{"title":"SIK2 antagonizes postinfarction cardiac repair by driving macrophage proinflammatory and impairing efferocytosis","authors":"Wu-Wei Rong, Zi-Qi Xu, Shuai Shao, Qian-Wan Deng, Meng-Yao Li, Jin-Qiu Wei, Yi-Hang Yang, Jia-Jia Zhao, Wen-Hui Zhai, Zhi-Wen Shang, Zhi Zhang, Wen-Yi Yang, Shao-Wen Liu, Ping-Jin Gao, Xiao-Dong Li, Ji-Guang Wang","doi":"10.1126/sciadv.adw6624","DOIUrl":"10.1126/sciadv.adw6624","url":null,"abstract":"<div >Macrophages play a key role in cardiac injury and repair after myocardial infarction (MI). Salt-inducible kinase 2 (SIK2), a member of the adenosine monophosphate–activated protein kinase family, is notably up-regulated in monocytes/macrophages of patients with MI and animal models. In this study, we investigated the role of SIK2 in macrophage-mediated inflammation and efferocytosis following MI. Macrophage-specific SIK2 deletion reduces infarct size and improves healing post-MI. Furthermore, SIK2-knockout macrophages decrease proinflammatory factor expression and enhance efferocytosis, thereby increasing repair factors expression. SIK2 associates with tumor necrosis factor receptor–associated factor 2 (TRAF2), promoting its phosphorylation and K63 polyubiquitylation, which exacerbates inflammation and hinders efferocytosis via the P38 and nuclear factor κB pathways. In contrast, the SIK2<sup>T175A</sup> mutation exhibits no effect. Macrophage-specific SIK2 overexpression worsens cardiac changes after MI, whereas P38 inhibition reduces this effect. In addition, pharmacological inactivation of SIK2 substantially enhances cardiac repair after MI in mice. These findings highlight the crucial role of macrophage SIK2 in the regulation of inflammation and efferocytosis via TRAF2 polyubiquitination in MI, thereby presenting potential therapeutic targets.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adw6624","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2026-10-16DOI: 10.1126/sciadv.aei3111
Lauren Aubrey, Nathalie Berube, Natalia Pessoa, Cynthia Swan, M. Afzal Javed, Claire Bertens, Erin Scruten, Rob Stevens, Carla Norleen, Kyla Cutts, Yanyun Huang, Yohannes Berhane, Bryce Warner, Antonio Facciuolo, Yan Zhou
{"title":"A caprine mammary infection model for highly pathogenic avian influenza H5N1","authors":"Lauren Aubrey, Nathalie Berube, Natalia Pessoa, Cynthia Swan, M. Afzal Javed, Claire Bertens, Erin Scruten, Rob Stevens, Carla Norleen, Kyla Cutts, Yanyun Huang, Yohannes Berhane, Bryce Warner, Antonio Facciuolo, Yan Zhou","doi":"10.1126/sciadv.aei3111","DOIUrl":"10.1126/sciadv.aei3111","url":null,"abstract":"<div >Highly pathogenic avian influenza (HPAI) H5N1 virus spillover into dairy cows represents the emergence of a mammalian host capable of sustaining a panzootic and creates a transmission pathway to humans. HPAI research involving dairy cows is constrained by the space requirements needed to house large animals in high biocontainment. A small ruminant model would enable larger sample sizes while reducing costs, improving safety, and lowering logistical barriers to conduct research. Here, we establish dairy goats as a model for HPAI mammary infection. Intramammary inoculation with HPAI H5N1 genotype D1.1 and genotype B3.13 resulted in acute mastitis, decreased milk yield, and high virus shedding in milk. Parenteral vaccination with an inactivated virus induced antigen-specific antibodies in blood and milk, reduced clinical disease, limited virus shedding in milk, and mitigated milk production losses. HPAI H5N1 disease dynamics in dairy cows can be recapitulated in dairy goats, providing a relevant model for investigating pathogenesis and for supporting the development of control strategies.