Pub Date : 2026-03-04DOI: 10.1038/s41422-026-01227-7
Jiawang Chen, Tao Xu, Chenchen Zhang, Li Li, Yan He, Zhaoxia Sun, Jiasheng He, Zhimo Yao, Peng Cai, Yipeng Huang, Fenfen Ye, Wei Guo, Manli Jia, Jia Qu, Jiang-Fan Chen, Yi Zhang
Chronic pain affects over 20% of the global population, yet frontline treatments remain limited in efficacy and are often hampered by serious side effects. In search of novel and effective neuromodulation alternatives, we discovered that 40 Hz flickering light effectively alleviates inflammatory and neuropathic pain in mice. We identified the retina-central amygdala (CeA) pathway as a critical conduit for the analgesic effects of 40 Hz flickering light. Using circuit-specific manipulations, we demonstrated that activation of the retina-CeA pathway is both sufficient to mimic and necessary to mediate the analgesic outcomes of 40 Hz light stimulation. In terms of mechanism, we found that 40 Hz light flickering significantly increases extracellular adenosine levels in the CeA. Local pharmacological blockade of equilibrative nucleoside transporters prevented this adenosine increase and abolished the analgesic effects of 40 Hz light flickering, whereas focal adenosine infusion phenocopied the light-induced analgesia. Both interventions required A2A receptor signaling to suppress nociceptive responses. Furthermore, we found that hyperalgesia could be destabilized in the CeA and reversed by 40 Hz light stimulation or adenosine infusion, mirroring memory reconsolidation processes and implicating the CeA as a key locus for pain memory erasure. Collectively, our findings demonstrate the multifaceted therapeutic benefits of 40 Hz light flickering as a novel non-invasive approach for pain management and reveal a distinct retina-CeA circuit and adenosine signaling mechanism for control of chronic pain and pain memory.
{"title":"40 Hz light flickering alleviates chronic pain via adenosine signaling in the retina-amygdala pathway","authors":"Jiawang Chen, Tao Xu, Chenchen Zhang, Li Li, Yan He, Zhaoxia Sun, Jiasheng He, Zhimo Yao, Peng Cai, Yipeng Huang, Fenfen Ye, Wei Guo, Manli Jia, Jia Qu, Jiang-Fan Chen, Yi Zhang","doi":"10.1038/s41422-026-01227-7","DOIUrl":"https://doi.org/10.1038/s41422-026-01227-7","url":null,"abstract":"Chronic pain affects over 20% of the global population, yet frontline treatments remain limited in efficacy and are often hampered by serious side effects. In search of novel and effective neuromodulation alternatives, we discovered that 40 Hz flickering light effectively alleviates inflammatory and neuropathic pain in mice. We identified the retina-central amygdala (CeA) pathway as a critical conduit for the analgesic effects of 40 Hz flickering light. Using circuit-specific manipulations, we demonstrated that activation of the retina-CeA pathway is both sufficient to mimic and necessary to mediate the analgesic outcomes of 40 Hz light stimulation. In terms of mechanism, we found that 40 Hz light flickering significantly increases extracellular adenosine levels in the CeA. Local pharmacological blockade of equilibrative nucleoside transporters prevented this adenosine increase and abolished the analgesic effects of 40 Hz light flickering, whereas focal adenosine infusion phenocopied the light-induced analgesia. Both interventions required A2A receptor signaling to suppress nociceptive responses. Furthermore, we found that hyperalgesia could be destabilized in the CeA and reversed by 40 Hz light stimulation or adenosine infusion, mirroring memory reconsolidation processes and implicating the CeA as a key locus for pain memory erasure. Collectively, our findings demonstrate the multifaceted therapeutic benefits of 40 Hz light flickering as a novel non-invasive approach for pain management and reveal a distinct retina-CeA circuit and adenosine signaling mechanism for control of chronic pain and pain memory.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"130 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346818","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 : 2026-03-01DOI: 10.1038/s41422-026-01223-x
Liankui Zhou, Ying Liu
Organisms leverage environmental cues to anticipate and adapt to changing conditions. Here, we show that Caenorhabditis elegans, despite being eyeless, utilizes photoperception as an anticipatory cue to enhance survival under thermal stress. Exposure to low-intensity light activates a heat-shock response via the photoreceptor LITE-1, triggering serotonin signaling that promotes thermotolerance through the serotonin receptor SER-5 in the intestine and muscle. Beyond acute stress protection, light perception modulates reproductive behavior by delaying egg laying under unfavorable conditions and induces intergenerational thermotolerance, enhancing progeny survival at elevated temperatures. Photoperception also improves population competitiveness, providing a competitive advantage in dynamic environments. These findings reveal a previously unrecognized role for photoperception in a non-photosynthetic animal and establish it as a key mechanism for thermal adaptation and fitness.
