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Cell insight

Pub Date : 2025-10-01 DOI: 10.1016/S2772-8927(25)00052-5

引用次数: 0

Development of a comparative high-throughput screening platform for identifying glioblastoma subtype specific inhibitors 一种鉴别胶质母细胞瘤亚型特异性抑制剂的比较高通量筛选平台的开发

Cell insight

Pub Date : 2025-09-29 DOI: 10.1016/j.cellin.2025.100284

Zilai Wang , Pin Zhang , Kiira M. Ratia , Ahmad Daher , Zongmin Zhao , Paul R. Carlier , Yuwei Jiang , Lijun Rong

Glioblastoma (GBM) is the most lethal primary malignant brain tumor in adults, with the development of effective therapeutic agents largely hampered by vast tumor heterogeneity and the impedance of efficient drug delivery by the blood-brain barrier (BBB). Our prior research has demonstrated that adult neural stem cells (NSCs) and oligodendrocyte precursor cells (OPCs) can act as cells of origin for two distinct GBM subtypes (Type 1and Type 2) in mice, with significant conservation to human Type I and Type II GBM in functional properties and distinct responses to the inhibition by Tucatinib and Dasatinib. Based on these findings, we have established a robust high-throughput screening (HTS) assay to identify lineage-dependent subtype-specific as well as lineage-independent small molecule inhibitors for therapeutic development. Reported in the current study, we conducted a HTS using a kinase inhibitor library (900 compounds) in Type 1 and Type 2 GBM cells. Our primary screen identified 84 common inhibitors, 11 Type 1-specific inhibitors, and 18 Type 2-specific inhibitors. The confirmation screen verified R406 and Ponatinib as selective inhibitors of Type 2 GBM cells, and this was further validated in dose-dependent assays. Additionally, R406 exhibited a synergistic effect with Tucatinib in Type 2 GBM cells, providing a rationale for combination therapy. Our study demonstrated the feasibility of identifying subtype-specific therapeutic vulnerabilities using cell-lineage based GBM models and laid the foundation for expanded HTS studies in larger scale screens in both mouse and human GBM subtypes.

胶质母细胞瘤（GBM）是成人中最致命的原发性恶性脑肿瘤，由于肿瘤的巨大异质性和血脑屏障（BBB）的有效给药阻抗，阻碍了有效治疗药物的开发。我们之前的研究表明，成体神经干细胞（NSCs）和少突胶质前体细胞（OPCs）可以作为小鼠两种不同GBM亚型（1型和2型）的细胞来源，在功能特性上与人类I型和II型GBM有显著的保守性，并且对图卡替尼和达沙替尼的抑制有明显的反应。基于这些发现，我们建立了一个强大的高通量筛选（HTS）试验，以确定谱系依赖的亚型特异性和谱系独立的小分子抑制剂，用于治疗开发。在目前的研究中，我们使用激酶抑制剂文库（900种化合物）在1型和2型GBM细胞中进行了HTS。我们的初步筛选确定了84种常见抑制剂，11种1型特异性抑制剂和18种2型特异性抑制剂。确认筛选证实R406和Ponatinib是2型GBM细胞的选择性抑制剂，并且在剂量依赖性试验中进一步验证了这一点。此外，R406与图卡替尼在2型GBM细胞中表现出协同作用，为联合治疗提供了理论依据。我们的研究证明了使用基于细胞谱系的GBM模型识别亚型特异性治疗脆弱性的可行性，并为在小鼠和人类GBM亚型中进行更大规模的HTS研究奠定了基础。

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引用次数: 0

Hypoxia-induced MT2A-tetrameric PKM2 interaction maintains PKM2 activity in a copper-ion-dependent manner 缺氧诱导的mt2a -四聚体PKM2相互作用以铜依赖的方式维持PKM2的活性

Cell insight

Pub Date : 2025-09-24 DOI: 10.1016/j.cellin.2025.100277

Ronghui Gao , Qifang Li , Jiahao Guo , Zirou Peng , Chuan Gao , Zirui Zhou , Hankun Hu , Jing Zhang

