Molecular Aspects of Medicine最新文献

Protein kinase D: Integrating cancer and metabolic disorders 蛋白激酶D：整合癌症和代谢紊乱

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-04-01 Epub Date: 2026-01-25 DOI: 10.1016/j.mam.2026.101446

A. Shemy , B. Sanchez , H. Mizuno , J. Van Lint , A. Voet

Obesity and type II diabetes mellitus (T2DM) are intricately linked to elevated cancer risk. Protein Kinase D (PKD) isoforms (PKD1, PKD2, and PKD3) have emerged as pivotal mediators at the centre of metabolic and oncogenic signalling. This review discusses isoform-specific roles of PKDs in the pathophysiology of both metabolic disorders and tumour progression. PKD1 exhibits a context-dependent dual role in cancer, acting as a tumour suppressor by reinforcing epithelial adhesion and restricting invasion in several carcinomas, yet exerting pro-tumorigenic effects in specific tissues such as the pancreas and skin. Metabolically, PKD1 supports insulin secretion in pancreatic β cells while promoting adipocyte lipogenesis and suppressing thermogenesis, mechanisms that contribute to systemic insulin resistance and may prime the tumour microenvironment. PKD2 promotes tumour progression through sustained hypoxia signalling, matrix remodelling, and immune evasion, driven by its regulation of HIF-1α, Snail, β-catenin, and PD-L1. PKD3 facilitates oncogenic proliferation and metabolic rewiring, particularly enhancing glycolysis via the p65/PFKFB3 axis and modulating insulin/glucagon signalling in hepatocytes. Obesity- or diabetes-related factors, such as diacylglycerol, leptin, and pro-inflammatory cytokines, enhance PKD signalling across tissues, reinforcing its role in connecting metabolic disorders to cancer. These findings highlight PKD isoforms as potential therapeutic targets, particularly in cancer settings where metabolic dysfunction plays a contributing role. While current PKD inhibitors lack isoform specificity, future therapeutic strategies focused on PKD2 and PKD3 modulation may offer selective control over invasion, immune evasion, and metabolic reprogramming in metabolically comorbid cancer patients.

肥胖和2型糖尿病（T2DM）与癌症风险升高有着复杂的联系。蛋白激酶D （PKD）异构体（PKD1， PKD2和PKD3）已成为代谢和致癌信号传导中心的关键介质。这篇综述讨论了pkd在代谢紊乱和肿瘤进展的病理生理中的亚型特异性作用。PKD1在癌症中表现出上下文依赖的双重作用，在几种癌症中作为肿瘤抑制因子，通过加强上皮黏附和限制侵袭，但在胰腺和皮肤等特定组织中发挥促肿瘤作用。在代谢方面，PKD1支持胰腺β细胞分泌胰岛素，同时促进脂肪细胞脂肪生成和抑制产热，这些机制有助于全身性胰岛素抵抗并可能启动肿瘤微环境。PKD2通过调控HIF-1α、Snail、β-catenin和PD-L1，通过持续缺氧信号传导、基质重塑和免疫逃避促进肿瘤进展。PKD3促进致癌增殖和代谢重组，特别是通过p65/PFKFB3轴增强糖酵解和调节肝细胞中的胰岛素/胰高血糖素信号传导。肥胖或糖尿病相关因素，如二酰基甘油、瘦素和促炎细胞因子，增强了PKD在组织中的信号传导，加强了它在代谢紊乱与癌症之间的联系。这些发现强调PKD异构体是潜在的治疗靶点，特别是在代谢功能障碍起作用的癌症环境中。虽然目前的PKD抑制剂缺乏同种异体的特异性，但未来的治疗策略关注于PKD2和PKD3调节，可能为代谢合并症癌症患者的侵袭、免疫逃避和代谢重编程提供选择性控制。

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引用次数: 0

Translational readthrough using TRIDs - Achievements and challenges for the treatment of inherited retinal disorders 使用TRIDs的翻译通读-遗传性视网膜疾病治疗的成就和挑战