{"title":"Light sensing enhances thermotolerance and competitive fitness via serotonergic signaling in an eyeless organism","authors":"Liankui Zhou, Ying Liu","doi":"10.1038/s41422-026-01223-x","DOIUrl":"https://doi.org/10.1038/s41422-026-01223-x","url":null,"abstract":"Organisms leverage environmental cues to anticipate and adapt to changing conditions. Here, we show that Caenorhabditis elegans, despite being eyeless, utilizes photoperception as an anticipatory cue to enhance survival under thermal stress. Exposure to low-intensity light activates a heat-shock response via the photoreceptor LITE-1, triggering serotonin signaling that promotes thermotolerance through the serotonin receptor SER-5 in the intestine and muscle. Beyond acute stress protection, light perception modulates reproductive behavior by delaying egg laying under unfavorable conditions and induces intergenerational thermotolerance, enhancing progeny survival at elevated temperatures. Photoperception also improves population competitiveness, providing a competitive advantage in dynamic environments. These findings reveal a previously unrecognized role for photoperception in a non-photosynthetic animal and establish it as a key mechanism for thermal adaptation and fitness.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"99 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147320045","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}
Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER-mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA). This pathway is activated in aged wild-type mice, Alzheimer's disease patients, and 5×FAD mice. Tissue-specific overexpression of Sec61a1 in the mouse cortex (Sec61a1Tg) is sufficient to induce cognitive decline without affecting motor activity. Knockdown of Sec61a1 or Mavs ablates mt-dsRNA-mediated innate immune signaling and alleviates cognitive decline in naturally aging wild-type mice. These results reveal a molecular mechanism of aging- and disease-associated cognitive decline and provide a potential therapeutic tool for intervention.
{"title":"Mitochondrial double-stranded RNA drives aging-associated cognitive decline.","authors":"Lixiao Zhang, Xiang Li, Hongdi Luo, Yujia Huo, Guangkeng Zhou, Pengcheng Wang, Sipeng Wu, Xinyong Lin, Kai Dai, Jiahao Shi, Zebao Wang, Jiaxin Xu, Renjian Li, Siyi Chen, Zhe Sun, Chunlin Zhao, Zizhuo Zhou, Zhenhong Wang, Chensi Liang, Jun Zhu, Xingjun Chen, Jintao Luo, Yong Yu, Zhirong Zhang, Geng Wang","doi":"10.1038/s41422-026-01224-w","DOIUrl":"https://doi.org/10.1038/s41422-026-01224-w","url":null,"abstract":"<p><p>Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER-mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA). This pathway is activated in aged wild-type mice, Alzheimer's disease patients, and 5×FAD mice. Tissue-specific overexpression of Sec61a1 in the mouse cortex (Sec61a1<sup>Tg</sup>) is sufficient to induce cognitive decline without affecting motor activity. Knockdown of Sec61a1 or Mavs ablates mt-dsRNA-mediated innate immune signaling and alleviates cognitive decline in naturally aging wild-type mice. These results reveal a molecular mechanism of aging- and disease-associated cognitive decline and provide a potential therapeutic tool for intervention.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-09DOI: 10.1038/s41422-026-01225-9
Ilio Vitale, Alessandro D'Ambrosio, Lorenzo Galluzzi
{"title":"Extrachromosomal DNA drives cancer evolution.","authors":"Ilio Vitale, Alessandro D'Ambrosio, Lorenzo Galluzzi","doi":"10.1038/s41422-026-01225-9","DOIUrl":"https://doi.org/10.1038/s41422-026-01225-9","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-03DOI: 10.1038/s41422-026-01221-z
Xinyi Wang, Hong Fu, Qingyang Sun, Boyan Huang, Zhe Xu, Xuzhao Zhai, Chuncao Deng, Laru Peng, Mengdan Zhang, Tianran Peng, An Gong, Jiasui Liu, Zhengzhi Zou, Guangjin Pan, Jiekai Chen, Guangming Wu, Man Zhang, Mingwei Min
A fundamental question in biology is whether all cells age. Embryonic stem cells (ESCs) defy the norm as rare normal cells capable of indefinite in vitro passage. However, the mechanisms underlying ESC lineage immortality remain unresolved. Using long-term live-cell imaging to follow the fates of single ESCs, we show that ESC lineage renewal is achieved through sporadic entry into a state characterized by the expression of two-cell embryo-specific markers. During this state, cells undergo asymmetric fate divisions, enriching accumulated DNA damage into one daughter lineage that is destined for elimination, while producing a second lineage that reverts to the pluripotent state. Importantly, the latter lineage exhibits signs of rejuvenation, including reduced DNA damage and enhanced chimeric efficiency. These findings underscore the crucial role of asymmetric cell division in maintaining the long-term health of the ESC lineage against mounting damage within individual cells and provide a potential model for studying cellular aging and rejuvenation in mammalian cells.
