Cell Discovery最新文献

{"title":"Suppressing protein damage response to overcome multidrug resistance in cancer therapy.","authors":"Fangyuan Shao, Zongjie Li, Hao Xiao, Yujun Chen, Yuheng Zhang, Ling Li, Yuzhong Peng, Xinyi Li, Yuxing Hou, Bo Li, Xiangpeng Chu, Maoxin Ran, Dongyang Tang, Xi Han, Jiaxin Yao, Cuiting Zhang, Lijian Wang, Haifeng Li, Nan Shao, Kai Miao, Xiaoling Xu, Yanxia Shi, Changhua Zhang, Jun Yan, Ying Lin, Chu-Xia Deng","doi":"10.1038/s41421-025-00826-9","DOIUrl":"10.1038/s41421-025-00826-9","url":null,"abstract":"<p><p>Multidrug resistance is a significant barrier in cancer therapy largely due to poorly understood regulatory mechanisms. Here we reveal that certain anticancer drugs can bind to newly synthesized proteins prior to reaching their canonical targets, resulting in various forms of protein damage. This binding disrupts protein functions, particularly those of mitochondrial proteins, resulting in substantial cytotoxicity. The protein damage is further exacerbated by mitochondrial reactive oxygen species generated as a consequence of the initial damage, creating a positive feedback loop. In response, cancer cells rapidly initiate a chain of events, which we term the Protein Damage Response (PDR). This includes damage recognition primarily mediated by protein ubiquitination and subsequent damage clearance via the proteasome system. Notably, patients with advanced, drug-resistant metastatic breast or colon cancers exhibit elevated proteasome activity. In an effort to predict drug resistance, we developed a sensitive kit for detecting proteasome levels, enabling the identification and subtyping of patients with high proteasome activity to support tailored therapeutic strategies. Using a three-dimensional tumor slice culture-based drug sensitivity assay and an investigator-initiated clinical trial, we demonstrate that three clinically approved proteasome inhibitors effectively overcome multidrug resistance in colon and breast cancer patients with elevated proteasome activity.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"80"},"PeriodicalIF":12.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198424","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}

{"title":"Chemosensation of the pheromone spermine by the olfactory TAAR-like receptor TAAR348.","authors":"Kexin Jiang, Liting Zeng, Weifeng Zhang, Xuefei He, You Zheng, Ling Wang, Zhongyuan Zhang, Jun Pu, Cheng Deng, Fan Yang, Suwen Zhao, Fei Xu","doi":"10.1038/s41421-025-00839-4","DOIUrl":"10.1038/s41421-025-00839-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"79"},"PeriodicalIF":12.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12476453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181824","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}

{"title":"MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity.","authors":"Pallavi Asthana, Liguo Li, Lin Lu, Jiayan Wu, Shuo Zhang, Ningning Li, Sheung Kin Ken Wong, Susma Gurung, Yijing Zhang, Yuwan Lin, Yufeng Peng, Zongtang Xu, Kui Ming Chan, Lixiang Zhai, Aiping Lyu, Zhao-Xiang Bian, Xin Ge, Ashok Iyaswamy, Min Li, Ya Su, Zhongjun Zhou, Pingyi Xu, Hoi Leong Xavier Wong","doi":"10.1038/s41421-025-00825-w","DOIUrl":"10.1038/s41421-025-00825-w","url":null,"abstract":"<p><p>Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity. Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"76"},"PeriodicalIF":12.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124275","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}

{"title":"Molecular mechanisms of PI3Kα activation by small-molecule activator 1938 and cancer-specific mutation H1047R.","authors":"Xiao Liu, Qingtong Zhou, Yanyan Chen, Wei Han, Jie Li, Yiting Mai, Ming-Wei Wang","doi":"10.1038/s41421-025-00833-w","DOIUrl":"10.1038/s41421-025-00833-w","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"77"},"PeriodicalIF":12.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085101","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}

{"title":"Author Correction: The Asprosin-OLFR734 hormonal signaling axis modulates male fertility.","authors":"Fangchao Wei, Aijun Long, Yiguo Wang","doi":"10.1038/s41421-025-00834-9","DOIUrl":"10.1038/s41421-025-00834-9","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"78"},"PeriodicalIF":12.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091190","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}