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aei3111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Fibroblast-like synoviocytes exacerbate autoimmune arthritis upon psychological stress in an IL-6–dependent manner","authors":"Jun Tamura, Shigeru Tanaka, Keishi Etori, Daisuke Hashiba, Shuhei Kameda, Atsuko Tomikawa, Ryo Kikuchi, Tatsuro Takahashi, Aiko Saku, Hirotoshi Kawashima, Junichi Nakamura, Seiji Ohtori, Shin-Ichiro Kagami, Koichi Hirose, Hiroshi Nakajima","doi":"10.1126/sciadv.aec9257","DOIUrl":"10.1126/sciadv.aec9257","url":null,"abstract":"<div >Psychological stress affects the immune system and exacerbates autoimmune diseases such as rheumatoid arthritis (RA), but the mechanisms underlying tissue inflammation during remission remain unclear. Here, we show that tube restraint stress exacerbates joint inflammation in a murine arthritis model during remission. This exacerbation required interleukin-6 (IL-6) produced by brown adipose tissue (BAT) following sympathetic activation. Fibroblast-like synoviocytes expressing the IL-6 receptor subunit gp130 were critical mediators, as IL-6 stimulated these cells to produce the neutrophil chemoattractant CXCL1. Pharmacological blockade of the β3-adrenergic receptor significantly attenuated stress-induced arthritis flares. In patients with RA, carriers of the hypofunctional Trp64Arg variant of <i>ADRB3</i> showed no positive correlation between psychological stress and disease activity, whereas noncarriers did. These findings identify a BAT–IL-6–fibroblast axis that reactivates inflammatory memory in arthritis and suggest that targeting stress-responsive pathways may provide a complementary therapeutic strategy alongside current RA treatments without broadly suppressing systemic immunity.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aec9257","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2026-10-16DOI: 10.1126/sciadv.aem8465
{"title":"Erratum for the Research Article “The design and reconstructible history of the Mayan eclipse table of the Dresden Codex”","authors":"","doi":"10.1126/sciadv.aem8465","DOIUrl":"10.1126/sciadv.aem8465","url":null,"abstract":"","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2026-10-16DOI: 10.1126/sciadv.aeh6791
Xinbei Li, Sang-Min Jeon, Ariella Kornfeld, Emily A. Eiss, Daniel S. Jin, Uche Onuchukwu, Manasi Inamdar, Suyeon Kim, Sreenivas Eadara, Matthew Russell, John Robinson, Michael J. Caterina, Mollie K. Meffert
{"title":"Peripheral nerve injury alters metabolic function and neuronal excitability through the Lin28/let-7 pathway","authors":"Xinbei Li, Sang-Min Jeon, Ariella Kornfeld, Emily A. Eiss, Daniel S. Jin, Uche Onuchukwu, Manasi Inamdar, Suyeon Kim, Sreenivas Eadara, Matthew Russell, John Robinson, Michael J. Caterina, Mollie K. Meffert","doi":"10.1126/sciadv.aeh6791","DOIUrl":"10.1126/sciadv.aeh6791","url":null,"abstract":"<div >Sensory neurons require efficient metabolic processes to reliably transmit information including touch, temperature, and noxious stimuli from peripheral to central nervous systems. Peripheral nerve injury is known to disrupt metabolic function resulting in aberrant sensory nervous system excitation, but molecular pathways linking nerve injury to persistent alterations in metabolism and neuronal activity have been incompletely understood. We find that a conserved metabolic regulator, RNA binding protein Lin28, is elevated in the somas of dorsal root ganglion (DRG) nociceptive neurons following nerve injury but exhibits a higher and more enduring local induction in peripheral sensory axons of the injured nerve. Growth suppressor let-7 family microRNAs (miRNAs), whose biogenesis is inhibited by Lin28, are down-regulated following injury, consistent with the spatiotemporal course of Lin28 induction. Genome-wide sensory