Cell insight最新文献_第3页

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 : 2025-10-01 Epub 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

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 : 2025-10-01 Epub 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

Cover 封面

Cell insight

Pub Date : 2025-08-01 Epub Date: 2025-07-31 DOI: 10.1016/S2772-8927(25)00042-2

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 : 2025-08-01 Epub 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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引用次数: 0

TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction TFAP4通过调节机械转导加剧病理性心脏纤维化

Cell insight

Pub Date : 2025-08-01 Epub Date: 2025-06-02 DOI: 10.1016/j.cellin.2025.100256

Jie Liu , Jingjing Feng , Jingxuan Zhao , Xiangjie Kong , Zhangyi Yu , Yuanru Huang , Zechun He , Mengxin Liu , Zheng Liu , Zhibing Lu , Li Wang

Cardiac fibroblast (CF) differentiation into myofibroblasts is a crucial driver of cardiac fibrosis, leading to extensive extracellular matrix (ECM) deposition that increases myocardial stiffness and eventually impairs heart function. Mechanotransduction has merged as a key regulator of CF activation and the fibrotic response post-myocardial infarction (MI). However, the molecular mechanisms linking CF activation to mechanical cues within the injured myocardium remain poorly understood. Here we identified transcription factor TFAP4 as a central regulator of fibrosis in both human and murine models. TFAP4 overexpression enhances CF proliferation, ECM protein expression, and myofibroblast differentiation. Notably, TFAP4 directly activates expression of mechanosensors including Itga11 and Piezo2, which are essential for transmitting mechanical signals that promote CF activation and fibrosis. Silencing Itga11 and Piezo2 reverses the pro-fibrotic effects of TFAP4, while TFAP4 downregulation in vivo reduces fibrosis and improves cardiac function post-MI. These findings identify TFAP4 as a pivotal link between mechanotransduction and fibrosis, suggesting it as a potential therapeutic target to mitigate fibrosis and enhance cardiac recovery following MI.

心脏成纤维细胞（CF）分化为肌成纤维细胞是心脏纤维化的关键驱动因素，导致广泛的细胞外基质（ECM）沉积，增加心肌硬度，最终损害心脏功能。机械转导已成为CF激活和心肌梗死（MI）后纤维化反应的关键调节因子。然而，将CF激活与受损心肌内机械信号联系起来的分子机制仍然知之甚少。在这里，我们发现转录因子TFAP4在人和小鼠模型中都是纤维化的中心调节因子。TFAP4过表达可促进CF增殖、ECM蛋白表达和肌成纤维细胞分化。值得注意的是，TFAP4直接激活包括Itga11和Piezo2在内的机械传感器的表达，这些机械传感器对于传递促进CF激活和纤维化的机械信号至关重要。沉默Itga11和Piezo2可逆转TFAP4的促纤维化作用，而体内TFAP4下调可减少心肌梗死后的纤维化并改善心功能。这些发现确定TFAP4是机械转导和纤维化之间的关键联系，表明它是减轻心肌梗死后纤维化和增强心脏恢复的潜在治疗靶点。

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引用次数: 0

Integrated 4D label-free proteome and SUMOylated proteome in glioma uncover novel pathological mechanisms and pave the way for precision therapy 脑胶质瘤中4D无标记蛋白质组和summoylated蛋白质组的整合揭示了新的病理机制，为精准治疗铺平了道路

Cell insight

Pub Date : 2025-08-01 Epub Date: 2025-05-19 DOI: 10.1016/j.cellin.2025.100253

Jiazheng Wang , Zhuo Li , Kaijie Mu , Qichao Qi , Zeli Zhang , Can Yan , Xukai Jiang , Anjing Chen