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-04-01 Epub Date: 2026-01-29 DOI: 10.1016/j.mam.2026.101455

Kerstin Nagel-Wolfrum , Nicole Wenck , Mark Zorin

Pathogenic nonsense variants introduce premature termination codons (PTCs) into gene coding sequences, resulting in truncated, typically nonfunctional proteins. Translational readthrough has emerged as a promising therapeutic strategy for genetic diseases caused by nonsense variants. Small molecules, known as translational readthrough-inducing drugs (TRIDs), act as therapeutic agents, by allowing the translation machinery to suppress nonsense variants. TRIDs induce ribosomes to bypass aberrant stop codons favoring the incorporation of near-cognate amino acids at PTC sites. This restores the synthesis of full-length, potentially functional proteins. As TRIDs function on the mRNA level, they enable the expression of various heterogeneous isoforms of the target gene, and moreover the size of the gene is not relevant. This paves the way for the treatment of patients carrying PTCs in genes with many splice variants and in large genes. Although the efficacy of TRIDs varies across genes and PTCs, one TRID could potentially be applied for different disease-causing genes, making the strategy particularly attractive from an economic perspective for rare and ultra-rare disorders. Here we describe basic aspects of translational readthrough, TRIDs currently under investigation for the treatment of Inherited Retinal Disorders and discuss the current needs to improve translational readthrough therapy. Finally, we describe a “pipeline” to identify the best TRIDs for a specific gene/PTC, which could provide a customized readthrough approach for each patient with a PTC-caused disease.

致病性无义变异体将过早终止密码子（ptc）引入基因编码序列，导致截断，通常是无功能蛋白质。翻译通读已成为无义变异引起的遗传疾病的一种有前途的治疗策略。小分子，被称为翻译读透诱导药物（TRIDs），作为治疗剂，通过允许翻译机制抑制无意义的变异。TRIDs诱导核糖体绕过异常停止密码子，有利于在PTC位点结合近同源氨基酸。这恢复了全长的、可能具有功能的蛋白质的合成。由于TRIDs在mRNA水平上起作用，它们使靶基因的各种异质亚型得以表达，而且与基因的大小无关。这为治疗具有许多剪接变异体和大基因的ptc患者铺平了道路。尽管TRID的功效因基因和ptc而异，但一个TRID可能潜在地应用于不同的致病基因，从经济角度来看，这使得该策略对罕见和超罕见疾病特别有吸引力。在这里，我们描述了翻译通读的基本方面，TRIDs目前正在研究用于治疗遗传性视网膜疾病，并讨论了目前需要改进翻译通读治疗。最后，我们描述了一个“管道”来确定特定基因/PTC的最佳TRIDs，这可以为每个患有PTC引起的疾病的患者提供定制的通读方法。

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引用次数: 0

Decoding emerging viral sepsis: Molecular crosstalk, dysregulation, and precision strategies 解码新出现的病毒败血症：分子串扰、失调和精确策略。

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-02-01 Epub Date: 2026-01-06 DOI: 10.1016/j.mam.2025.101442

Bin Wang , Yujian Fu , Fang Duan , Sijun Pan , Yang Zheng

Emerging and re-emerging viral pathogens pose a major challenge to global public health systems. One of the most significant complications associated with these viruses is viral sepsis, a severe condition characterized by organ dysfunction resulting from an unregulated host response to a viral infection. The present review comprehensively describes the molecular mechanisms underlying viral sepsis induced by emerging and re-emerging viral pathogens, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), influenza virus, dengue virus (DENV), Ebola virus (EBOV), and human immunodeficiency virus (HIV). It discusses the complex molecular interactions between particular viral factors and host cellular pathways, highlighting significant dysregulations in various immune responses, metabolic reprogramming, and endothelial integrity that induce sepsis development. Furthermore, this review thoroughly addresses nascent precision strategies, including advanced diagnostics, targeted therapeutics, and immunomodulatory interventions, carefully tailored to distinct viral etiologies and host endotypes. By shedding light on the intricate molecular landscape of viral sepsis, this review aims to provide a robust framework for future mechanistic research and accelerate the development of effective, personalized interventions to combat this challenging complication.