{"title":"STK4 inhibits the E3 activity of HOIP by phosphorylating its allosteric ubiquitin-binding site.","authors":"Yaru Wang, Xindi Zhou, Zhiqiao Lin, Yichao Huang, Yuchao Zhang, Haobo Liu, Yuqian Zhou, Jianping Liu, Lifeng Pan","doi":"10.1038/s41421-025-00824-x","DOIUrl":"10.1038/s41421-025-00824-x","url":null,"abstract":"<p><p>HOIP, an RBR-type E3 ligase and the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), plays crucial roles in various cellular processes, including the NF-κB signaling pathway. The E3 activity of HOIP can be inhibited by the kinase STK4-mediated phosphorylation, although the mechanism is poorly understood. In this study, using biochemical, mass spectrometry and structural approaches, we systemically characterize the association of STK4 with HOIP, and unveil that STK4 can directly bind to the RING2-LDD module of HOIP through its kinase domain. The determined crystal structure of STK4 in complex with HOIP RING2-LDD not only elucidates the detailed binding mechanism of STK4 with HOIP, but also uncovers, for the first time, a unique binding mode of STK4 with its substrate. Moreover, we reveal that STK4 can directly phosphorylate the T786 residue of HOIP that is located in the allosteric ubiquitin-binding site of HOIP. Importantly, the phosphorylation of HOIP T786 mediated by STK4 can block the binding of ubiquitin to the allosteric site of HOIP, thereby attenuating the E3 activity of HOIP. In all, our findings provide mechanistic insights into the interaction between STK4 and HOIP as well as the negative regulation of HOIP's E3 activity by STK4-mediated phosphorylation, which are valuable for further understanding the regulatory modes of RBR-type E3 ligases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"75"},"PeriodicalIF":12.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12441119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074400","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}

{"title":"Intrauterine hyperglycemia impairs mouse primordial germ cell development and fertility by sex-specific epigenetic reprogramming interference.","authors":"Jiangshan Cong, Qing Li, Yangyang Li, Minghao Li, Yan Shi, Peiran Hu, Xidi Yin, Qianyun Zhang, Jianzhong Sheng, Jinsong Li, Guolian Ding, Yu Zhang, Hefeng Huang","doi":"10.1038/s41421-025-00821-0","DOIUrl":"10.1038/s41421-025-00821-0","url":null,"abstract":"<p><p>Adverse intrauterine environments, such as hyperglycemia, impair sexual reproduction and species continuity, yet the underlying mechanisms remain poorly understood. In this study, we demonstrated that intrauterine hyperglycemia significantly disrupted primordial germ cell (PGC) development, especially in female offspring, thus reducing fertility. Using Oct4-EGFP transgenic mice with intrauterine hyperglycemia exposure, we revealed that hyperglycemia compromised sexually specific chromatin accessibility and DNA methylation reprogramming during PGC development. Particularly, in female PGCs, hyperglycemia leads to the aberrant retention of chromatin accessibility at pluripotency gene promoters such as Nanog and Tfap2c, inhibiting proper gene silencing and blocking the initiation of meiosis, which ultimately hinders oocyte maturation. Conversely, male PGCs exhibit less severe changes in chromatin accessibility and gene transcription. Intriguingly, the global DNA methylation reconstruction is impaired in male PGCs, particularly in key imprinted gene regions, suggesting potential developmental ramifications for later stages and even subsequent generations. Particularly, our findings indicate that intrauterine hyperglycemia adversely affects sex differentiation in PGCs by disrupting the expression of critical sex-determining transcription factors. Collectively, these findings highlight how intrauterine hyperglycemia interferes with sex-specific epigenetic reprogramming during PGC development, leading to abnormal germ cell development, reduced fertility, and adverse intergenerational effects.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"74"},"PeriodicalIF":12.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022820","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}

{"title":"Structural basis of the RNA-mediated Retron-Eco2 oligomerization.","authors":"Yanjing Wang, Chen Wang, Yongqi Yin, Yongqing Cui, Zhikang Dai, Chang Liu, Yanke Chen, Zeyuan Guan, Tingting Zou","doi":"10.1038/s41421-025-00823-y","DOIUrl":"10.1038/s41421-025-00823-y","url":null,"abstract":"<p><p>In the evolutionary arms race between bacteria and viruses, retrons have emerged as distinctive antiphage defense systems. Here, we elucidate the structure and function of Retron-Eco2, which comprises a non-coding RNA (ncRNA) that encodes multicopy single-stranded DNA (msDNA, a DNA‒RNA hybrid) and a fusion protein containing a reverse transcriptase (RT) domain and a topoisomerase-primase-like (Toprim) effector domain. The Eco2 msDNA and RT-Toprim fusion protein form a 1:1 stoichiometric nucleoprotein complex that further assembles into a trimer (msDNA:RT-Toprim ratio of 3:3) with a distinctive triangular configuration. The RNA portion of the msDNA in one protomer closely intertwines around the RT domain of an adjacent protomer, mediating the formation of this self-inhibitory assembly. Upon activation, the Toprim effector domain exhibits RNase activity, degrading RNA to arrest phage replication. We further reveal that phage mutants evading Eco2-mediated defense harbor mutations in the endonuclease IV-like protein DenB, underscoring DenB's critical role in triggering the activation of this system. Together, these findings provide key structural and functional insights into Retron-Eco2, laying the groundwork for harnessing its potential in biotechnology and synthetic biology applications.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"73"},"PeriodicalIF":12.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944266","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}

