Molecular Aspects of Medicine最新文献

{"title":"Protein kinase D: Integrating cancer and metabolic disorders","authors":"A. Shemy ,&nbsp;B. Sanchez ,&nbsp;H. Mizuno ,&nbsp;J. Van Lint ,&nbsp;A. Voet","doi":"10.1016/j.mam.2026.101446","DOIUrl":"10.1016/j.mam.2026.101446","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"108 ","pages":"Article 101446"},"PeriodicalIF":10.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational readthrough using TRIDs - Achievements and challenges for the treatment of inherited retinal disorders","authors":"Kerstin Nagel-Wolfrum ,&nbsp;Nicole Wenck ,&nbsp;Mark Zorin","doi":"10.1016/j.mam.2026.101455","DOIUrl":"10.1016/j.mam.2026.101455","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"108 ","pages":"Article 101455"},"PeriodicalIF":10.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding emerging viral sepsis: Molecular crosstalk, dysregulation, and precision strategies","authors":"Bin Wang ,&nbsp;Yujian Fu ,&nbsp;Fang Duan ,&nbsp;Sijun Pan ,&nbsp;Yang Zheng","doi":"10.1016/j.mam.2025.101442","DOIUrl":"10.1016/j.mam.2025.101442","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101442"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vav3, a potential diagnostic and prognostic marker of diabetes, regulates glycolipid metabolism","authors":"Chenmoji Wang ,&nbsp;Mengjuan Wei ,&nbsp;Yu Wang ,&nbsp;Huimin He ,&nbsp;Chengcheng Huang ,&nbsp;Deshan Liu ,&nbsp;Yun Qiao","doi":"10.1016/j.mam.2025.101429","DOIUrl":"10.1016/j.mam.2025.101429","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101429"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145685645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting emerging viruses with phage display-driven engineered antibodies: Bridging molecular design and clinical application","authors":"Ah Hyun Cho ,&nbsp;Su Yeon Cho ,&nbsp;Soohyun Kim ,&nbsp;Sukmook Lee","doi":"10.1016/j.mam.2025.101441","DOIUrl":"10.1016/j.mam.2025.101441","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101441"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serine metabolism in the central nervous system: advances and challenges on a conditionally essential amino acid","authors":"Natasa Kustrimovic,&nbsp;Valentina Rabattoni,&nbsp;Daniele Riva,&nbsp;Zoraide Motta,&nbsp;Silvia Sacchi,&nbsp;Loredano Pollegioni","doi":"10.1016/j.mam.2025.101438","DOIUrl":"10.1016/j.mam.2025.101438","url":null,"abstract":"<div><div>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 <em>in vitro</em> models, and translating these insights to the central nervous system poses major challenges. The lack of specific tools to monitor L-Ser flux <em>in vivo</em>, 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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101438"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc bioavailability in alcohol-associated liver disease: Mechanisms and therapeutic implications","authors":"Yinrui Feng ,&nbsp;Qingshan Yang ,&nbsp;Dan Wang ,&nbsp;Qing Chu ,&nbsp;Zhenfang Zhou ,&nbsp;Yundi Liu ,&nbsp;Kefei Chen ,&nbsp;Volker M. Lauschke","doi":"10.1016/j.mam.2025.101430","DOIUrl":"10.1016/j.mam.2025.101430","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101430"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elimination of cervical cancer: the impact of HPV vaccination, primary HPV screening, and expanded access to cancer treatment services","authors":"Michaela T. Hall ,&nbsp;Amelia Hyatt ,&nbsp;Megan A. Smith ,&nbsp;Julie Torode ,&nbsp;Telma Costa ,&nbsp;Diep Thi Ngoc Nguyen ,&nbsp;Timothy Balshaw ,&nbsp;Paul Grogan ,&nbsp;Kim Sweeny ,&nbsp;Carmen Auste ,&nbsp;Claire Nightingale ,&nbsp;Mei Ling Yap ,&nbsp;David Hawkes ,&nbsp;Andrew Vallely ,&nbsp;Monica Molano ,&nbsp;Sanchia Aranda ,&nbsp;Edward Trimble ,&nbsp;Lisa J. Whop ,&nbsp;Marion Saville ,&nbsp;Deborah Bateson ,&nbsp;Karen Canfell","doi":"10.1016/j.mam.2025.101423","DOIUrl":"10.1016/j.mam.2025.101423","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101423"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging viroporins, RBP dynamics, and skeletal remodeling: Targeting liquid-liquid phase separation for dual antiviral and bone-protective therapies","authors":"Ying Huai ,&nbsp;Xue Wang ,&nbsp;Jingchuan Yan,&nbsp;Shuang Li,&nbsp;Haien Zhao,&nbsp;Bo Liao","doi":"10.1016/j.mam.2026.101445","DOIUrl":"10.1016/j.mam.2026.101445","url":null,"abstract":"<div><div>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 <em>β</em>-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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101445"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities","authors":"Faaizah Fazal ,&nbsp;Nawab John Dar ,&nbsp;Shakir Ahamad ,&nbsp;Sameera Khan ,&nbsp;Nargis Bano ,&nbsp;Supriyo Saha ,&nbsp;Aamir Nazir ,&nbsp;Shahnawaz Ali Bhat","doi":"10.1016/j.mam.2025.101444","DOIUrl":"10.1016/j.mam.2025.101444","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101444"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}