neuron-specific and nociceptor-enriched profiling of miRNA:target RNA interactions reveals abundant let-7 miRNA targeting of metabolic transcripts in healthy sensory axons, which is diminished by nerve injury. Consistently, injured sciatic nerves exhibit disrupted cellular respiration near the site of nerve injury, which is alleviated by local restoration of let-7 miRNAs. Selective Lin28 knockout in nociceptive sensory neurons also alleviates the metabolic disturbances of nerve injury as well as suppressing injury-induced elevation of activity in ipsilateral peripheral sensory neurons and central spinal cord dorsal horn neurons. These results implicate the Lin28/let-7 pathway as a critical driver of metabolic dysregulation and the pathophysiology of heightened sensory nervous system activity following nerve injury.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aeh6791","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2026-10-16DOI: 10.1126/sciadv.aeh7253
Wenwu Lin, Yuyan Liu, Peter D. Nagy
{"title":"Co-opted CHIP E3 Ub-ligase provides protein quality control by regulating molecular properties of condensates formed by a positive-strand RNA virus","authors":"Wenwu Lin, Yuyan Liu, Peter D. Nagy","doi":"10.1126/sciadv.aeh7253","DOIUrl":"10.1126/sciadv.aeh7253","url":null,"abstract":"<div >Positive-strand RNA viruses are important pathogens that built viral replication organelles (VROs) via exploiting co-opted host proteins and intracellular membranes in infected cells. Tomato bushy stunt virus (TBSV) membranous VROs are associated with dynamic virus-induced replication (vir)–condensate substructures driven by TBSV p33 replication protein. We targeted micropeptide “killswitch” to VROs to enhance p33 self-association and remodel vir-condensates. Recruitment of killswitch induced p33 aggregations, reduced mobility of co-opted glycolytic enzymes in vir-condensate, limited ATP production within VROs, and inhibited TBSV replication. We discovered that TBSV co-opts CHIP/STUB1 E3 ubiquitin ligase involved in protein quality control to limit detrimental effect of protein aggregations in VROs. Expression of CHIP reduced accumulation of aggregated TBSV p33. Knockdown of CHIP resulted in inhibition of TBSV replication, enhanced accumulation of aggregation-prone p33 mutants, and inhibited mobility of co-opted client host proteins in vir-condensate. Subverted CHIP plays critical role in regulating protein interactions, stability, and maintenance of dynamic vir-condensate. Hijacking protein quality control mechanism is a previously unknown phenomenon during (+)RNA virus replication.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aeh7253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2026-10-16DOI: 10.1126/sciadv.aeh5363
Mingzhu Yang, Aodhán Butler, Natalia López Carranza, Jakob Vinther, Rowan Whittle, Daniela Henkel, Hana Jurikova, Gert Wörheide, Mattia Giacomelli, Philip C. J. Donoghue, Davide Pisani, Sandra J. Carlson, Erik A. Sperling
{"title":"A comprehensive phylogenomic framework for brachiopod evolution among lophotrochozoans","authors":"Mingzhu Yang, Aodhán Butler, Natalia López Carranza, Jakob Vinther, Rowan Whittle, Daniela Henkel, Hana Jurikova, Gert Wörheide, Mattia Giacomelli, Philip C. J. Donoghue, Davide Pisani, Sandra J. Carlson, Erik A. Sperling","doi":"10.1126/sciadv.aeh5363","DOIUrl":"10.1126/sciadv.aeh5363","url":null,"abstract":"<div >Brachiopods appeared early in the Cambrian radiation and represent an important clade for understanding the origin of animal body plans and the evolution of biomineralized structures. A robust phylogenetic framework of the living representatives is needed to answer persistent questions about the evolution of brachiopod mineralogy, shell