Molecular biomedicine最新文献

{"title":"The ubiquitin-proteasome system and proteostasis in the cochlea and sensorineural hearing disorders.","authors":"Yiming Zhong, Bing Kong, Jinju Xu, Weiyi Huang, Yi Pan, Yuenan Liu, Mingliang Xiang, Bin Ye, Yilin Shen","doi":"10.1186/s43556-026-00616-z","DOIUrl":"10.1186/s43556-026-00616-z","url":null,"abstract":"<p><p>The ubiquitin-proteasome system (UPS) is the major machinery for intracellular protein degradation, playing an indispensable role in maintaining proteostasis across all tissues. Sensorineural hearing loss affects billions of people worldwide and is characterized by the irreversible degeneration of cochlear hair cells and spiral ganglion neurons. However, effective treatments remain unavailable. Although UPS dysfunction has been increasingly recognized in aging and neurodegenerative diseases, its specific contributions to cochlear development, homeostasis, and hearing disorders have received relatively limited attention. This review systematically summarizes the roles of UPS-mediated proteostasis in the auditory system. Major UPS related components including E1/E2/E3 ubiquitin ligases, deubiquitinating enzymes and proteasome subunits were discussed in this review. A comprehensive summary of the importance of UPS in cochlear development and the maintenance of inner ear auditory function has been made. Various UPS molecules and their potential pathogenic mechanisms or related signaling pathways are summarized in different types of hearing loss, including congenital hearing loss, age-related hearing loss, noise-induced hearing loss, and drug-related hearing loss. This review first highlights the tissue-specific functional divergence of UPS among cochlear structures. It also proposes the UPS as a central regulatory hub linking multiple pathological pathways in hearing loss including mitophagy, autophagy, oxidative stress, DNA damage repair, endoplasmic reticulum (ER) associated degradation, and NF-κB mediated inflammation. Finally, the emerging therapeutic strategies that target UPS components to restore cochlear proteostasis and hearing loss are discussed. These insights lay a solid foundation for developing UPS-targeted interventions for sensorineural hearing loss, in order to achieve precise treatments according to cochlear cell-specific ubiquitinomics in the future.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanotransduction through oxidative stress upregulates circLyst to drive vascular remodeling in hypertensive humans and rodents.","authors":"Juanjuan Tan, Weiyi Hu, Li Shen, Biyang Luo, Huajin Liu, Feng Li, Hui Qin, Yuanwang Yu, Haifang Wang, Jing Dong, Qi Zhang, Hong Zhang, Fan Lv, Yingxin Qi, Kai Wang, Yi Yang, Zhiqiang Yan, Kai Huang","doi":"10.1186/s43556-026-00593-3","DOIUrl":"10.1186/s43556-026-00593-3","url":null,"abstract":"<p><p>Aberrant cyclic stretch serves as a critical driver of vascular remodeling in hypertension, yet the underlying molecular mechanisms remain largely unknown. Here, we studied the role of a novel circRNA, termed circ_2465 (circLyst), in vascular remodeling in both human and rodent samples under high cyclic stretch. Next-generation sequencing data revealed that 165 circRNAs were differentially expressed in the thoracic aortas of spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto rats (WKYs), of which 60 circRNAs were significantly upregulated while 105 circRNAs were significantly downregulated. CircLyst, verified as a novel circRNA by ribonuclease R (RNase R) digestion and Actinomycin D assays, was induced in the thoracic aortas of SHRs and stably located in the cytoplasm as detected by fluorescence in situ hybridization (FISH). This elevation was confirmed in hypertensive patients and was recapitulated in vascular smooth muscle cells (VSMCs) exposed to high cyclic stretch in vitro. Mechanistically, oxidative stress, mediated by NADPH oxidases NOX1 and NOX4, induced circLyst expression. CircLyst then functioned as a sponge for miR-298-5p, derepressing its target gene Col23a1, thereby promoting VSMC proliferation and migration-key events in vascular remodeling. Importantly, both systemic and VSMC-specific targeting of circLyst attenuated pathological remodeling and blunted hypertension in animal models. Collectively, our findings establish the oxidative-stress-driven circLyst/miR-298-5p/Col23a1 axis as a critical regulator of vascular remodeling and highlight circLyst as a potential therapeutic target for hypertensive vascular disease.