新出现和再出现的病毒性病原体对全球公共卫生系统构成重大挑战。与这些病毒相关的最重要的并发症之一是病毒性败血症，这是一种以器官功能障碍为特征的严重疾病，是由宿主对病毒感染的不调节反应引起的。本文综述了新出现和再出现的病毒病原体，如严重急性呼吸综合征冠状病毒-2 （SARS-CoV-2）、流感病毒、登革热病毒（DENV）、埃博拉病毒（EBOV）和人类免疫缺陷病毒（HIV）诱导的病毒性败血症的分子机制。它讨论了特定病毒因子和宿主细胞通路之间复杂的分子相互作用，强调了各种免疫反应、代谢重编程和内皮完整性中诱导败血症发展的显著失调。此外，这篇综述彻底解决了新兴的精确策略，包括先进的诊断，靶向治疗和免疫调节干预，精心定制不同的病毒病因和宿主内型。通过揭示病毒败血症复杂的分子景观，本综述旨在为未来的机制研究提供一个强大的框架，并加速开发有效的、个性化的干预措施来对抗这一具有挑战性的并发症。

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引用次数: 0

Vav3, a potential diagnostic and prognostic marker of diabetes, regulates glycolipid metabolism Vav3调节糖脂代谢，是糖尿病的潜在诊断和预后标志物

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-02-01 Epub Date: 2025-12-06 DOI: 10.1016/j.mam.2025.101429

Chenmoji Wang , Mengjuan Wei , Yu Wang , Huimin He , Chengcheng Huang , Deshan Liu , Yun Qiao

Vav3 can significantly affect the energy metabolism of cancer cells by changing the cytoskeletal structure, involving the mechanism of disulfidptosis, while affecting the function of glucose transporters, regulating cellular glucose and lipid metabolism. This provides an interesting research idea for the exploration of the pathogenesis of diabetes and the targeted regulation of glucose and lipid metabolism. Vav3 protein not only participates in β-cell damage in type 1 diabetes but also extensively regulates insulin release and glucose metabolism in type 2 diabetes. Vav3 proteins directly or indirectly regulate energy metabolism in multiple organs such as the pancreas, skeletal muscle, and liver and are involved in some pathological processes such as oxidative stress, inflammation, and autophagy. These pathological processes are not only regulated by the Vav3 protein, but also in turn affect the expression level of the Vav3 gene, exacerbating the progression of diabetic complications such as diabetic osteoporosis and even diabetes-related cancers. Therefore, the regulated molecular patterns of Vav3 in the microenvironment of diabetic glucose and lipid metabolism disorder provide a new direction for further exploration of diabetic energy metabolism mechanism. Vav3 may be a potential diagnostic and prognostic marker of diabetes. Meanwhile, as an oncogene, it also builds a bridge and increases the depth of the connection between diabetes and cancer.

Vav3可以通过改变细胞骨架结构，参与二硫垂的机制，显著影响癌细胞的能量代谢，同时影响葡萄糖转运体的功能，调节细胞糖脂代谢。这为探索糖尿病的发病机制和糖脂代谢的靶向调控提供了一个有趣的研究思路。Vav3蛋白不仅参与1型糖尿病β细胞损伤，还广泛调节2型糖尿病胰岛素释放和葡萄糖代谢。Vav3蛋白直接或间接调节胰腺、骨骼肌、肝脏等多个器官的能量代谢，参与氧化应激、炎症、自噬等病理过程。这些病理过程不仅受Vav3蛋白调控，还会反过来影响Vav3基因的表达水平，加剧糖尿病并发症如糖尿病性骨质疏松甚至糖尿病相关癌症的进展。因此，Vav3在糖尿病糖脂代谢紊乱微环境中的调控分子模式，为进一步探索糖尿病能量代谢机制提供了新的方向。Vav3可能是糖尿病的潜在诊断和预后指标。同时，作为致癌基因，它也搭建了一座桥梁，增加了糖尿病和癌症之间的联系深度。