{"title":"Asymmetric division in a two-cell-like state rejuvenates embryonic stem cells","authors":"Xinyi Wang, Hong Fu, Qingyang Sun, Boyan Huang, Zhe Xu, Xuzhao Zhai, Chuncao Deng, Laru Peng, Mengdan Zhang, Tianran Peng, An Gong, Jiasui Liu, Zhengzhi Zou, Guangjin Pan, Jiekai Chen, Guangming Wu, Man Zhang, Mingwei Min","doi":"10.1038/s41422-026-01221-z","DOIUrl":"10.1038/s41422-026-01221-z","url":null,"abstract":"A fundamental question in biology is whether all cells age. Embryonic stem cells (ESCs) defy the norm as rare normal cells capable of indefinite in vitro passage. However, the mechanisms underlying ESC lineage immortality remain unresolved. Using long-term live-cell imaging to follow the fates of single ESCs, we show that ESC lineage renewal is achieved through sporadic entry into a state characterized by the expression of two-cell embryo-specific markers. During this state, cells undergo asymmetric fate divisions, enriching accumulated DNA damage into one daughter lineage that is destined for elimination, while producing a second lineage that reverts to the pluripotent state. Importantly, the latter lineage exhibits signs of rejuvenation, including reduced DNA damage and enhanced chimeric efficiency. These findings underscore the crucial role of asymmetric cell division in maintaining the long-term health of the ESC lineage against mounting damage within individual cells and provide a potential model for studying cellular aging and rejuvenation in mammalian cells.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 3","pages":"219-232"},"PeriodicalIF":25.9,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102114","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}
Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and how organelle-level forces trigger mechanotransduction for antitumor immunity. Here, we developed a magneto-mechanical force-triggered lysosomal membrane permeabilization (MagLMP) strategy to induce durable macrophage repolarization for in vivo applications. Self-assembled magnetic nanomotors are driven by rotational magnetic fields, facilitating dynamic damage to the lysosomal membrane by a finely tuned torque-induced vortex. Intriguingly, galectin 9 (Gal9) was found to be critical for sensing cyclic MagLMP, which dynamically activated AMP-activated protein kinase (AMPK), enhanced activation of nuclear factor kappa B (NF-κB), and induced metabolic alterations for sustained M1-like macrophage repolarization, followed by mounting of antitumor immunity. Through single-cell RNA sequencing of tumor tissues, as well as macrophage depletion-reconstitution models involving intratumoral transfer of Gal9-KO bone marrow-derived macrophages (BMDMs) and AMPK shRNA-transduced Gal9-KO BMDMs, we confirmed the Gal9-AMPK-NF-κB axis as the essential pathway by which MagLMP functions in antitumor therapy. In a mouse model of lung adenocarcinoma in situ, overall survival was extended after intravenous administration of nanomotors followed by cyclic MagLMP, and one third of mice survived for more than 300 days. Together, these results demonstrate an intracellular mechanical strategy that can dynamically manipulate innate immune responses in vivo, providing a tool for durable immunotherapy through organelle mechanotransduction.
