Jiamin Zhang, Yuanzu Zhang, Beibei Zhang, Jianhua Li, Yunqing Zhu, Jianzhong Du","doi":"10.1038/s41467-025-56953-0","DOIUrl":"https://doi.org/10.1038/s41467-025-56953-0","url":null,"abstract":"Chemical reactions with incompatible mechanisms (such as nucleophilic reactions and electrophilic reactions, cationic polymerization and anionic polymerization) are usually difficult to perform simultaneously in one-pot. In particular, synchronous cationic-anionic polymerization has been an important challenge in the field of polymer synthesis due to possible coupling termination of both chain ends. We recently found that such terminal couplings can be significantly inhibited by a bismuth salt with a strong nucleophilic anion (e.g., BiCl3) and disclosed the mechanism. Accordingly, we propose a cationic-anionic polymerization (CAP) method where cationic ring-opening polymerization (CROP) of 2-oxazolines (Ox) and anionic ring-opening polymerization (AROP) of cyclic esters (CE) can be initiated sequentially and propagated simultaneously in one-pot, using bismuth salts as the initial initiators, to afford a multifunctional copolymer polyoxazoline-block-polyester (POx-b-PCE). Furthermore, a block copolymer PAPOZ20-b-PCL5 synthesized by CAP can self-assemble into micellar aggregates, which exhibit excellent intrinsic antibacterial activities without loading any extra antibiotic components. Overall, such a CAP method opens new avenues for synthesizing multi-component copolymers and biomaterials.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"479 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thermal biasing for lattice symmetry breaking and topological edge state imaging

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57194-x

Dohyun Kim, Jaeuk Seo, Sangsu Yer, Seungil Baek, Woohyun Cho, Shoujun Zheng, Yong-Hyun Kim, Mali Zhao, Heejun Yang

{"title":"Thermal biasing for lattice symmetry breaking and topological edge state imaging","authors":"Dohyun Kim, Jaeuk Seo, Sangsu Yer, Seungil Baek, Woohyun Cho, Shoujun Zheng, Yong-Hyun Kim, Mali Zhao, Heejun Yang","doi":"10.1038/s41467-025-57194-x","DOIUrl":"https://doi.org/10.1038/s41467-025-57194-x","url":null,"abstract":"Marginally twisted bilayer graphene with large Bernal stacked domains involves symmetry-breaking features with domain boundaries that exhibit topological edge states normally obscured by trivial bands. A vertical electric field can activate these edge states through inversion symmetry breaking and opening a bandgap around the edge state energy. However, harnessing pristine topological states at the Fermi level without violent electric or magnetic bias remains challenging, particularly above room temperature. Here, we demonstrate that thermal biasing can break the vertically stacked lattice symmetry of twisted bilayer graphene via the interatomic Seebeck effect, enabling thermoelectric imaging of topological edge states at tunable Fermi levels above room temperature. The high spatial resolution in the imaging is achieved through atomic-scale thermopower generation between a metallic tip and the sample, reflecting the local electronic band structure and its derivative features of twisted bilayer graphene at the Fermi level. Our findings suggest that thermal biasing provides a sensitive, non-destructive method for symmetry breaking and topological state imaging above room temperature, making it a practical and accessible approach.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"6 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57047-7

Mark A. Sanborn, Xinge Wang, Shang Gao, Yang Dai, Jalees Rehman

{"title":"Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy","authors":"Mark A. Sanborn, Xinge Wang, Shang Gao, Yang Dai, Jalees Rehman","doi":"10.1038/s41467-025-57047-7","DOIUrl":"https://doi.org/10.1038/s41467-025-57047-7","url":null,"abstract":"Senescent cells accumulate in most tissues with organismal aging, exposure to stressors, or disease progression. It is challenging to identify senescent cells because cellular senescence signatures and phenotypes vary widely across distinct cell types and tissues. Here we developed an analytical algorithm that defines cell-type-specific and universal signatures of cellular senescence across a wide range of cell types and tissues. We utilize 72 mouse and 64 human weighted single-cell transcriptomic signatures of cellular senescence to create the SenePy scoring platform. SenePy signatures better recapitulate in vivo cellular senescence than signatures derived from in vitro senescence studies. We use SenePy to map the kinetics of senescent cell accumulation in healthy aging as well as multiple disease contexts, including tumorigenesis, inflammation, and myocardial infarction. SenePy characterizes cell-type-specific in vivo cellular senescence and could lead to the identification of genes that serve as mediators of cellular senescence and disease progression.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"26 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57180-3