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CUE domain-containing 2 promotes diffuse large B-cell lymphoma progression via PP2A-B55β degradation and shapes macrophage-mediated immune responses.","authors":"Li-Jie Zeng, Wei-Xiang Lu, Yuan-Zheng Liang, Jing Yang, Jin-Yan Zhu, Liang Wang","doi":"10.1186/s43556-026-00626-x","DOIUrl":"10.1186/s43556-026-00626-x","url":null,"abstract":"<p><p>CUE domain-containing 2 (CUEDC2) regulates ubiquitin-mediated protein turnover, cell-cycle progression, and inflammatory signaling, but its role in diffuse large B-cell lymphoma (DLBCL) remains unclear. DLBCL is the most common aggressive non-Hodgkin lymphoma, and a substantial proportion of patients develop relapsed or refractory disease. Here, by integrating clinical bioinformatics, immunohistochemistry, and functional studies in DLBCL cell lines, we demonstrate that CUEDC2 is overexpressed in DLBCL and is associated with advanced disease stage and poor prognosis. Mechanistically, proteomic and ubiquitination analyses revealed that CUEDC2 interacts with the protein phosphatase 2A (PP2A) regulatory subunit B55 and promotes its ubiquitination-associated proteasomal degradation, accompanied by activation of NF-κB and mTOR signaling. Rescue studies support the role of PP2A-B55 as a downstream effector contributing to CUEDC2-associated proliferation and chemoresistance, and isoform-specific experiments identify PP2A-B55β as a preferentially regulated isoform. In addition, CUEDC2 knockdown in macrophages promoted M1-like polarization, enhanced phagocytosis, and supported CD8⁺ T cell activation and lymphoma cell apoptosis in vitro, without a detectable change in PP2A-B55 protein abundance. These immune effects were accompanied by changes in cellular metabolism and histone lactylation, although their causal relationships remain unresolved. Together, these findings support a tumor cell-intrinsic CUEDC2-PP2A-B55β-NF-κB/mTOR axis in DLBCL and suggest a potentially distinct immunomodulatory role for CUEDC2. Further mechanistic studies and in vivo validation are required to establish its therapeutic potential.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppressor with morphogenetic effect on genitalia 7 (SMG7) drives hepatocellular carcinoma progression through context-dependent nonsense-mediated decay (NMD) dysregulation.","authors":"Betsaida Ojeda-Pérez, Víctor J Fernández-Ramírez, María I Pozo-Relaño, Belén Gracia-Herencia, Izabela Hawro, Jose Córdoba-Chacón, Raul M Luque, Manuel L Rodriguez-Peralvarez, Juan L López-Cánovas, Manuel D Gahete","doi":"10.1186/s43556-026-00577-3","DOIUrl":"10.1186/s43556-026-00577-3","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major risk factor for hepatocellular carcinoma (HCC), yet the molecular mechanisms linking metabolic stress to tumor progression remain poorly defined. RNA surveillance pathways, including nonsense-mediated decay (NMD), may represent a relevant but unexplored regulatory layer in this context. In this study, we analyzed the expression of NMD components across multiple human HCC and MASLD cohorts, identifying suppressor with morphogenetic effect on genitalia 7 (SMG7) as a key regulator of NMD associated with HCC progression. In vitro functional assays, NMD target expression, transcriptomic profiling, and weighted gene co-expression network analysis (WGCNA) were used to identify downstream pathways and mediators. More than 40% of NMD components were dysregulated in HCC. Among them, SMG7 was consistently upregulated across HCC and MASLD cohorts, induced by lipotoxic stress, and identified as a hub gene in HCC transcriptional networks. SMG7 overexpression promoted proliferation, migration, and clonogenicity, whereas its silencing reduced tumor aggressiveness in a context-dependent manner inversely associated with UPF1 levels. Combined depletion of SMG7 and UPF1 suppressed aggressive traits in vitro and limited tumor growth in vivo. Transcriptomic and network analyses identified Z-DNA-binding protein 1 (ZBP1) as a downstream mediator of SMG7 dysregulation in SNU-387 HCC cells, a finding further supported by functional rescue experiments. These results identify the SMG7-ZBP1 axis as a metabolic stress-responsive pathway linking NMD dysfunction to liver tumor progression and highlight NMD modulation as a therapeutic strategy to restrain tumor aggressiveness while enhancing tumor immunogenicity.