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引用次数: 0

Targeting emerging viruses with phage display-driven engineered antibodies: Bridging molecular design and clinical application 用噬菌体显示驱动的工程抗体靶向新兴病毒：桥接分子设计和临床应用。

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-02-01 Epub Date: 2025-12-14 DOI: 10.1016/j.mam.2025.101441

Ah Hyun Cho , Su Yeon Cho , Soohyun Kim , Sukmook Lee

Phage display (PD) is a powerful platform that accelerates the discovery and engineering of therapeutic antibodies across diverse diseases, including emerging and re-emerging viral infections. The COVID-19 pandemic highlighted the urgency for rapid and adaptable antibody development against highly mutable pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PD technology enables the rapid and high-throughput identification, optimization, and efficient reformatting of virus-neutralizing antibodies, yielding fully PD-derived antibodies and reformatted derivatives from PD fragments without requiring convalescent samples or animal immunization. This approach supports a proactive and scalable strategy for pandemic preparedness. This review provides a comprehensive overview of PD-derived therapeutic antibodies targeting infectious diseases, focusing on approved agents and candidates in clinical or preclinical development for SARS-CoV-2. We highlight recent case studies, including our own, showing the successful application of PD in generating potent neutralizing and multispecific antibody formats. These offer functional advantages such as enhanced breadth and affinity while also serving as versatile molecular tools for elucidating viral pathogenesis and immune evasion mechanisms. Despite PD's technological strengths, the clinical advancement of PD-derived candidates has been influenced by external circumstances associated with the evolving pandemic landscape, highlighting the need to strategically leverage PD's strengths to accelerate translational outcomes in future outbreaks. This review offers a well-rounded viewpoint on PD, outlining its applications, addressing its challenges, and incorporating emerging innovations into PD workflows. These advances position PD-derived candidates as a strategic, versatile, and rapid-response platform that bridges molecular insights with clinical translation, offering a robust framework for addressing current and future infectious disease challenges.

噬菌体展示（Phage display， PD）是一个强大的平台，可以加速发现和设计针对各种疾病的治疗性抗体，包括新发和再发病毒感染。COVID-19大流行突出表明，迫切需要针对高度可变病原体，包括严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)，快速开发适应性强的抗体。PD技术能够快速、高通量地鉴定、优化和有效地重组病毒中和抗体，产生完全PD衍生的抗体和PD片段的重组衍生物，而不需要恢复期样本或动物免疫。这种方法支持积极主动和可扩展的大流行防范战略。本文综述了针对传染病的pd衍生治疗性抗体的全面概述，重点介绍了已批准的SARS-CoV-2临床或临床前开发的药物和候选药物。我们强调了最近的案例研究，包括我们自己的，显示了PD在产生有效中和和多特异性抗体格式中的成功应用。这些具有增强的广度和亲和力等功能优势，同时也可作为阐明病毒发病机制和免疫逃避机制的多功能分子工具。尽管PD具有技术优势，但PD衍生候选药物的临床进展受到与不断演变的大流行形势相关的外部环境的影响，这突出了在未来疫情中战略性地利用PD优势加速转化结果的必要性。这篇综述提供了一个关于PD的全面观点，概述了它的应用，解决了它的挑战，并将新兴的创新融入到PD工作流程中。这些进展将pd衍生候选药物定位为一个战略性的，多功能的，快速反应的平台，将分子见解与临床翻译联系起来，为解决当前和未来的传染病挑战提供了一个强大的框架。

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引用次数: 0

Serine metabolism in the central nervous system: advances and challenges on a conditionally essential amino acid 中枢神经系统丝氨酸代谢：条件必需氨基酸的研究进展与挑战