Jahaun Azadmanesh, Katelyn Slobodnik, Lucas R. Struble, Jeffrey J. Lovelace, Erika A. Cone, Medhanjali Dasgupta, William E. Lutz, Siddhartha Kumar, Amarnath Natarajan, Leighton Coates, Kevin L. Weiss, Dean A. A. Myles, Thomas Kroll, Gloria E. O. Borgstahl

{"title":"The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase","authors":"Jahaun Azadmanesh, Katelyn Slobodnik, Lucas R. Struble, Jeffrey J. Lovelace, Erika A. Cone, Medhanjali Dasgupta, William E. Lutz, Siddhartha Kumar, Amarnath Natarajan, Leighton Coates, Kevin L. Weiss, Dean A. A. Myles, Thomas Kroll, Gloria E. O. Borgstahl","doi":"10.1038/s41467-025-57180-3","DOIUrl":"https://doi.org/10.1038/s41467-025-57180-3","url":null,"abstract":"Human manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide (({{{{rm{O}}}}}_{2}^{bullet -})) to molecular oxygen (O2) and hydrogen peroxide (H2O2) with proton-coupled electron transfers (PCETs). A key catalytic residue, Tyr34, determines the activity of human MnSOD and also becomes post-translationally inactivated by nitration in various diseases associated with mitochondrial dysfunction. Tyr34 has an unusual pKa due to its proximity to the Mn metal and undergoes cyclic deprotonation and protonation events to promote the electron transfers of MnSOD. Neutron diffraction, X-ray spectroscopy, and quantum chemistry calculations in oxidized, reduced and product inhibited enzymatic states shed light on the role of Tyr34 in MnSOD catalysis. The data identify the contributions of Tyr34 in MnSOD activity that support mitochondrial function and give a thorough characterization of how a single tyrosine modulates PCET catalysis. Product inhibition occurs by an associative displacement mechanism.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"11 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering nanozyme immunomodulator with magnetic targeting effect for cascade-enzyodynamic and ultrasound-reinforced metallo-immunotherapy in prostate carcinoma

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57190-1

Yandong Wang, Haodong Li, Junyang Lin, Yutang Li, Keqin Zhang, Hui Li, Qiang Fu, Yanyan Jiang

{"title":"Engineering nanozyme immunomodulator with magnetic targeting effect for cascade-enzyodynamic and ultrasound-reinforced metallo-immunotherapy in prostate carcinoma","authors":"Yandong Wang, Haodong Li, Junyang Lin, Yutang Li, Keqin Zhang, Hui Li, Qiang Fu, Yanyan Jiang","doi":"10.1038/s41467-025-57190-1","DOIUrl":"https://doi.org/10.1038/s41467-025-57190-1","url":null,"abstract":"Conventional immunotherapy exhibits low response rates due to the immunosuppressive tumor microenvironment (TME). To overcome this limitation, this study introduces ZFPG nanoparticles (ZFPG NPs) with ZnFe2O4@Pt cores and glucose oxidase (GOx) shells. The ZFPG NPs possess five-enzyme activities, good sonosensitivity, and remarkable magnetic targeting properties, which facilitate sono-metallo-immunotherapy for prostate cancer treatment in male mice. Specifically, the magnetic targeting ability effectively improves their accumulation in tumors while still showing enrichment in the liver and kidneys. The multienzyme cascade catalysis and sonosensitivity of these NPs effectively deplete glutathione and glucose, and enhance the generation and utilization of H2O2, thereby inducing multiple ROS bursts. Furthermore, these comprehensive effects up-regulate the HMOX1 to promote the Fe2+ and lipid peroxides accumulation, thereby inducing immunogenic ferroptosis. This strategy facilitates anti-tumor immunity by ameliorating the immunosuppressive TME and inhibiting lung metastatic progression. This joint warfare strategy offers a powerful solution to address conventional immunotherapy limitations.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"24 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Low-temperature pressure-assisted liquid-metal printing for β-Ga2O3 thin-film transistors