morphology, and identification of the brachiopod sister group among Lophotrochozoa. To the best of our knowledge, we present the first phylogenomic analysis of Brachiopoda and related lophotrochozoan lineages using a comprehensive dataset encompassing all five extant brachiopod orders and using a custom-developed data-refining strategy, compositionally heterogeneous substitution models, and a novel implementation of the parametric-bootstrap likelihood ratio test. We recover monophyly of Lophophorata, with strong support for Brachiopoda as sister to Bryozoa plus Phoronida. Within Brachiopoda, we recover the clade of inarticulated phosphatic Linguliformea sister to the inarticulated calcitic Craniiformea, with both sister to the articulated calcitic Rhynchonellata, with miniaturized Thecideida unexpectedly nested within Terebratulida. Our phylogeny implies that at least one evolutionary transition in primary mineralogy occurred in Brachiopoda, a phenomenon not recognized in any other metazoan group.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aeh5363","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2026-10-16DOI: 10.1126/sciadv.aef7208
Yuxuan Guo, Xinwen Zheng, Tianyi Wang, Jinchao Li, Cong Wang, Chenjiang You, Xin-Jian He, Arp Schnittger, Ji Qi, Jun Wang, Yingxiang Wang
{"title":"Suppression of meiotic double-strand break formation in somatic cells by DREAM factors TCX5/6 maintains genome stability","authors":"Yuxuan Guo, Xinwen Zheng, Tianyi Wang, Jinchao Li, Cong Wang, Chenjiang You, Xin-Jian He, Arp Schnittger, Ji Qi, Jun Wang, Yingxiang Wang","doi":"10.1126/sciadv.aef7208","DOIUrl":"10.1126/sciadv.aef7208","url":null,"abstract":"<div >Meiotic recombination in reproductive cells is initiated by DNA double-strand breaks (DSBs) and requires the expression of meiosis-specific genes, yet how the transcription of those genes is regulated in either meiotic or somatic cells remains unclear. Here, using a representative meiosis-specific <i>DMC1</i> gene promoter as a bait, we identified two DREAM factors TCX5 and TCX6 required for direct repression of <i>DMC1</i> in somatic cells. Transcriptomic analyses show broad ectopic up-regulation of meiotic genes in <i>tcx5/6</i> leaves<i>.</i> Consistently, <i>tcx5/6</i> somatic cells form DSBs and exhibit hypersensitivity to DNA damage compared to wild type. Further genetic analyses reveal that <i>SPO11-1</i> is dispensable for ectopic meiotic gene activation but essential for the DNA damage response in <i>tcx5/6</i> somatic cells. Last, we demonstrated that TCX5/6 repress meiotic gene expression through H3K4me3 modification. This finding uncovers an unexpected mechanism for suppressing meiotic recombination in somatic cells, thus preventing genetic diversity and genome instability in organisms.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aef7208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2026-10-16DOI: 10.1126/sciadv.aee4875
Marcin Muszyński, Pavel Kokhanchik, Rafał Mirek, Darius Urbonas, Pietro Tassan, Piotr Kapuściński, Przemysław Oliwa, Ioannis Georgakilas, Thilo Stöferle, Rainer F. Mahrt, Michael Forster, Ullrich Scherf, Dmitriy Dovzhenko, Rafał Mazur, Przemysław Morawiak, Wiktor Piecek, Przemysław Kula, Barbara Piętka, Dmitry Solnyshkov, Guillaume Malpuech, Jacek Szczytko