{"title":"Dynamic magneto-mechanical force in lysosomes induces durable macrophage repolarization for antitumor immunity","authors":"Yingze Li, Mengge Zheng, Zhenyan Zhu, Yajuan Zhang, Peng Ning, Haotian Chen, Rui Gao, Chang Xu, Xueyan Wei, Yali Liu, Yingying Wang, Ruimei Zhou, Yuan Li, Zhenguang Li, Cheng Lv, Chen Liu, Junfang Xu, Zihan Guo, Zhixiang Hu, Lan Fang, Ke Wei, Mengying Feng, Changshi Zhou, Yunlang She, Weiyan Sun, Erzhen Chen, Gustavo R. Plaza, Bin He, Jason Miska, Weiwei Yang, Yichao Tang, Haipeng Liu, Chang Chen, Yu Cheng","doi":"10.1038/s41422-025-01217-1","DOIUrl":"10.1038/s41422-025-01217-1","url":null,"abstract":"Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and how organelle-level forces trigger mechanotransduction for antitumor immunity. Here, we developed a magneto-mechanical force-triggered lysosomal membrane permeabilization (MagLMP) strategy to induce durable macrophage repolarization for in vivo applications. Self-assembled magnetic nanomotors are driven by rotational magnetic fields, facilitating dynamic damage to the lysosomal membrane by a finely tuned torque-induced vortex. Intriguingly, galectin 9 (Gal9) was found to be critical for sensing cyclic MagLMP, which dynamically activated AMP-activated protein kinase (AMPK), enhanced activation of nuclear factor kappa B (NF-κB), and induced metabolic alterations for sustained M1-like macrophage repolarization, followed by mounting of antitumor immunity. Through single-cell RNA sequencing of tumor tissues, as well as macrophage depletion-reconstitution models involving intratumoral transfer of Gal9-KO bone marrow-derived macrophages (BMDMs) and AMPK shRNA-transduced Gal9-KO BMDMs, we confirmed the Gal9-AMPK-NF-κB axis as the essential pathway by which MagLMP functions in antitumor therapy. In a mouse model of lung adenocarcinoma in situ, overall survival was extended after intravenous administration of nanomotors followed by cyclic MagLMP, and one third of mice survived for more than 300 days. Together, these results demonstrate an intracellular mechanical strategy that can dynamically manipulate innate immune responses in vivo, providing a tool for durable immunotherapy through organelle mechanotransduction.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 3","pages":"197-218"},"PeriodicalIF":25.9,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01217-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As innate immune cells in the brain, microglia directly contact excitatory neurons and regulate their activities under various conditions; however, the mechanisms of direct microglia-neuron functional interactions remain largely unknown. Here, we identified one special population of neocortical microglia that specifically associate with the axon initial segments (AISs) of excitatory neurons, and could regulate their activities and contribute to visual perception. We found that brief depolarization of AIS-associated microglia, but not the AIS-non-associated microglia, significantly promoted the action potential firing of related excitatory neurons, which relied mechanistically on microglial K+ release through the outward K+ channel THIK-1. Interestingly, in vivo visual stimulation with drifting gratings evoked microglial transient depolarizations specifically on the processes, which depended on muscarinic receptors and triggered K+ release through THIK-1; meanwhile, visual stimulation induced more robust calcium responses in neurons associated with microglia at their AISs compared with nearby unassociated neurons. Disruption of the AIS-microglia interaction disturbed calcium responses specifically in neurons associated with microglia at their AISs, impaired the coordinated activity of the entire neural ensemble, and thereby affected the visual discrimination behavior of awake mice. Collectively, our findings identified a new type of microglia-neuron functional interaction that may be critical for higher-order brain functions.