Glioma, the most common primary intracranial tumor, has seen increased scrutiny with the advent of high-throughput detection technologies, yet many aspects of its tumorigenesis and progression remain enigmatic. In this study, we utilized 4D label-free mass quantitative proteomics to analyze glioma protein expression, with a focus on SUMOylated proteins through SUMO peptide enrichment. Bioinformatics analysis was applied to identify differentially expressed proteins (DEPs) and differentially SUMOylated proteins, elucidating their functions and interactions. By integrating proteomics and transcriptomics data, we pinpointed core proteins with consistent upregulation and assessed their potential as drug targets in glioma through virtual screening of eight cytoplasmic proteins with small molecule binding cavities. Our findings reveal that low-grade glioma (LGG) exhibits more DEPs than glioblastoma (GBM) when compared to normal brain tissue, but GBM shows more disrupted functions. LGG is characterized by a higher number of SUMOylated proteins in key processes, whereas GBM has fewer, with these SUMOylated proteins implicated in diverse functions, including RNA and protein regulation, metabolism, and immunity. There is also a significant discrepancy between RNA and protein levels for most molecules. The virtual docking of core oncogenic molecules suggests potential therapeutic targets and transformation opportunities. This study deepens our comprehension of glioma proteomics and SUMOylation, revealing novel pathological mechanisms and laying the groundwork for targeted glioma therapies.

神经胶质瘤是最常见的原发性颅内肿瘤，随着高通量检测技术的出现，人们对其进行了越来越多的研究，但其肿瘤发生和进展的许多方面仍然是谜。在本研究中，我们利用4D无标记的大量定量蛋白质组学分析胶质瘤蛋白的表达，重点是通过SUMO肽富集研究SUMO化蛋白。应用生物信息学分析鉴定差异表达蛋白（DEPs）和差异summoylated蛋白，阐明它们的功能和相互作用。通过整合蛋白质组学和转录组学数据，我们确定了具有一致上调的核心蛋白，并通过虚拟筛选8种具有小分子结合腔的细胞质蛋白，评估了它们作为胶质瘤药物靶点的潜力。我们的研究结果表明，与正常脑组织相比，低级别胶质瘤（LGG）比胶质母细胞瘤（GBM）表现出更多的dep，但GBM表现出更多的功能破坏。LGG的特点是在关键过程中有较多的SUMOylated蛋白，而GBM则较少，这些SUMOylated蛋白涉及多种功能，包括RNA和蛋白质调节、代谢和免疫。对于大多数分子来说，RNA和蛋白质的水平也存在显著差异。核心致癌分子的虚拟对接提示了潜在的治疗靶点和转化机会。该研究加深了我们对胶质瘤蛋白质组学和SUMOylation的理解，揭示了新的病理机制，为胶质瘤靶向治疗奠定了基础。

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引用次数: 0

Gene therapy strategies for aging intervention 基因治疗策略干预衰老

Cell insight

Pub Date : 2025-08-01 Epub Date: 2025-05-23 DOI: 10.1016/j.cellin.2025.100254

Yaobin Jing , Jie Ren , Jing Qu , Guang-Hui Liu

Aging is characterized by a progressive decline in organ and tissue structure and function, significantly increasing the risk of many chronic diseases. Developing interventions to delay aging holds the potential to reduce the burden of age-associated diseases and promote healthy longevity. Gene therapy has emerged as a clinically transformable approach, leveraging advanced gene editing and delivery systems to target the molecular underpinnings of aging. This review systematically explores the potential of gene therapy strategies in aging intervention, focusing on approaches that enhance genomic and epigenetic stability, restore metabolic homeostasis, modulate immune responses, and rejuvenate senescent cells. By providing a comprehensive overview and forward-looking insights, this article aims to inform future research directions and translational applications of gene therapy in mitigating aging-related decline.

衰老的特征是器官和组织结构和功能的逐渐衰退，大大增加了许多慢性疾病的风险。制定延缓衰老的干预措施有可能减轻与年龄有关的疾病的负担，促进健康长寿。基因治疗已经成为一种临床可转化的方法，利用先进的基因编辑和传递系统来针对衰老的分子基础。这篇综述系统地探讨了基因治疗策略在衰老干预中的潜力，重点是增强基因组和表观遗传稳定性、恢复代谢稳态、调节免疫反应和使衰老细胞恢复活力的方法。通过全面的综述和前瞻性的见解，本文旨在为基因治疗在缓解衰老相关衰退中的未来研究方向和转化应用提供信息。