{"title":"Observation of a supersolid phase in a spin-orbit coupled exciton-polariton Bose-Einstein condensate","authors":"Marcin Muszyński, Pavel Kokhanchik, Rafał Mirek, Darius Urbonas, Pietro Tassan, Piotr Kapuściński, Przemysław Oliwa, Ioannis Georgakilas, Thilo Stöferle, Rainer F. Mahrt, Michael Forster, Ullrich Scherf, Dmitriy Dovzhenko, Rafał Mazur, Przemysław Morawiak, Wiktor Piecek, Przemysław Kula, Barbara Piętka, Dmitry Solnyshkov, Guillaume Malpuech, Jacek Szczytko","doi":"10.1126/sciadv.aee4875","DOIUrl":"10.1126/sciadv.aee4875","url":null,"abstract":"<div >In Bose-Einstein condensates, spin-orbit coupling (SOC) produces supersolidity. It is a peculiar state of matter, which, in addition to the superfluid behavior, shows periodic density modulation typical for crystals. Here, we report the fabrication of an original type of optical microcavity, allowing the achievement of room-temperature supersolidity for a quantum fluid of light. The microcavity is filled with a nematic liquid crystal (LC) and two layers of the organic polymer methyl-substituted ladder-type poly(<i>p</i>-phenylene) (MeLPPP) hosting exciton resonances. We demonstrate exciton-polariton condensation in the two distinct degenerate minima of the dispersion created by the LC-induced Rashba-Dresselhaus SOC. The condensate real-space distribution shows density stripes located randomly from one condensate realization to another despite the presence of a random disorder potential. This demonstrates the immunity of stripes against disorder and the spontaneous breaking of translational invariance. We also report the random appearance of vortices, another feature of superfluids.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aee4875","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2026-10-16DOI: 10.1126/sciadv.ady0296
Wenxin Hu (胡文欣), Honglin Chen (陈竑霖), Steven He, Joshua M. L. Casan, Carolyn Shembrey, Sharon Li, Lauren M. Brown, Andrea Zhao, Lynda Truong, Isabella Buchner, Dane Vassiliadis, Timothy P. Hughes, Deborah L. White, Catherine L. Carmichael, Antoine De Weck, Ilia Voskoboinik, Quentin Gouil, Joseph A. Trapani, Paul G. Ekert, Teresa Sadras, Mohamed Fareh
{"title":"Programmable and selective silencing of oncogenic fusion transcripts by CRISPR-Cas13b via breakpoint sequence recognition","authors":"Wenxin Hu (胡文欣), Honglin Chen (陈竑霖), Steven He, Joshua M. L. Casan, Carolyn Shembrey, Sharon Li, Lauren M. Brown, Andrea Zhao, Lynda Truong, Isabella Buchner, Dane Vassiliadis, Timothy P. Hughes, Deborah L. White, Catherine L. Carmichael, Antoine De Weck, Ilia Voskoboinik, Quentin Gouil, Joseph A. Trapani, Paul G. Ekert, Teresa Sadras, Mohamed Fareh","doi":"10.1126/sciadv.ady0296","DOIUrl":"10.1126/sciadv.ady0296","url":null,"abstract":"<div >Oncogenic gene fusions are key drivers of cancer, yet most remain undruggable by current therapies. Here, we establish CRISPR-<i>Psp</i>Cas13b as a personalizable platform for systematic silencing of various fusion transcripts. We reveal that recognition and cleavage of the breakpoint sequence by <i>Psp</i>Cas13b disrupt the fusion transcript, resulting in efficient protein depletion. <i>Psp</i>Cas13b cleavage produces aberrant, translation-incompetent target RNA species, a subset of which harbors internal deletions proximal to the cleavage site. We demonstrate that targeting the BCR::ABL1 breakpoint sequence efficiently degrades both wild-type and drug-resistant BCR::ABL1 mutants, which are the primary drivers of tyrosine kinase inhibitor resistance and relapse in chronic myeloid leukemia. Molecular profiling revealed that <i>Psp</i>Cas13b impairs BCR::ABL1 tyrosine phosphokinase activity and triggers extensive transcriptomic and proteomic remodeling, leading to erythroid differentiation and apoptosis in drug-resistant cells. Beyond BCR::ABL1, personalized design of <i>Psp</i>Cas13b effectively silences other undruggable oncogenic fusions. Collectively, this study establishes a molecular framework for precise targeting of undruggable or drug-resistant oncogenic transcripts.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ady0296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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