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregnancy-related disorders: molecular mechanisms and management.","authors":"Chehao Lee, Chan Zhu, Yang Li, Jiao Yang, Xuan Zhang, Wen Jiang, Deying Mou, Huafeng Li, Qian Hu","doi":"10.1186/s43556-026-00566-6","DOIUrl":"10.1186/s43556-026-00566-6","url":null,"abstract":"<p><p>Pregnancy-related disorders (PRDs), including preeclampsia (PE), gestational diabetes mellitus (GDM), hyperemesis gravidarum (HG), and intrahepatic cholestasis of pregnancy (ICP), remain major causes of maternal and perinatal morbidity. This review synthesizes their molecular, endocrine, immune, and clinical features. We propose the Placental-Maternal Adaptation Failure Continuum (PMAFC), in which gestational/fetoplacental stress load interacts with maternal adaptive reserve. This load includes placenta-derived signals, the physiological demands of gestation and fetal growth, and secondary maternal or fetal mediators. Placental drive denotes the placenta-derived component, whereas maternal adaptive reserve reflects the capacity of vascular, metabolic, hepatic, neuroendocrine, and immune systems to compensate for pregnancy-related challenges. We distinguish experimentally derived mechanistic hypotheses from findings supported by human studies and consider persistent post-pregnancy changes, termed pregnancy memory, as a potential link to later maternal cardiometabolic risk. We also separate established care from investigational biomarkers and interventions. The soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio can support clinical assessment in selected PE pathways. Cell-free RNA, chromosome 19 microRNA cluster biomarkers, and polygenic risk scores remain investigational. Apheresis has limited human proof-of-concept evidence, whereas sFlt-1 silencing, growth differentiation factor 15 receptor blockade, and strategies to restore hepatobiliary transporter function remain under clinical or preclinical evaluation. PMAFC is an evidence-organizing framework, not a validated predictive or therapeutic algorithm.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal stress-associated extracellular vesicle signaling linked to lysosomal cathepsin D and NEK7-NLRP3 neuroinflammation.","authors":"Gunhyuk Park, Ho-Ryong Yoo, Hye-Sun Lim","doi":"10.1186/s43556-026-00608-z","DOIUrl":"10.1186/s43556-026-00608-z","url":null,"abstract":"<p><p>Systemic exposure to neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects both the central nervous system (CNS) and peripheral organs; however, the contribution of peripheral organ stress to neuroinflammation remains incompletely understood. Here, we propose a peripheral-to-central signaling mechanism in which renal stress-associated extracellular vesicles (EVs) are linked to microglial inflammasome activation. Using computational and biochemical approaches, cathepsin D (CTSD) was identified as a molecular target of the MPTP metabolite 1-methyl-4-phenylpyridinium (MPP +). MPP + accumulated in renal tissue and was associated with lysosomal stress and tubular injury, accompanied by increased release of circulating EVs enriched with renal injury markers. Pharmacological inhibition of pepstatin A-sensitive lysosomal protease activity attenuated renal injury and EV release. MPTP exposure was also associated with blood-brain barrier disruption, potentially permitting circulating EV-associated signaling to influence the CNS. Plasma-derived EVs isolated under MPTP-treated conditions were associated with increased microglial activation, whereas pharmacological inhibition of EV biogenesis attenuated this response. Mechanistically, EV exposure was associated with inflammatory responses involving NIMA-related kinase 7 (NEK7)-NOD-like receptor family pyrin domain-containing 3-associated inflammatory signaling and IL-1β maturation. Consistent with these findings, NEK7 deficiency attenuated microglial activation and dopaminergic neuron loss in vivo. Together, these findings suggest that renal stress-associated EVs may be involved in linking peripheral stress to central neuroinflammatory responses. This study provides a tentative but verifiable framework for renal stress-EV-inflammasome communication in toxin-induced neuroinflammation.