引用次数: 0

IRF1 amplifies HSV-1-triggered antiviral innate immunity in a feed-forward manner IRF1以前馈方式放大hsv -1触发的抗病毒先天免疫

Cell insight

Pub Date : 2025-08-01 Epub Date: 2025-05-22 DOI: 10.1016/j.cellin.2025.100255

Ming Gao , Yining Qi , Junjie Zhang

Herpes simplex virus 1 (HSV-1) is a prevalent human pathogen that establishes lifelong infection and causes a wide range of diseases. Antiviral innate immunity is critical for controlling HSV-1 replication; however, how host cells elicit a full spectrum of antiviral innate immune responses against HSV-1 remains poorly understood. Here, our studies indicate that Interferon regulatory factor 1 (IRF1) amplifies HSV-1-induced antiviral innate immunity in a feed-forward manner. Our data reveal that HSV-1 infection induces IRF1 expression, and MITA/STING contributes to the induction of IRF1 during HSV-1 infection. Moreover, IRF1 restricts HSV-1 replication dependent on its DNA-binding activity. Knockout of IRF1 significantly diminishes the induction of a large subset of interferon-stimulated genes (ISGs) critical for antiviral defense during HSV-1 infection. Notably, IRF1 interacts with IRF3, promoting its recruitment to the promoters of ISGs as well as type I and III interferons, thereby facilitating the activation of antiviral signaling. These findings uncover a novel amplifying role of IRF1 in HSV-1-induced antiviral immunity, which deepens our understanding of innate immune responses against viral infections.

单纯疱疹病毒1 （HSV-1）是一种流行的人类病原体，可建立终身感染并引起多种疾病。抗病毒先天免疫对控制HSV-1复制至关重要；然而，宿主细胞如何引发针对HSV-1的全谱抗病毒先天免疫反应仍然知之甚少。本研究表明，干扰素调节因子1 （IRF1）以前馈方式增强hsv -1诱导的抗病毒先天免疫。我们的数据表明，HSV-1感染诱导IRF1表达，MITA/STING在HSV-1感染期间促进IRF1的诱导。此外，IRF1依靠其dna结合活性来限制HSV-1的复制。敲除IRF1显著减少了在HSV-1感染期间对抗病毒防御至关重要的干扰素刺激基因（ISGs）的诱导。值得注意的是，IRF1与IRF3相互作用，促进其招募到isg以及I型和III型干扰素的启动子，从而促进抗病毒信号的激活。这些发现揭示了IRF1在hsv -1诱导的抗病毒免疫中的新的放大作用，加深了我们对病毒感染的先天免疫反应的理解。

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引用次数: 0

The roles of macrophages and monocytes in COVID-19 Severe Respiratory Syndrome 巨噬细胞和单核细胞在COVID-19严重呼吸综合征中的作用

Cell insight

Pub Date : 2025-08-01 Epub Date: 2025-05-08 DOI: 10.1016/j.cellin.2025.100250

Jun Li , Rui Shan , Heather Miller , Alexander Filatov , Maria G. Byazrova , Lu Yang , Chaohong Liu

The global COVID-19 pandemic has highlighted the pivotal role of the immune system in the development of severe respiratory symptoms, termed COVID-19 Severe Respiratory Syndrome (COVID-19-SR). This review aims to dissect the involvement of lung macrophages and monocytes in orchestrating immune responses to SARS-CoV-2, influencing disease severity and outcomes. Initially, we provide an overview of SARS-CoV-2's invasion process and the body's primary immune defense mechanisms, including the antibody complement system and cytokine production. We then delve into the roles of the monocyte-macrophage system in mediating hyperinflammation and cytokine storms, discussing how abnormal cytokine and chemokine levels contribute to disease progression. Subsequent sections examine the perturbations and overactivation of the monocyte-macrophage compartment during infection, linking these changes to the observed immune dysregulation in COVID-19 patients. In light of these insights, we explore therapeutic strategies targeting macrophages, such as dexamethasone, antisense lipid nanoparticles(ALN), and inhaled recombinant human granulocyte-macrophage colony-stimulating factor (rh-GM-CSF), which aim to modulate inflammation, suppress viral replication, and enhance viral clearance. Additional potential treatments include GSDMD inhibitors and GPR183 antagonists, which warrant further investigation. This review synthesizes current understanding of the immunopathology underlying COVID-19-SR, proposing macrophage- and monocyte-centered therapeutic avenues and outlining future research priorities essential for advancing clinical management and improving patient outcomes.