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57200-2

Chi-Hsin Huang, Ruei-Hong Cyu, Yu-Lun Chueh, Kenji Nomura

{"title":"Low-temperature pressure-assisted liquid-metal printing for β-Ga2O3 thin-film transistors","authors":"Chi-Hsin Huang, Ruei-Hong Cyu, Yu-Lun Chueh, Kenji Nomura","doi":"10.1038/s41467-025-57200-2","DOIUrl":"https://doi.org/10.1038/s41467-025-57200-2","url":null,"abstract":"Developing a low-temperature and cost-effective manufacturing process for energy-efficient and high-performance oxide-thin-film transistors (TFTs) is a crucial step toward advancing next-generation device applications such as wearable and flexible electronics. Among several methods, a liquid-metal printing technique is considered a promising, cost-effective oxide semiconductor process due to its inherent advantages, such as vacuum-free, low-thermal budget, high throughput, and scalability. In this study, we have developed a pressure-assisted liquid-metal printing technique enabling the low-temperature synthesis of polycrystalline wide bandgap n-channel oxide-TFTs. The n-channel oxide TFTs based on ~3 nm-thick β-Ga2O3 channels exhibited good TFT switching properties with a threshold voltage of ~3.8 V, a saturation mobility of ~11.7 cm2 V−1 s−1, an on/off-current ratio of ~109, and a subthreshold slope of ~163 mV/decade. We also observed p-channel operation in the off-stoichiometric GaOx channels fabricated at high-pressure conditions. Toward oxide-based circuit applications, we developed high-performance oxide-TFT-based inverters. While our approach can promote the advancement of low-temperature manufacturing for oxide TFT technology, further work will be necessary to confirm the role of the applied pressure in the β-Ga2O3 crystallization process.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"128 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57073-5

Hao Yan, Zhenguo Xin, Ziwei Sang, Xingwang Li, Jia Xie, Jiale Wu, Shen Pang, Ying Wen, Weishan Wang

{"title":"A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production","authors":"Hao Yan, Zhenguo Xin, Ziwei Sang, Xingwang Li, Jia Xie, Jiale Wu, Shen Pang, Ying Wen, Weishan Wang","doi":"10.1038/s41467-025-57073-5","DOIUrl":"https://doi.org/10.1038/s41467-025-57073-5","url":null,"abstract":"Non-ribosomal peptides (NRPs) are pharmaceutically important natural products that include numerous clinical drugs. However, the biosynthesis of these NRPs is intricately regulated and improving production through manipulation of multiple regulatory targets remains largely empirical. We here develop a screening-based, multi-target rational combination strategy and demonstrate its effectiveness in enhancing the titers of three NRP drugs ˗ daptomycin, thaxtomin A and surfactin. Initially, we devise a reliable colorimetric analog co-expression and co-biosynthesis reporter system for screening high-yielding phenotypes. Subsequently, through coupling CRISPR interference to induce genome-wide differential expression, we identify dozens of repressors that inhibit the biosynthesis of these NRPs. To address the challenge of multi-target combination, we further developed a dual-target screen approach and introduced an interplay map based on the synergy coefficient of each pairwise interaction. Employing this strategy, we engineer the final strains with multi-target synergistic combination and achieve the titer improvement of the three NRPs. Our work provides a rational multi-target combination strategy for production improvement of NRPs.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"68 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Achieving burst Li+ channels via quasi-two-dimensional fluorinated metal-organic framework modulating functionalized interface

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57106-z

Lingchen Kong, Yu Li, Cong Peng, Ziyue Zhao, Junwei Xiao, Yimin Zhao, Wei Feng

{"title":"Achieving burst Li+ channels via quasi-two-dimensional fluorinated metal-organic framework modulating functionalized interface","authors":"Lingchen Kong, Yu Li, Cong Peng, Ziyue Zhao, Junwei Xiao, Yimin Zhao, Wei Feng","doi":"10.1038/s41467-025-57106-z","DOIUrl":"https://doi.org/10.1038/s41467-025-57106-z","url":null,"abstract":"The development of disordered Li dendrite and the adverse reaction between Li and electrolyte impede practical use of Li metal batteries (LMB). Herein, we propose quasi-two-dimensional fluorinated metal-organic framework carbon (q2D-FcMOF) that is utilized to construct artificial solid electrolyte interface (ASEI) to achieve robust interfacial protective double-layer. The outer organic layer provides ample space for Li deposition, while the inner inorganic LiF layer promotes conduction of Li+ and blocks electron transport. Metal clusters within the hybrid layer are uniformly dispersed, encouraging Li+ to cluster around metal active sites that are thermodynamically compatible with Li. Consequently, q2D-FcZ8@Li symmetrical batteries demonstrate an ultralong cycle life over 3600 h. When paried with commercial cathodes, the cells exhibite cyclability under conditions of high-loading, lean-electrolyte, even exposure to air for some time. This research suggests an effective method for fabricating ASEI using 2D quasi-ordered superstructure MOF NPs, which is expected to the development of LMB.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"6 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polymorphic relaxor phase and defect dipole polarization co-reinforced capacitor energy storage in temperature-monitorable high-entropy ferroelectrics