Hypoxia is a hallmark of solid tumors associated with tumor malignancy. Mitochondrial metabolic reprogramming is a key step in the process of cellular adaptation to hypoxic stress for tumor growth, but the regulatory mechanisms are not fully understood. In this study, through mitochondrial proteomics analysis, we find that metallothionein-2A (MT2A) is top-ranked among the significantly upregulated proteins in mitochondrial extract in response to hypoxia. Further, we show that hypoxia can induce the mitochondrial translocation of MT2A, a process that is dependent on copper ion. MT2A is highly expressed in hypoxic tumor tissues compared to normoxic ones in breast cancer patients, among whom higher expression of MT2A is associated with a worse prognosis, and it is required for breast tumor growth. Mechanistically, we reveal that copper ion is also essential for hypoxia-induced mitochondrial translocation of Pyruvate kinase M2 (PKM2), and facilitates the interaction of MT2A with the tetrameric form of PKM2 to maintain its activity, thereby promoting glycolysis and oxidative phosphorylation. Thus, our findings reveal the MT2A-copper-PKM2 axis as a potential therapeutic target to treat breast cancer.

缺氧是与恶性肿瘤相关的实体瘤的标志。线粒体代谢重编程是肿瘤生长过程中细胞适应缺氧胁迫的关键步骤，但其调控机制尚不完全清楚。本研究通过线粒体蛋白质组学分析发现，在线粒体提取物中，金属硫蛋白- 2a （metallothionein-2A, MT2A）在缺氧条件下的显著上调蛋白中排名第一。此外，我们发现缺氧可以诱导MT2A的线粒体易位，这一过程依赖于铜离子。在乳腺癌患者中，MT2A在缺氧肿瘤组织中较常氧肿瘤组织高表达，MT2A表达越高预后越差，是乳腺肿瘤生长所必需的。在机制上，我们发现铜离子也是缺氧诱导的丙酮酸激酶M2 （PKM2）线粒体易位所必需的，并促进MT2A与PKM2的四聚体形式相互作用以维持其活性，从而促进糖酵解和氧化磷酸化。因此，我们的研究结果揭示了mt2a -铜- pkm2轴作为治疗乳腺癌的潜在治疗靶点。

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引用次数: 0

Host-virus molecular arms race: RNAi-mediated antiviral defense and viral suppressor of RNAi 宿主-病毒分子军备竞赛：RNAi介导的抗病毒防御和RNAi的病毒抑制因子

Cell insight

Pub Date : 2025-08-27 DOI: 10.1016/j.cellin.2025.100276

Bowen Zhang , Xi Zhou , Yujie Ren

RNA interference (RNAi) is a highly conserved post-transcriptional gene silencing (PTGS) mechanism widely presented in eukaryotes. During viral infection, double-stranded RNA viral replicative intermediate (vRI-dsRNA) derived from the viral genome is recognized and processed by Dicer to generate small interfering RNA (siRNA). The viral siRNA (vsiRNA) is subsequently loaded into the RNA-induced silencing complex (RISC), which targets and degrades viral RNAs to achieve antiviral immune response. During long-term evolution, viruses have evolved to counteract RNAi by encoding viral suppressors of RNAi (VSRs) through various strategies, thereby evading the immune clearance. Here we review how VSRs function as immune evasion factors against antiviral RNAi, along with their evolutionary significance in shaping both viral adaptation and host-pathogen co-evolution. We also discuss recent advancements and unresolved controversies regarding RNAi-mediated antiviral immunity in mammals. Finally, we provide a comprehensive analysis of emerging therapeutic strategies and vaccine designs that leverage the RNAi-VSR interaction mechanisms, while addressing their potential prospects and challenges in clinical translation.