{"title":"The axon initial segment-associated microglia regulate neuronal activity and visual perception.","authors":"Yaping Wang,Qiushi Wang,Chen Gao,Shu He,Cheng Wei,Jia Song,Xinli Liu,Xiaoli Liu,Shi Feng,Wen Yao,Wen Wu,Tian-Ming Gao,Siqiang Ren","doi":"10.1038/s41422-026-01218-8","DOIUrl":"https://doi.org/10.1038/s41422-026-01218-8","url":null,"abstract":"As innate immune cells in the brain, microglia directly contact excitatory neurons and regulate their activities under various conditions; however, the mechanisms of direct microglia-neuron functional interactions remain largely unknown. Here, we identified one special population of neocortical microglia that specifically associate with the axon initial segments (AISs) of excitatory neurons, and could regulate their activities and contribute to visual perception. We found that brief depolarization of AIS-associated microglia, but not the AIS-non-associated microglia, significantly promoted the action potential firing of related excitatory neurons, which relied mechanistically on microglial K+ release through the outward K+ channel THIK-1. Interestingly, in vivo visual stimulation with drifting gratings evoked microglial transient depolarizations specifically on the processes, which depended on muscarinic receptors and triggered K+ release through THIK-1; meanwhile, visual stimulation induced more robust calcium responses in neurons associated with microglia at their AISs compared with nearby unassociated neurons. Disruption of the AIS-microglia interaction disturbed calcium responses specifically in neurons associated with microglia at their AISs, impaired the coordinated activity of the entire neural ensemble, and thereby affected the visual discrimination behavior of awake mice. Collectively, our findings identified a new type of microglia-neuron functional interaction that may be critical for higher-order brain functions.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"219 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056570","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}
Protein structure bridges the sequence–function relationship, enabling deep exploration of biological processes across diverse organisms. Insects, the most diverse animal lineage, accounting for over 50% of all described animal species, provide an exceptional system for exploring sequence–structure–function relationships. Here, we reconstructed a comprehensive and well-resolved phylogeny of 4854 insects, spanning all orders. Leveraging this framework, we created an atlas of 13.29 million predicted protein structures from 824 representative species, including 11.63 million newly predicted structures. Structural clustering revealed that proteins with divergent sequences but similar structures could be effectively grouped together. Structural similarity searches against proteins with well-characterized functions yielded annotations for 7.61 million insect proteins, including up to 14% of previously unannotated proteins. We further identified 750 million remote homologs between insect proteins, many of which trace back to ancient branches of the insect phylogeny. Remarkably, despite extensive sequence divergence, cGAS-like receptors (cGLRs) were structurally conserved across all 824 insects. Experimental assays demonstrated that these structurally identified cGLRs play a crucial role in antiviral defense in the yellow fever mosquito. Our findings highlight the significance of structural genomics for understanding protein function and evolution across the tree of life.
{"title":"Structural genomics sheds light on protein functions and remote homologs across the insect tree of life","authors":"Weiyin Wu, Chunlai Cui, Yixiao Zhu, Jingxuan Chen, Qiancheng Zhuang, Yazhou Wang, Zicheng Liu, Han Gao, Guo-Zheng Ou, Chao Liu, Mei Tao, Yun Chen, Ronghui Pan, Guojie Zhang, Hua Cai, Jinghua Yang, Xue-xin Chen, Xiaofan Zhou, Sibao Wang, Xing-Xing Shen","doi":"10.1038/s41422-026-01220-0","DOIUrl":"https://doi.org/10.1038/s41422-026-01220-0","url":null,"abstract":"Protein structure bridges the sequence–function relationship, enabling deep exploration of biological processes across diverse organisms. Insects, the most diverse animal lineage, accounting for over 50% of all described animal species, provide an exceptional system for exploring sequence–structure–function relationships. Here, we reconstructed a comprehensive and well-resolved phylogeny of 4854 insects, spanning all orders. Leveraging this framework, we created an atlas of 13.29 million predicted protein structures from 824 representative species, including 11.63 million newly predicted structures. Structural clustering revealed that proteins with divergent sequences but similar structures could be effectively grouped together. Structural similarity searches against proteins with well-characterized functions yielded annotations for 7.61 million insect proteins, including up to 14% of previously unannotated proteins. We further identified 750 million remote homologs between insect proteins, many of which trace back to ancient branches of the insect phylogeny. Remarkably, despite extensive sequence divergence, cGAS-like receptors (cGLRs) were structurally conserved across all 824 insects. Experimental assays demonstrated that these structurally identified cGLRs play a crucial role in antiviral defense in the yellow fever mosquito. Our findings highlight the significance of structural genomics for understanding protein function and evolution across the tree of life.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"86 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057206","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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