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-02-01 Epub Date: 2025-12-18 DOI: 10.1016/j.mam.2025.101438

Natasa Kustrimovic, Valentina Rabattoni, Daniele Riva, Zoraide Motta, Silvia Sacchi, Loredano Pollegioni

Once considered a non-essential amino acid, L-serine (L-Ser) is now recognized as conditionally essential in the brain, orchestrating a complex network of metabolic and signalling pathways. L-Ser provides carbon units to the one-carbon metabolism, supporting nucleotide synthesis and methylation reactions, and serves as a precursor for phosphatidylserine and sphingolipids. L-Ser plays crucial roles in glutathione and heme metabolism and interfaces with mitochondrial one-carbon pathways, thereby linking it to energy production, redox homeostasis, and epigenetic regulation. Its conversion into glycine and D-serine further supports neurotransmission, synaptic plasticity, and cognitive functions. Throughout the lifespan, L-Ser and its derivatives contribute to maintaining neuronal and glial homeostasis. However, fundamental questions remain regarding how L-Ser biosynthesis, transport, and compartmentalization are coordinated in the intact brain and how their dysregulation contributes to disease. Current knowledge largely derives from cancer biology or in vitro models, and translating these insights to the central nervous system poses major challenges. The lack of specific tools to monitor L-Ser flux in vivo, limited understanding of post-translational regulation of key enzymes and incomplete mapping of transport mechanisms across the blood–brain barrier still hampers deeper mechanistic and translational insight. This review compiles the most recent evidence, emphasizing the translational relevance of L-Ser-based interventions and underscoring the urgent need for systematic clinical trials to fully evaluate its therapeutic potential.

l -丝氨酸（L-Ser）曾经被认为是一种非必需氨基酸，现在被认为是大脑中有条件必需的，它协调了一个复杂的代谢和信号通路网络。l -丝氨酸为单碳代谢提供碳单位，支持核苷酸合成和甲基化反应，并作为磷脂酰丝氨酸和鞘脂的前体。l -丝氨酸在谷胱甘肽和血红素代谢中起着至关重要的作用，并与线粒体单碳途径相连接，从而将其与能量产生、氧化还原稳态和表观遗传调控联系起来。其转化为甘氨酸和d -丝氨酸进一步支持神经传递、突触可塑性和认知功能。在整个生命周期中，L-Ser及其衍生物有助于维持神经元和神经胶质的稳态。然而，关于l -丝氨酸的生物合成、转运和区区化如何在完整的大脑中协调以及它们的失调如何导致疾病的基本问题仍然存在。目前的知识主要来自癌症生物学或体外模型，将这些见解转化为中枢神经系统提出了重大挑战。缺乏特定的工具来监测体内l -丝氨酸通量，对关键酶的翻译后调控的了解有限，以及对血脑屏障运输机制的不完整定位，仍然阻碍了更深的机制和翻译认识。本综述汇编了最新的证据，强调了基于l - ser的干预措施的转化相关性，并强调了系统临床试验以充分评估其治疗潜力的迫切需要。

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引用次数: 0

Zinc bioavailability in alcohol-associated liver disease: Mechanisms and therapeutic implications 锌在酒精相关肝病中的生物利用度：机制和治疗意义

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-02-01 Epub Date: 2025-12-05 DOI: 10.1016/j.mam.2025.101430

Yinrui Feng , Qingshan Yang , Dan Wang , Qing Chu , Zhenfang Zhou , Yundi Liu , Kefei Chen , Volker M. Lauschke

Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. Hepatic zinc deficiency is a consistent feature of ALD, yet the therapeutic efficacy of zinc supplementation remains limited. This review examines the causal role of zinc deficiency in ALD pathogenesis and highlights low zinc bioavailability as a key determinant in disease progression. We discuss the regulatory roles of zinc transporters (ZIPs, ZnTs), metallothioneins, and redox-sensitive ligands in maintaining zinc homeostasis. Furthermore, we introduce zinc-glutathione (ZnGSH) as a novel zinc formulation that improves intestinal absorption and hepatic utilization of zinc. Unlike conventional zinc salts, ZnGSH overcomes multiple physiological barriers to zinc uptake in ALD, offering enhanced bioavailability in both gut and liver tissues. Thus, supplementation with bioavailable zinc may present a promising therapeutic strategy for ALD and, potentially, also other chronic liver diseases.