RNA干扰（RNAi）是一种高度保守的转录后基因沉默（PTGS）机制，广泛存在于真核生物中。在病毒感染过程中，来自病毒基因组的双链RNA病毒复制中间体（vRI-dsRNA）被Dicer识别并加工生成小干扰RNA （siRNA）。病毒siRNA （vsiRNA）随后被装载到rna诱导沉默复合体（RISC）中，该复合体靶向并降解病毒rna以实现抗病毒免疫反应。在长期的进化过程中，病毒通过各种策略通过编码RNAi的病毒抑制因子（VSRs）来对抗RNAi，从而逃避免疫清除。在这里，我们回顾了VSRs作为抗病毒RNAi的免疫逃避因子的功能，以及它们在塑造病毒适应和宿主-病原体共同进化中的进化意义。我们还讨论了哺乳动物rnai介导的抗病毒免疫的最新进展和未解决的争议。最后，我们全面分析了利用RNAi-VSR相互作用机制的新兴治疗策略和疫苗设计，同时阐述了它们在临床转化中的潜在前景和挑战。

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引用次数: 0

Faithful inheritance: Parental histone recycling and epigenetic memory in fission yeast 忠实遗传：裂变酵母亲本组蛋白循环和表观遗传记忆

Cell insight

Pub Date : 2025-08-08 DOI: 10.1016/j.cellin.2025.100275

Yimeng Fang , Takenori Toda , Songtao Jia

Accurate transmission of chromatin states during DNA replication is central to epigenetic inheritance. Recent advances have illuminated mechanisms by which parental histones, which carry key post-translational modifications, are recycled and redistributed to daughter strands. This review synthesizes emerging insights into the molecular machinery that mediates histone recycling during replication. It highlights the interplay between histone chaperones and replication factors and examines how perturbations in these pathways influence heterochromatin inheritance. The fission yeast serves as a powerful model for recent investigations, revealing new principles that are conserved across eukaryotes.

DNA复制过程中染色质状态的准确传递是表观遗传的核心。最近的进展已经阐明了携带关键翻译后修饰的亲本组蛋白被回收并重新分配到子链的机制。这篇综述综合了在复制过程中介导组蛋白循环的分子机制的新见解。它强调了组蛋白伴侣和复制因子之间的相互作用，并研究了这些途径中的扰动如何影响异染色质遗传。裂变酵母为最近的研究提供了一个强大的模型，揭示了在真核生物中保守的新原理。

引用次数: 0

Cover 封面

Cell insight

Pub Date : 2025-08-01 DOI: 10.1016/S2772-8927(25)00042-2

引用次数: 0

PAK4 phosphorylates and stabilizes MYC to promote acute myeloid leukemia PAK4磷酸化并稳定MYC促进急性髓性白血病

Cell insight

Pub Date : 2025-07-31 DOI: 10.1016/j.cellin.2025.100274

Ting Xie , Peipei Sun , Hao Huang , Qilong Li , Hudan Liu , Jue Jiang

MYC dysregulation plays a crucial role in acute myeloid leukemia (AML), yet the mechanisms governing its stabilization remain incompletely understood. MYC protein turnover is tightly regulated by post-translational modifications (PTMs), especially phosphorylation-dependent ubiquitination. Our previous study identified phosphorylation at MYC Serine 67 (S67) is critical to sustain its oncogenic activity in T-cell acute lymphoblastic leukemia (T-ALL). Here, we demonstrate that MYC S67 phosphorylation is also present in AML and catalyzed by p21-activated kinase 4 (PAK4). PAK4 directly binds MYC via its MBII domain, phosphorylates S67 and disrupts FBXW7-dependent ubiquitination, thereby stabilizing MYC to sustain MYC-driven leukemogenic programs. PAK4 inhibition destabilizes MYC and suppresses AML proliferation; however, it fails to elicit robust apoptosis, primarily due to the compensatory upregulation of the anti-apoptotic factor MCL-1. Combining the PAK4 inhibitor KPT-9274 with the MCL-1 antagonist S63845 induces synergistic lethality in AML cells. These findings provide the mechanistic insight of MYC stabilization in AML and establish a PAK4 inhibition-based targeted strategy as a promising therapeutic approach for AML treatment.