COVID-19全球大流行凸显了免疫系统在严重呼吸道症状（称为COVID-19- sr）发展中的关键作用。本综述旨在剖析肺巨噬细胞和单核细胞在协调对SARS-CoV-2的免疫反应、影响疾病严重程度和结局中的作用。首先，我们概述了SARS-CoV-2的入侵过程和人体的主要免疫防御机制，包括抗体补体系统和细胞因子的产生。然后，我们深入研究单核-巨噬细胞系统在介导高炎症和细胞因子风暴中的作用，讨论异常细胞因子和趋化因子水平如何促进疾病进展。随后的章节研究了感染期间单核-巨噬细胞室的扰动和过度激活，将这些变化与COVID-19患者观察到的免疫失调联系起来。鉴于这些见解，我们探索了针对巨噬细胞的治疗策略，如地塞米松，反义脂质纳米颗粒（ALN）和吸入重组人粒细胞-巨噬细胞集落刺激因子（rh-GM-CSF），旨在调节炎症，抑制病毒复制，增强病毒清除。其他潜在的治疗方法包括GSDMD抑制剂和GPR183拮抗剂，值得进一步研究。本综述综合了目前对COVID-19-SR免疫病理学基础的理解，提出了以巨噬细胞和单核细胞为中心的治疗途径，并概述了未来的研究重点，这对推进临床管理和改善患者预后至关重要。

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引用次数: 0

cGAS, an innate dsDNA sensor with multifaceted functions cGAS，一种具有多方面功能的先天dsDNA传感器

Cell insight

Pub Date : 2025-06-01 Epub Date: 2025-04-17 DOI: 10.1016/j.cellin.2025.100249

Yutong Liu , Pinglong Xu

Cyclic GMP-AMP synthase (cGAS) functions as a pivotal intracellular sensor for the innate immune sensing of double-stranded DNA (dsDNA), monitoring those nucleic acids from foreign and endogenous sources. Upon assembling into cellular condensates with dsDNA and regulators, cGAS synthesizes 2′3′-cGAMP that activates the downstream STING signaling. This activation triggers a variety of intracellular responses, including autophagy, mRNA translation, interferon signaling, and inflammatory responses. Context-dependently, cGAS resides in diverse cellular compartments, including the nucleus, micronuclei, plasma membrane, and organelle surfaces. Beyond its DNA-sensing role, cGAS can play complex roles in these locations, such as DNA damage repairing, membrane restoration, chromatin condensation, angiogenesis, and aging regulation. This comprehensive review summarizes recent advances in the activation, regulation, and pharmacological management of cGAS, focusing on its molecular mechanisms, post-translational modifications (PTMs), and therapeutic interventions. The functional implications of cGAS in various disease contexts, including infectious diseases, autoinflammatory diseases, autoimmune diseases, aging, and cancers, are also covered.

环GMP-AMP合成酶（cGAS）作为双链DNA （dsDNA）先天免疫传感的关键细胞内传感器，监测来自外源和内源的核酸。在与dsDNA和调节因子组装成细胞凝聚体后，cGAS合成2 ' 3 ' -cGAMP，激活下游STING信号传导。这种激活触发多种细胞内反应，包括自噬、mRNA翻译、干扰素信号传导和炎症反应。与环境相关，cGAS存在于不同的细胞室中，包括细胞核、微核、质膜和细胞器表面。除了DNA传感作用外，cGAS还可以在这些位置发挥复杂的作用，如DNA损伤修复、膜修复、染色质凝聚、血管生成和衰老调节。本文综述了近年来在cGAS的激活、调控和药理管理方面的研究进展，重点介绍了其分子机制、翻译后修饰（PTMs）和治疗干预措施。cGAS在各种疾病背景下的功能含义，包括感染性疾病、自身炎症性疾病、自身免疫性疾病、衰老和癌症，也被涵盖。

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引用次数: 0