酒精相关性肝病（ALD）是世界范围内肝脏相关发病率和死亡率的主要原因。肝性锌缺乏是ALD的一贯特征，但锌补充剂的治疗效果仍然有限。这篇综述探讨了锌缺乏在ALD发病机制中的因果作用，并强调低锌的生物利用度是疾病进展的关键决定因素。我们讨论了锌转运蛋白（zip, znt），金属硫蛋白和氧化还原敏感配体在维持锌稳态中的调节作用。此外，我们还介绍了锌谷胱甘肽（ZnGSH）作为一种新的锌制剂，可以改善锌的肠道吸收和肝脏利用。与传统锌盐不同，ZnGSH克服了ALD中锌摄取的多种生理障碍，提高了肠道和肝脏组织的生物利用度。因此，补充生物可利用锌可能是一种有希望的治疗ALD的策略，也可能是其他慢性肝脏疾病的治疗策略。

引用次数: 0

Elimination of cervical cancer: the impact of HPV vaccination, primary HPV screening, and expanded access to cancer treatment services 消除宫颈癌：人乳头瘤病毒疫苗接种、原发性人乳头瘤病毒筛查和扩大获得癌症治疗服务的影响

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-02-01 Epub Date: 2025-12-18 DOI: 10.1016/j.mam.2025.101423

Michaela T. Hall , Amelia Hyatt , Megan A. Smith , Julie Torode , Telma Costa , Diep Thi Ngoc Nguyen , Timothy Balshaw , Paul Grogan , Kim Sweeny , Carmen Auste , Claire Nightingale , Mei Ling Yap , David Hawkes , Andrew Vallely , Monica Molano , Sanchia Aranda , Edward Trimble , Lisa J. Whop , Marion Saville , Deborah Bateson , Karen Canfell

In 2022, over 662,000 cases of cervical cancer were diagnosed globally and over 348,000 deaths occurred from the disease, with almost 94 % of these deaths occurring in low- and lower-middle income countries (LMIC). Effective intervention strategies, including prophylactic Human Papillomavirus (HPV) vaccination for adolescents and primary HPV screening for adult women, are highly effective and cost-effective methods of prevention; however, delivering population-wide access to these prevention methods has been challenging, particularly in LMIC. The World Health Organization (WHO) has launched a global strategy for the elimination of cervical cancer as a public health problem through the scale-up of HPV vaccination, cervical screening and precancer and cancer treatment services. In this review article, we present the rationale, history and strategy behind the global cervical cancer elimination efforts, including the evidence underpinning the WHO's three pillars of cervical cancer control, and essential considerations for implementation, sustainable financing, and health systems implications. Many countries and regions are currently formulating frameworks to achieve cervical cancer elimination within their setting. Here, we consider implementation challenges for both LMIC, and high-income countries (HIC), calling upon the experiences of implementation guided by the WHO Western Pacific Region and Australian frameworks as exemplar settings.

