Cell insight最新文献_第3页

Single cell sequencing and spatial multiomics of diabetic kidney segmentation insights zonation-specific therapeutic metabolic pathways 单细胞测序和空间多组学的糖尿病肾分割见解分区特异性治疗代谢途径

Cell insight

Pub Date : 2025-06-01 DOI: 10.1016/j.cellin.2025.100252

Shi Qiu , Zhibo Wang , Sifan Guo , Dandan Xie , Ying Cai , Xian Wang , Chunsheng Lin , Songqi Tang , Yiqiang Xie , Aihua Zhang

Diabetic nephropathy (DN) exhibits profound spatial metabolic heterogeneity across kidney regions, yet how compartmentalized pathways drive disease progression remains poorly defined. A deeper understanding of the organizational spatial environment and metabolic pathways of diabetic kidney damage will provide new insights to develop new therapies. By integrating high-resolution spatial multi-omics and single-cell transcriptomics, we mapped region-specific metabolic dysregulation in diabetic kidneys, identifying glutathione metabolism, pentose phosphate, and glycolytic pathways as zonally disrupted in cortical and medullary regions. Spatial metabolomics revealed distinct anatomical clustering of ten clinically associated metabolites, while spatial proteomic profiling uncovered sixty-four region-enriched proteins linked to these pathways. Specifically, depending on anatomic location, spatial protein signatures across multiple regions of diabetic mouse kidneys were enriched in each segmentation, respectively. Cross-species integration identified GPX3 as a fibroblast-enriched biomarker strongly correlated with kidney dysfunction and closely related to clinical indicators. Notably, astragaloside IV (ASIV) treatment reversed spatial metabolic perturbations in diabetic mice, restoring glutathione and glycolytic pathway activity in a compartment-specific manner. Single-cell analyses identified five cell types—endothelial cells, fibroblasts, epithelial cells, macrophages and neutrophils—and further revealed fibroblasts as key contributors to regulatory effects via GPX3 overexpression. Importantly, the higher expression of Gpx3 in fibroblasts compared to other cell types, Gpx3 (AUC = 0.995), was further validated, demonstrating the high sensitivity and specificity for DN patients. This multimodal atlas establishes the spatially resolved metabolic blueprint of DN, bridging molecular zoning with anatomical localization of renal tissue to unveil actionable therapeutic targets for metabolic disorders in kidney disease.

糖尿病肾病（DN）在肾脏区域表现出深刻的空间代谢异质性，然而区隔通路如何驱动疾病进展仍然不清楚。深入了解糖尿病肾损害的组织空间环境和代谢途径将为开发新的治疗方法提供新的见解。通过整合高分辨率空间多组学和单细胞转录组学，我们绘制了糖尿病肾脏区域特异性代谢失调，确定谷胱甘肽代谢、戊糖磷酸和糖酵解途径在皮质和髓质区域被带状破坏。空间代谢组学揭示了10种临床相关代谢物的独特解剖聚类，而空间蛋白质组学分析揭示了64种与这些途径相关的区域富集蛋白。具体来说，根据解剖位置的不同，糖尿病小鼠肾脏多个区域的空间蛋白质特征分别在每个片段中富集。跨物种整合鉴定GPX3是一种富含成纤维细胞的生物标志物，与肾功能异常密切相关，与临床指标密切相关。值得注意的是，黄芪甲苷（ASIV）治疗逆转了糖尿病小鼠的空间代谢扰动，以特定的隔间方式恢复谷胱甘肽和糖酵解途径的活性。单细胞分析鉴定出五种细胞类型——内皮细胞、成纤维细胞、上皮细胞、巨噬细胞和中性粒细胞，并进一步揭示成纤维细胞是GPX3过表达调控作用的关键因素。重要的是，Gpx3在成纤维细胞中的表达高于其他细胞类型，进一步验证了Gpx3 (AUC = 0.995)，显示了对DN患者的高敏感性和特异性。这种多模式图谱建立了DN的空间分解代谢蓝图，将分子分区与肾组织的解剖定位联系起来，揭示肾脏疾病代谢紊乱的可行治疗靶点。

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Cover 封面

Cell insight

Pub Date : 2025-06-01 DOI: 10.1016/S2772-8927(25)00032-X

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 : 2025-05-23 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。

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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 : 2025-05-22 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

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 : 2025-05-19 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

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 : 2025-05-08 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 : 2025-04-17 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

Corrigendum to “STING guides the STX17-SNAP29-VAMP8 complex assembly to control autophagy” [Cell Insight 3 (2024) 100147] “STING引导STX17-SNAP29-VAMP8复合物组装控制自噬”的勘误表[Cell Insight 3 (2024) 100147]

Cell insight

Pub Date : 2025-04-11 DOI: 10.1016/j.cellin.2025.100239

Xiaoyu Song , Yufeng Xi , Ming Dai , Tao Li , Shihao Du , Yuxin Zhu , Mengjie Li , Yunze Li , Siqi Liu , Xia Ding , Xuebiao Yao , Ying Lai , Xing Liu

引用次数: 0

Targeting PD-1 post-translational modifications for improving cancer immunotherapy 靶向PD-1翻译后修饰改善癌症免疫治疗