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD8⁺ T Cell infiltration and spatial organization in cancer: mechanisms, barriers, and therapeutic strategies.","authors":"Lylou Milian, Mannon Geindreau, Cassandre Pignol, Frédérique Vegran","doi":"10.1186/s43556-026-00612-3","DOIUrl":"https://doi.org/10.1186/s43556-026-00612-3","url":null,"abstract":"<p><p>The infiltration of tumors by CD8⁺ T lymphocytes is a critical determinant of antitumor immunity and response to immunotherapy. However, the presence of tumor-specific CD8⁺ T cells does not necessarily translate into effective tumor control, as multiple biological barriers can prevent their recruitment, spatial distribution, persistence, and functional activity. This review provides a comprehensive overview of the multistep mechanisms regulating CD8⁺ T-cell infiltration, from immune priming and systemic trafficking to vascular entry, intratumoral migration, and tissue residency. We discuss how alterations in chemokine networks, dysfunctional tumor vasculature, extracellular matrix remodeling, stromal barriers, and immunosuppressive signals collectively drive immune exclusion and resistance to therapy. Unlike previous reviews that have focused on individual aspects of T-cell trafficking, tumor immune contexture, or immune exclusion, we integrate these interconnected mechanisms as successive biological checkpoints and link them to therapeutic strategies aimed at overcoming specific barriers. These include restoration of antigen presentation and dendritic cell function, reprogramming of chemokine pathways, vascular normalization, stromal remodeling, innate immune activation, and induction of tertiary lymphoid structures. This integrated framework highlights why increasing CD8⁺ T-cell infiltration alone may be insufficient and supports the development of rational, sequential, and spatially guided combination strategies. Advances in spatial transcriptomics, single-cell technologies, and multiplex imaging are expected to enable personalized identification of dominant immune barriers and rational design of combination therapies. Ultimately, the goal is shifting from simply activating T cells toward engineering tumor ecosystems that support sustained CD8⁺ T-cell infiltration, organization, and effector function.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in antituberculosis drugs and therapeutics: from mechanistic breakthroughs to clinical translation.","authors":"Zhixiang Pan, Guan Liu, Yuehua Li, Hegui Yan, Yu Peng, Yiyi Wang, Hongri Gong, Juan Du, Shuang Wei","doi":"10.1186/s43556-026-00610-5","DOIUrl":"https://doi.org/10.1186/s43556-026-00610-5","url":null,"abstract":"<p><p>Tuberculosis (TB), caused by Mycobacterium tuberculosis, reclaimed its status as the deadliest single-pathogen infectious disease globally in 2023, accounting for 10.8 million new cases and 1.25 million deaths in 2023. The escalating crisis of drug-resistant TB, suboptimal BCG vaccine efficacy in adults, and persistent treatment gaps for vulnerable populations collectively drive an urgent shift toward mechanism-driven, precision-oriented therapeutic strategies.This review presents a critically integrated appraisal of anti-TB research advances spanning 2020 to 2025, drawing on structural biology, multi-omics, and real-world clinical evidence. It distinguishes itself from conventional descriptive literature compilations through systematic cross-population efficacy comparisons, in-depth dissection of translational bottlenecks, and explicit maturity stratification of emerging biotherapies. We synthesize progress across six interconnected domains: mechanistic insights into drug targets and spatiotemporal resistance evolution, novel short-course therapeutic regimens, precision medicine strategies, host-directed therapies, targeted delivery systems for extrapulmonary TB, and next-generation vaccine development. Three transformative breakthroughs are particularly highlighted: structural biology-guided rational drug design, spatial immune profiling of tuberculous granulomas, and AI-assisted diagnostic pipelines.We conclude by delineating priority research directions aligned with the WHO End TB Strategy, providing a translational roadmap to advance global TB elimination efforts. This rigorous, multi-dimensional synthesis offers an authoritative reference for advancing basic and translational anti-TB research and informing global public health strategy.