MYC失调在急性髓性白血病（AML）中起着至关重要的作用，但控制其稳定的机制仍不完全清楚。MYC蛋白的周转受到翻译后修饰（PTMs）的严格调控，尤其是磷酸化依赖的泛素化。我们之前的研究发现MYC丝氨酸67 （S67）的磷酸化对于维持其在t细胞急性淋巴细胞白血病（T-ALL）中的致癌活性至关重要。在这里，我们证明MYC S67磷酸化也存在于AML中，并由p21活化激酶4 （PAK4）催化。PAK4通过其MBII结构域直接结合MYC，磷酸化S67并破坏fbxw7依赖的泛素化，从而稳定MYC以维持MYC驱动的白血病发生程序。PAK4抑制MYC不稳定并抑制AML增殖；然而，由于抗凋亡因子MCL-1的代偿性上调，它不能引起强烈的细胞凋亡。PAK4抑制剂KPT-9274与MCL-1拮抗剂S63845联合可诱导AML细胞的协同致死。这些发现提供了AML中MYC稳定的机制见解，并建立了基于PAK4抑制的靶向策略，作为AML治疗的一种有希望的治疗方法。

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引用次数: 0

Beyond interferons: Non-canonical roles of MITA/STING 超越干扰素：MITA/STING的非规范作用

Cell insight

Pub Date : 2025-07-24 DOI: 10.1016/j.cellin.2025.100266

Liting Zhang , Chuchu Zhang , Junjie Zhang

Mediator of IRF3 activation (MITA)/Stimulator of Interferon Genes (STING) (also known as MPYS/ERIS) is a crucial adaptor protein for initiating antiviral innate immune responses to intracellular DNA and DNA viruses. MITA binds cGAMP, a second messenger synthesized by cGAS in response to intracellular DNA, culminating in the induction of type I interferons (IFNs), inflammatory cytokines, and interferon-stimulated genes (ISGs). While the canonical IFN-dependent MITA signaling has been extensively studied, recent research has unveiled a growing repertoire of IFN-independent functions of MITA in various physiological processes and pathological conditions. These non-canonical roles of MITA are increasingly recognized for their involvement in critical processes such as antiviral activity, senescence, autophagy, metabolism, lysosomal biogenesis, and the development of neurological disorders. In this review, we summarize the latest advances in understanding MITA's non-canonical functions and provide insights into key scientific questions that remain to be addressed. Deciphering how MITA is involved in these complex physiological and pathological processes will not only deepen our understanding of MITA signaling, but may also offer new therapeutic targets for treating related diseases.

IRF3激活介质(MITA)/干扰素基因刺激因子（STING）（也称为MPYS/ERIS）是启动针对细胞内DNA和DNA病毒的抗病毒先天免疫应答的关键衔接蛋白。MITA结合cGAMP， cGAMP是cGAS在响应细胞内DNA时合成的第二信使，最终诱导I型干扰素（ifn）、炎症细胞因子和干扰素刺激基因（ISGs）。虽然典型的ifn依赖性MITA信号已被广泛研究，但最近的研究揭示了MITA在各种生理过程和病理条件下ifn独立功能的不断增长。人们越来越认识到MITA的这些非规范作用，因为它们参与了一些关键过程，如抗病毒活性、衰老、自噬、代谢、溶酶体生物发生和神经系统疾病的发展。在这篇综述中，我们总结了理解MITA非规范功能的最新进展，并提供了仍有待解决的关键科学问题的见解。破译MITA如何参与这些复杂的生理和病理过程，不仅可以加深我们对MITA信号传导的理解，而且可能为治疗相关疾病提供新的治疗靶点。

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引用次数: 0

Microbiota-derived bile acid metabolic enzymes and their impacts on host health 微生物来源的胆汁酸代谢酶及其对宿主健康的影响

Cell insight

Pub Date : 2025-07-12 DOI: 10.1016/j.cellin.2025.100265

Haohan Ma , Kai Wang , Changtao Jiang

Bile acids are amphipathic sterol molecules regulated by both the host and gut microbiota, serving as classical mediators for deciphering host-microbiota interactions. Synthesized primarily in the liver and undergoing extensive structural modifications along the gastrointestinal tract, bile acids are dynamically shaped by diverse bile acid metabolic enzymes, especially from gut microbiota. Beyond their canonical detergent-like functions, bile acids act as receptor modulators, immune regulators, and microbiota sculptors, profoundly involved in regulating host metabolic processes, maintaining immune homeostasis, and contributing to metabolic disorders when dysregulated. The modifications of bile acids by microbial enzymes critically influence their functional diversity. However, despite the vast array of bile acid modifications observed, significant gaps remain in the systematic identification and characterization of microbial bile acid metabolic enzymes. This review underscores the urgency of exploring the biosynthetic pathways for the production of key bile acids and highlights its potential to advance precision therapeutic strategies targeting gut microbiota and their enzymatic machinery.