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57139-4

Xiangfu Zeng, Jinfeng Lin, Gaolei Dong, Jie Shen, Luomeng Tang, Qifa Lin, Simin Wang, Min Gao, Chunlin Zhao, Tengfei Lin, Laihui Luo, Chao Chen, Baisheng Sa, Cong Lin, Xiao Wu, Jiwei Zhai

{"title":"Polymorphic relaxor phase and defect dipole polarization co-reinforced capacitor energy storage in temperature-monitorable high-entropy ferroelectrics","authors":"Xiangfu Zeng, Jinfeng Lin, Gaolei Dong, Jie Shen, Luomeng Tang, Qifa Lin, Simin Wang, Min Gao, Chunlin Zhao, Tengfei Lin, Laihui Luo, Chao Chen, Baisheng Sa, Cong Lin, Xiao Wu, Jiwei Zhai","doi":"10.1038/s41467-025-57139-4","DOIUrl":"https://doi.org/10.1038/s41467-025-57139-4","url":null,"abstract":"Energy storage high-entropy ceramics are famous for their ultrahigh power density and ultrafast discharge rate. However, achieving a synchronous combination of high energy density and efficiency along with intelligent temperature-monitorable function remains a significant challenge. Here, based on high-entropy strategy and phase field simulation, the polarization response of domains in Bi0.5Na0.5TiO3-based ceramics is optimized by constructing a concomitant nanostructure of defect dipole polarization and a polymorphic relaxor phase. The optimal ceramic possesses a high recyclable energy storage density (11.23 J cm−3) and a high energy storage efficiency (90.87%) at 670 kV cm−1. Furthermore, real-time temperature sensing is explored based on abnormal fluorescent negative thermal expansion, highlighting the application of intelligent cardiac defibrillation pulse capacitors. This study develops an effective strategy for enhancing the overall energy storage performance of ferroelectric ceramics to overcome the problems of insufficient energy supply and thermal runaway in traditional counterparts.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"82 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer

IF 16.6 1区综合性期刊

Nature Communications Pub Date : 2025-02-22 DOI: 10.1038/s41467-025-57046-8

Xue Yang, Xiuquan Ma, Tianyue Zhao, David R. Croucher, Elizabeth V. Nguyen, Kimberley C. Clark, Changyuan Hu, Sharissa L. Latham, Charles Bayly-Jones, Bao V. Nguyen, Srikanth Budnar, Sung-Young Shin, Lan K. Nguyen, Thomas R. Cotton, Anderly C. Chüeh, Terry C. C. Lim Kam Sian, Margaret M. Stratton, Andrew M. Ellisdon, Roger J. Daly

{"title":"Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer","authors":"Xue Yang, Xiuquan Ma, Tianyue Zhao, David R. Croucher, Elizabeth V. Nguyen, Kimberley C. Clark, Changyuan Hu, Sharissa L. Latham, Charles Bayly-Jones, Bao V. Nguyen, Srikanth Budnar, Sung-Young Shin, Lan K. Nguyen, Thomas R. Cotton, Anderly C. Chüeh, Terry C. C. Lim Kam Sian, Margaret M. Stratton, Andrew M. Ellisdon, Roger J. Daly","doi":"10.1038/s41467-025-57046-8","DOIUrl":"https://doi.org/10.1038/s41467-025-57046-8","url":null,"abstract":"The PEAK family of pseudokinases, comprising PEAK1-3, play oncogenic roles in several poor prognosis human cancers, including triple negative breast cancer (TNBC). However, therapeutic targeting of pseudokinases is challenging due to their lack of catalytic activity. To address this, we screen for PEAK1 effectors and identify calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G. PEAK1 promotes CAMK2 activation in TNBC cells via PLCγ1/Ca2+ signalling and direct binding to CAMK2. In turn, CAMK2 phosphorylates PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurpose RA306, a second generation CAMK2 inhibitor. RA306 inhibits PEAK1-enhanced migration and invasion of TNBC cells in vitro and significantly attenuates TNBC xenograft growth and metastasis in a manner mirrored by PEAK1 ablation. Overall, these studies establish PEAK1 as a critical cell signalling nexus that integrates Ca2+ and tyrosine kinase signals and identify CAMK2 as a therapeutically ‘actionable’ target downstream of PEAK1.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"65 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0