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebral cavernous malformations: epidemiology, molecular pathogenesis, diagnosis and therapy.","authors":"Suyun Yu, Weiwei Zheng, Yanhong Pan, Liwenyu Chen, Jing Ma, Mengyuan Gao, Wei Zou, Yin Lu, Yang Zhao","doi":"10.1186/s43556-026-00619-w","DOIUrl":"https://doi.org/10.1186/s43556-026-00619-w","url":null,"abstract":"<p><p>Cerebral cavernous malformations (CCMs) are cerebrovascular diseases characterized by vascular lesions of the central nervous system (CNS) that can result in epileptic seizures, headaches, focal neurologic deficits (FNDs), and hemorrhagic stroke. Germline and somatic loss-of-function (LOF) mutations in one of the three established CCM-associated genes, namely CCM1 (or krev interaction trapped protein 1, KRIT1), CCM2, and CCM3 (or programmed cell death 10, PDCD10), which have been validated as core drivers of CCM pathogenesis and progression. Over the past few decades, a substantially improved understanding of the hallmarks and molecular basis of CCMs has been achieved. Key pathological hallmarks include but are not limited to excessive angiogenesis, vascular leakage, endothelial-mesenchymal transition (EndMT), defective autophagy, inflammation and immune response, oxidative stress, influenced gut microbiome and altered brain vascular microenvironment. These hallmarks are orchestrated by dysregulated signaling cascades, notably MEKK3-KLF2/4, PI3K-mTOR, and RhoA-ROCK, which integrate genetic, inflammatory, and hemodynamic cues. Concurrently, sophisticated neuroimaging (MRI with SWI/QSM) and genetic testing now enable precise diagnosis and risk stratification. Although surgical resection remains the mainstay for accessible symptomatic lesions, a wave of mechanism‑based pharmacological candidates has shown promising efficacy in preclinical models, and several have advanced to early‑phase clinical trials. This review summarizes the current understanding of CCM epidemiology, molecular pathogenesis, diagnosis and therapy, highlighting how the evolving multi‑hit concept and the dissection of downstream signaling are paving the way towards personalized management of this complicated vascular disease.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An inducible co-stimulator ligand (ICOSL)-based peptide therapy for proteinuric kidney diseases targeting αvβ3 integrin.","authors":"Alexis P Jimenez-Uribe, Yan Xu, Yanxia Cao, Ryan Spear, Kwi Hye Koh, Adrian P Mansini, Ariana G Alcantar, Felix Kliewe, Nicole Endlich, Jochen Reiser, Steve Mangos, Eunsil Hahm","doi":"10.1186/s43556-026-00594-2","DOIUrl":"10.1186/s43556-026-00594-2","url":null,"abstract":"<p><p>Dysregulated αvβ3 integrin activation in podocytes contributes to proteinuric kidney disease by disrupting podocyte architecture and the glomerular filtration barrier. However, no treatments currently exist that therapeutically target this integrin. We previously identified inducible co-stimulator ligand (ICOSL) as an endogenous antagonist of αvβ3 integrin that protects kidney function through its arginine-glycine-aspartic acid (RGD) motif, independent of its canonical role in immunity. Leveraging the therapeutic advantages of small peptides and the renoprotective function of ICOSL, we used a structure-guided approach to design a 19-amino acid human ICOSL-derived peptide (hICOSL-19) containing the RGD motif and evaluated its therapeutic potential for proteinuric kidney disease. hICOSL-19 exhibited high-affinity binding to αvβ3 integrin, similar to full-length ICOSL, and retained its αvβ3-antagonistic activity. PEGylation of hICOSL-19 (PhICOSL-19) extended its circulating half-life while preserving its antagonistic function. In murine models of acute and chronic proteinuric kidney disease, including immune-mediated glomerulonephritis and diabetic nephropathy, PhICOSL-19 treatment significantly reduced proteinuria, limited glomerular injury, and preserved podocyte architecture. In vitro and in vivo safety assessments further showed no detectable podocyte cytotoxicity, T-cell activation, or anti-drug antibody response. These findings suggest that an ICOSL-derived peptide targeting αvβ3 integrin represents a potential therapeutic strategy for proteinuric kidney diseases associated with αvβ3 integrin activation.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}