Cell insight

Pub Date : 2025-04-10 DOI: 10.1016/j.cellin.2025.100248

Jie Shi , Chuan He , Li Chen , Xixin Xing , Wenyi Wei , Jinfang Zhang

Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor that suppresses immune responses largely through its interaction with PD-L1. Tumors exploit this mechanism to evade immune surveillance, positioning immune checkpoint inhibitors targeting the PD-1/PD-L1 axis as groundbreaking advancements in cancer therapy. However, the overall effectiveness of these therapies is often constrained by an incomplete understanding of the underlying mechanisms. Recent research has uncovered the pivotal role of various post-translational modifications (PTMs) of PD-1, including ubiquitination, UFMylation, phosphorylation, palmitoylation, and glycosylation, in regulating its protein stability, localization, and protein-protein interactions. As much, dysregulation of these PTMs can drive PD-1-mediated immune evasion and contribute to therapeutic resistance. Notably, targeting PD-1 PTMs with small-molecule inhibitors or monoclonal antibodies (MAbs) has shown potential to bolster anti-tumor immunity in both pre-clinical mouse models and clinical trials. This review highlights recent findings on PD-1's PTMs and explores emerging therapeutic strategies aimed at modulating these modifications. By integrating these mechanistic insights, the development of combination cancer immunotherapies can be further rationally advanced, offering new avenues for more effective and durable treatments.

程序性细胞死亡蛋白1 （PD-1）是一种重要的免疫检查点受体，主要通过与PD-L1的相互作用抑制免疫反应。肿瘤利用这种机制逃避免疫监视，定位靶向PD-1/PD-L1轴的免疫检查点抑制剂是癌症治疗的突破性进展。然而，这些疗法的总体有效性往往受到对潜在机制的不完全理解的限制。最近的研究揭示了PD-1的各种翻译后修饰（PTMs），包括泛素化，ufmy化，磷酸化，棕榈酰化和糖基化，在调节其蛋白质稳定性，定位和蛋白质-蛋白质相互作用中的关键作用。同样，这些ptm的失调可以驱动pd -1介导的免疫逃避，并有助于治疗抵抗。值得注意的是，在临床前小鼠模型和临床试验中，用小分子抑制剂或单克隆抗体（mab）靶向PD-1 PTMs已显示出增强抗肿瘤免疫的潜力。本综述重点介绍了PD-1 ptm的最新发现，并探讨了旨在调节这些修饰的新兴治疗策略。通过整合这些机制的见解，癌症免疫联合疗法的发展可以进一步合理推进，为更有效和持久的治疗提供新的途径。

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引用次数: 0

Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting 肿瘤内HIF-1α调节一种病毒质配体的产生，导致宿主消瘦

Cell insight

Pub Date : 2025-04-08 DOI: 10.1016/j.cellin.2025.100247

Gen Xiao , Yingge Li , Yanhui Hu , Kai Tan , Mengyang Wang , Kerui Zhu , Mingkui San , Qian Cheng , Dilinigeer Tayier , Tingting Hu , Peixuan Dang , Jiaying Li , Chen Cheng , Norbert Perrimon , Zhiyong Yang , Wei Song

Tumor-host interactions play critical roles in cancer-associated cachexia. Previous studies have identified several cachectic proteins secreted by tumors that impair metabolic homeostasis in multiple organs, leading to host wasting. The molecular mechanisms by which malignant tumors regulate the production or secretion of these cachectic proteins, however, still remain largely unknown. In this study, we used different Drosophila cachexia models to investigate how malignant tumors regulate biosynthesis of ImpL2, a conserved cachectic protein that inhibits systemic insulin/IGF signaling and suppresses anabolism of host organs. Through bioinformatic and biochemical analysis, we found that hypoxia-inducible factor HIF-1α/Sima directly binds to the promoter region of ImpL2 gene for the first time, promoting its transcription in both tumors and non-tumor cells. Interestingly, expressing HphA to moderately suppress HIF-1α/Sima activity in adult yki^3SA gut tumors or larval scrib¹ Ras^V12 disc tumors sufficiently decreased ImpL2 expression and improved organ wasting, without affecting tumor growth. We further revealed conserved regulatory mechanisms conserved across species, as intratumor HIF-1α enhances the production of IGFBP-5, a mammalian homolog of fly ImpL2, contributing to organ wasting in both tumor-bearing mice and patients. Therefore, our study provides novel insights into the mechanisms by which tumors regulate production of cachectic ligands and the pathogenesis of cancer-induced cachexia.

肿瘤-宿主相互作用在癌症相关恶病质中起关键作用。先前的研究已经确定了肿瘤分泌的几种恶病质蛋白，它们破坏了多个器官的代谢稳态，导致宿主消瘦。然而，恶性肿瘤调节这些恶病质蛋白产生或分泌的分子机制在很大程度上仍然未知。在这项研究中，我们使用不同的果蝇恶病质模型来研究恶性肿瘤如何调节ImpL2的生物合成，ImpL2是一种保守的恶病质蛋白，可抑制全身胰岛素/IGF信号传导并抑制宿主器官的合成代谢。通过生物信息学和生化分析，我们首次发现缺氧诱导因子HIF-1α/Sima直接结合到ImpL2基因的启动子区域，促进其在肿瘤细胞和非肿瘤细胞中的转录。有趣的是，在成人yki3SA肠道肿瘤或幼虫scrib1 RasV12椎间盘肿瘤中，表达HphA可适度抑制HIF-1α/Sima活性，充分降低ImpL2表达并改善器官消耗，而不影响肿瘤生长。我们进一步揭示了跨物种保守的调控机制，如肿瘤内HIF-1α增强IGFBP-5的产生，IGFBP-5是苍蝇ImpL2的哺乳动物同源物，有助于荷瘤小鼠和患者的器官消耗。因此，我们的研究为肿瘤调节恶病质配体产生的机制和癌症诱导恶病质的发病机制提供了新的见解。

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引用次数: 0