胆汁酸是由宿主和肠道微生物群共同调节的两亲性甾醇分子，是解读宿主-微生物群相互作用的经典介质。胆汁酸主要在肝脏中合成，并沿着胃肠道进行广泛的结构修饰，各种胆汁酸代谢酶，特别是肠道微生物群，动态地形成胆汁酸。除了其典型的清洁剂功能外，胆汁酸还作为受体调节剂、免疫调节剂和微生物群雕塑家，深刻地参与调节宿主代谢过程，维持免疫稳态，并在失调时导致代谢紊乱。微生物酶对胆汁酸的修饰对胆汁酸的功能多样性有重要影响。然而，尽管观察到大量的胆汁酸修饰，但在微生物胆汁酸代谢酶的系统鉴定和表征方面仍存在重大差距。这篇综述强调了探索关键胆汁酸生产的生物合成途径的紧迫性，并强调了其在推进针对肠道微生物群及其酶机制的精确治疗策略方面的潜力。

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引用次数: 0

The NF-κB-SLC7A11 axis regulates ferroptosis sensitivity in inflammatory macrophages NF-κB-SLC7A11轴调节炎性巨噬细胞对铁下垂的敏感性

Cell insight

Pub Date : 2025-06-11 DOI: 10.1016/j.cellin.2025.100257

Mengjie Yang , Xiaowei Chen , Xiran Hu , Hexiang Li , Hao Huang , Yingzhe Fang , Jue Jiang , Hudan Liu , Yuan Wang , Guoliang Qing

M1-polarized macrophages exhibit remarkable resistance to ferroptosis, a form of regulated cell death driven by excessive lipid peroxidation. Yet the underlying mechanisms remain to be defined. Through CRISPR-based functional screen of metabolic genes combining transcriptomics analysis, we herein identified the cystine/glutamate antiporter SLC7A11 as a pivotal mediator of ferroptosis resistance in M1 macrophages. Mechanistically, lipopolysaccharide (LPS) engagement with the Toll-like receptor 4 (TLR4) resulted in NF-κB activation, leading to RELA-dependent transcriptional upregulation of Slc7a11 expression. SLC7A11 in turn promoted cystine uptake and subsequent glutathione (GSH) synthesis. Genetic ablation of Slc7a11 reduced GSH production, sensitizing M1 macrophages to RSL3-induced ferroptosis. In aggregate, our findings unveil the RELA-SLC7A11 axis as a critical metabolic checkpoint dictating macrophage ferroptosis sensitivity, which might be employed to modulate macrophage functions in inflammatory diseases.

m1极化巨噬细胞表现出对铁凋亡的显著抵抗，铁凋亡是一种由过度脂质过氧化驱动的受调节细胞死亡形式。然而，其潜在机制仍有待确定。通过基于crispr的代谢基因功能筛选结合转录组学分析，我们发现胱氨酸/谷氨酸反转运蛋白SLC7A11是M1巨噬细胞嗜铁性耐药的关键介质。从机制上讲，脂多糖（LPS）与toll样受体4 （TLR4）结合导致NF-κB活化，导致rela依赖性Slc7a11表达的转录上调。SLC7A11反过来促进胱氨酸摄取和随后的谷胱甘肽（GSH）合成。基因消融Slc7a11减少GSH的产生，使M1巨噬细胞对rsl3诱导的铁凋亡敏感。总之，我们的研究结果揭示了RELA-SLC7A11轴作为一个关键的代谢检查点，决定巨噬细胞铁凋亡的敏感性，这可能被用来调节炎症性疾病中的巨噬细胞功能。

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