{"title":"Immunological and pathological characteristics of brain parenchymal and leptomeningeal metastases from non-small cell lung cancer.","authors":"Cheng Zhou, Shenbing Shan, Lei Wen, Da Liu, Changguo Shan, Xin Jin, Zhaoming Zhou, Hainan Li, Juan Li, Luyue Wang, Junguo Bu, Bin Li, Weishan Huang, Junhao Hu, Hongbo Guo, Wu Wei","doi":"10.1038/s41421-025-00828-7","DOIUrl":"10.1038/s41421-025-00828-7","url":null,"abstract":"<p><p>Brain parenchymal metastases (BM) and leptomeningeal metastases (LM) represent distinct subtypes of central nervous system metastases (CNSm) from lung cancer, posing significant clinical challenges. The local immune landscape of LM remains elusive. Herein, we utilized single-cell RNA sequencing to build a cell atlas of LM, and systematically examine the immune profiling and cell heterogeneity between BM and LM. Our analysis reveals that BM has more CXCL9⁺ macrophages, CXCL13⁺CD4⁺ T cells and B cells than LM, exhibiting the presence of tertiary lymphoid (TLS) structures, which is associated with a favorable response to tyrosine kinase inhibitors (TKI). Conversely, a remarkably immunosuppressive tumor microenvironment (TME) is detected in LM, characterized by lymphocyte depletion and a concurrent enrichment of SPP1⁺ macrophages, compared to BM. Furthermore, we identified significant blood-brain barrier (BBB) cell discrepancies between BM and LM, and substantial phenotypic reprogramming of BBB cells in CNSm. This reprogramming encompassed alterations in transporter gene expression, extracellular matrix production and dysregulated cell-cell interactions, potentially contributing to the metastatic process. In summary, this study highlights the divergent cellular and molecular landscapes of BM vs LM, offering critical insights into potential therapeutic targets and informing the development of improved treatment strategies for non-small cell lung cancer patients with CSNm.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"72"},"PeriodicalIF":12.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944222","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}

{"title":"Targeting miR-337 mitigates disuse-induced bone loss.","authors":"Jiao Li, Ding Ma, Chunxue Zhang, Xueling Zheng, Ruihan Hao, Bin Zuo, Fei Xiao, Yang Li, Yuhang Liu, Zhouyi Duan, Yao Xiong, Orion R Fan, Wenmin Zhu, Liming Dai, Bingjun Zhang, Yi Eve Sun, Xiaoling Zhang","doi":"10.1038/s41421-025-00822-z","DOIUrl":"10.1038/s41421-025-00822-z","url":null,"abstract":"<p><p>Disuse-induced bone loss occurs in long-term bed-ridden patients and in astronauts during spaceflight. The underlying mechanisms are poorly understood. In a rodent model of disuse-induced bone loss (called hindlimb unloading (HU)), we observed that decreased numbers of leptin receptor (LepR) positive mesenchymal stem cells (MSCs) in adult bone marrow, contribute to bone loss. MicroRNA-337-3p (miR-337) was upregulated in MSCs upon HU and inhibited MSC proliferation by directly targeting IRS-1 to suppress the PI3kinase-Akt-mTOR pathway. Piezo1 was the upstream receptor for sensing mechanical stress and regulated miR-337 through the Hippo-YAP signaling pathway. Remarkably, the knockout of miR-337 significantly attenuated HU-induced, but not ovariectomy-induced, bone loss by increasing MSC proliferation and osteogenesis. Finally, the transplantation of miR-337^-/- MSCs into wild-type HU mice was sufficient to mitigate bone loss. These findings reveal the cellular and molecular mechanisms underlying disuse-induced bone loss and highlight a feasible therapeutic strategy to prevent disuse- or microgravity-induced bone loss on Earth and during spaceflight.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"71"},"PeriodicalIF":12.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12378244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944235","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}