2022年，全球诊断出66.2万多例宫颈癌病例，34.8万多人死于该疾病，其中近94%的死亡发生在低收入和中低收入国家。有效的干预战略，包括青少年预防性人乳头瘤病毒（HPV）疫苗接种和成年妇女原发性HPV筛查，是非常有效和具有成本效益的预防方法；然而，使所有人口都能获得这些预防方法一直具有挑战性，特别是在中低收入国家。世界卫生组织（世卫组织）发起了一项全球战略，通过扩大人乳头瘤病毒疫苗接种、子宫颈筛查以及癌前病变和癌症治疗服务，消除作为公共卫生问题的宫颈癌。在这篇综述文章中，我们介绍了全球消除宫颈癌努力背后的基本原理、历史和战略，包括支持世卫组织宫颈癌控制三大支柱的证据，以及实施、可持续融资和卫生系统影响的基本考虑因素。许多国家和地区目前正在制定框架，以实现在其环境中消除宫颈癌。在此，我们考虑了中低收入国家和高收入国家（HIC）面临的实施挑战，呼吁以世卫组织西太平洋区域和澳大利亚框架为指导的实施经验作为范例。

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引用次数: 0

Emerging viroporins, RBP dynamics, and skeletal remodeling: Targeting liquid-liquid phase separation for dual antiviral and bone-protective therapies 新出现的病毒孔蛋白、RBP动力学和骨骼重塑：针对液-液相分离的双重抗病毒和骨保护治疗

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-02-01 Epub Date: 2026-01-07 DOI: 10.1016/j.mam.2026.101445

Ying Huai , Xue Wang , Jingchuan Yan, Shuang Li, Haien Zhao, Bo Liao

Emerging and re-emerging viral pathogens, particularly Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Chikungunya virus (CHIKV), are currently recognized as a significant global public health issue, commonly leading to devastating persistent complications including inflammatory bone disorders and long-lasting arthralgia. Although systemic cytokine storm has been reported as a significant factor, the particular intracellular processes through which these viruses affect bone homeostasis are still poorly understood. Recent studies underscore Liquid-Liquid Phase Separation (LLPS) and RNA-Binding Proteins (RBPs) as significant regulatory mechanisms manipulated by these viruses. Particularly, the SARS-CoV-2 Nucleocapsid protein exploits its intrinsically disordered regions to promote LLPS, facilitating viral assembly by the active inhibition of a key host anti-viral mechanism, known as host Stress Granules. Studies suggest that this biophysical interaction can affect the stability of the HuR RBD, impairing the nuclear β-catenin localization and then Wnt-mediated osteogenesis. Despite increasing recognition of post-viral musculoskeletal complications, the mechanistic links between viral persistence, host RBP dysfunction, and impaired bone remodeling remain poorly defined. This review incorporates viral LLPS, stress granule impairment, and osteogenic signaling into a unified ‘Two-Hit’ pathogenic framework. It also addresses key knowledge gaps, including the lack of longitudinal clinical validation and in vivo evidence associating LLPS impairment to skeletal disorders. Interestingly, this framework represents translational opportunities for dual-action therapeutic strategies that simultaneously impair viral condensates and recover host RBP-associated osteogenic signaling. Targeting the virus–host phase interface can introduce a potential approach not only for antiviral therapies but also for inhibiting post-viral musculoskeletal complications.

新出现和再出现的病毒性病原体，特别是2型严重急性呼吸综合征冠状病毒（SARS-CoV-2）、寨卡病毒（ZIKV）和基孔肯雅病毒（CHIKV），目前被认为是一个重大的全球公共卫生问题，通常会导致破坏性的持续性并发症，包括炎症性骨疾病和长期关节痛。尽管系统性细胞因子风暴已被报道为一个重要因素，但这些病毒影响骨稳态的特定细胞内过程仍然知之甚少。最近的研究强调液-液相分离（LLPS）和rna结合蛋白（rbp）是这些病毒操纵的重要调控机制。特别是，SARS-CoV-2核衣壳蛋白利用其内在无序区域促进LLPS，通过主动抑制宿主抗病毒机制（称为宿主应激颗粒）促进病毒组装。研究表明，这种生物物理相互作用可以影响HuR RBD的稳定性，损害细胞核β-连环蛋白的定位，进而破坏wnt介导的成骨。尽管越来越多的人认识到病毒后肌肉骨骼并发症，但病毒持续存在、宿主RBP功能障碍和骨重塑受损之间的机制联系仍然不明确。本综述将病毒LLPS、应激颗粒损伤和成骨信号纳入统一的“双打击”致病框架。它还解决了关键的知识空白，包括缺乏纵向临床验证和体内证据将LLPS损伤与骨骼疾病联系起来。有趣的是，这个框架代表了双重作用治疗策略的转化机会，同时损害病毒凝聚体和恢复宿主rbp相关的成骨信号。靶向病毒-宿主期界面不仅可以引入抗病毒治疗的潜在方法，还可以抑制病毒后肌肉骨骼并发症。

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引用次数: 0

cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities cGAS-STING信号在阿尔茨海默病中的作用：小胶质机制和治疗机会

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine

Pub Date : 2026-02-01 Epub Date: 2026-01-01 DOI: 10.1016/j.mam.2025.101444

Faaizah Fazal , Nawab John Dar , Shakir Ahamad , Sameera Khan , Nargis Bano , Supriyo Saha , Aamir Nazir , Shahnawaz Ali Bhat

Alzheimer's disease (AD) is increasingly recognized as a neuroinflammatory disorder driven by microglial dysfunction. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a critical role in neuroinflammation and has been strongly implicated in the pathology of AD. Chronic activation of cGAS-STING contributes to neurodegeneration by driving persistent type I interferon release and excessive pro-inflammatory cytokine production. However, the pathway exhibits context-dependent effects. Transient activation promotes antiviral defense, autophagy, and cellular quality control in the central nervous system. Sustained engagement exacerbates neuroinflammation and synaptic loss. Preclinical studies demonstrate that pharmacological inhibitors (such as NR, TSG, H-151, TDI-6750, TDI-8246) mitigate amyloid beta and tau pathology, attenuate microglial reactivity, and enhance cognitive outcomes. Yet, its essential physiological roles, including antimicrobial immunity and autophagy regulation, pose challenges for therapeutic targeting. This potentially disrupts neuroimmune homeostasis. In this review, we highlight the role of cGAS-STING in AD and explore its potential as a therapeutic target using small-molecule drug candidates. Despite these promising findings, challenges remain, including optimizing blood-brain barrier (BBB) penetration, ensuring immune specificity, and addressing long-term safety concerns. Due to these challenges, no cGAS-STING inhibitors have entered clinical trials for AD. However, the future of AD treatment may involve modulation of neuroinflammatory pathways, with cGAS-STING inhibitors playing a central role in reshaping neuroimmune homeostasis.

阿尔茨海默病（AD）越来越被认为是一种由小胶质细胞功能障碍驱动的神经炎性疾病。干扰素基因环GMP-AMP合成酶刺激因子（cGAS-STING）通路在神经炎症中起关键作用，并与AD的病理密切相关。cGAS-STING的慢性激活通过驱动持续的I型干扰素释放和过度的促炎细胞因子产生，有助于神经退行性变。然而，该通路表现出环境依赖效应。短暂激活促进中枢神经系统的抗病毒防御、自噬和细胞质量控制。持续接触会加剧神经炎症和突触丧失。临床前研究表明，药物抑制剂（如NR、TSG、H-151、TDI-6750、TDI-8246）可减轻淀粉样蛋白和tau蛋白的病理，减弱小胶质细胞的反应性，并增强认知结果。然而，其重要的生理作用，包括抗微生物免疫和自噬调节，对治疗靶向提出了挑战。这可能会破坏神经免疫稳态。在这篇综述中，我们强调了cGAS-STING在AD中的作用，并探讨了其作为小分子候选药物治疗靶点的潜力。尽管有这些有希望的发现，挑战仍然存在，包括优化血脑屏障（BBB）渗透，确保免疫特异性，以及解决长期安全问题。由于这些挑战，没有cGAS-STING抑制剂进入阿尔茨海默病的临床试验。然而，AD治疗的未来可能涉及神经炎症通路的调节，cGAS-STING抑制剂在重塑神经免疫稳态中发挥核心作用。

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