Cellular and Molecular Life Sciences最新文献

{"title":"Correction to: Computational analysis of multi-omics data reveals CXCL10⁺ DC-Treg interaction drives immunosuppressive microenvironment in AFP-positive hepatocellular carcinoma.","authors":"Zhi-Hui Luo, Wei-Ming Chen, Xin-Meng Yang, Jingwei Zhao, Ying-Lian Zhang, Qing-Han Huang, Ming-Yang Zhang, Na Wang, Fubing Wang, Jingjiao Zhou","doi":"10.1007/s00018-026-06268-0","DOIUrl":"10.1007/s00018-026-06268-0","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13365102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The degradation of maternal RNA-binding protein 4E-T regulates translational activation to ensure maternal-to-zygotic transition in mouse embryos.","authors":"Pinhua Wang, Siqi Wang, Haojie Yin, Maosheng Ye, Mingrui Li, Shuai Zhou, Yufeng Wang, Yueshuai Guo, Longfei Jia, Xuejiang Guo, Qiang Wang, Yue Hu, Ran Huo","doi":"10.1007/s00018-026-06328-5","DOIUrl":"10.1007/s00018-026-06328-5","url":null,"abstract":"<p><p>The maternal-to-zygotic transition (MZT) is essential for early embryonic development, comprising zygotic genome activation (ZGA) as well as the degradation of maternal RNAs and proteins, whereas our understanding of repressors' role in this process remains limited in mammals. In our study, we inhibited protein degradation at the 1-cell stage using the proteasome inhibitor MG132 and observed impaired pre-implantation development and defective ZGA. Proteomic analysis of MG132-treated embryos showed that significantly up-regulated proteins in abundance were enriched for RNA-binding proteins (RBPs). Further functional screening highlighted one critical factor, 4E-T (EIF4ENIF1), whose overexpression caused 2-cell stage arrest and failure of ZGA initiation. Moreover, the abnormal accumulation of 4E-T translationally repressed key factors of the 1-cell embryo, including ZBED3 and KDM4A. Mechanistically, the reprsssion is linked to direct interactions of 4E-T with eIF4E and eIF4E1B. These findings suggest that specific maternal RBPs may act as repressors that require precise degradation post-fertilization to relieve translational repression and ensure successful MZT.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SnRNA-seq and genome-wide CRISPR screening define the complete transcriptional trajectory and functional drivers of podocyte stress.","authors":"Jianbo Qing, Jiaying Hu, Xiao Wang, Xiaoyun Shen, Yimiao Ma, Mingjing Gao, Junnan Wu","doi":"10.1007/s00018-026-06335-6","DOIUrl":"10.1007/s00018-026-06335-6","url":null,"abstract":"<p><p>Podocyte injury is a central driver of proteinuria and progressive kidney dysfunction. Although podocytes are continuously exposed to diverse stressors in both physiological and pathological contexts, the dynamic processes underlying their adaptation and eventual failure remain poorly defined. Here, we performed integrative single-nucleus RNA sequencing of kidney tissues from patients with six types of representative chronic glomerulonephritis, capturing a spectrum of podocyte injury states. We identified distinct podocyte subpopulations and reconstructed a dynamic trajectory characterized by an initial adaptive activation followed by progressive functional decline. Integration with time-resolved transcriptomics identified 778 candidate genes associated with podocyte stress responses. To distinguish putative functional drivers from secondary transcriptional changes, we integrated these candidates with a genome-wide CRISPR-Cas9 knockout screen, prioritizing genes required for podocyte survival under stress conditions. Subsequent siRNA-mediated validation of five representative candidates-BST1, TALDO1, ATP6V1E1, PPP2R1A and CHL1-showed that knockdown of these genes significantly compromised cell viability and accelerated apoptosis, highlighting a coordinated survival network spanning metabolic regulation, autophagy, and cytoskeletal stability. Our findings define a dynamic framework of podocyte stress adaptation and failure, and suggest that targeting stress-response pathways may prolong podocyte survival, thereby extending the therapeutic window for intervention in chronic kidney disease.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix stiffness induced CREB3L1 activation contributed to skin fibrosis through calcium influx triggered endoplasmic reticulum stress.","authors":"Dongsheng Wen, Yeke Yu, Siyi He, Ya Gao, Chiakang Ho, Xinran Ye, Jiaming Sun, Yuxin Liu, Lu Huang, Yangdan Liu, Qingfeng Li, Yifan Zhang","doi":"10.1007/s00018-026-06347-2","DOIUrl":"10.1007/s00018-026-06347-2","url":null,"abstract":"<p><strong>Background: </strong>Skin fibrosis substantially contributes to morbidity and mortality. Fibrotic remodeling, characterized by accumulated and stiffened extracellular matrix, persistently exerts mechanical cues and consistently activates fibroblasts, implying biomechanics as a major driver of fibrosis. However, our understanding towards mechanisms of biomechanics induced fibrosis remained limited.</p><p><strong>Methods: </strong>Integrated single-cell sequencing analysis was performed to reveal the atlas of fibrotic skin. ChIP sequencing was performed to reveal the binding sites of CREB3L1. Nanoindenter was used to identify the mechanical properties. Gel contraction assay, wound healing assay, and live cell imaging were conducted to assess the behavior of fibroblasts cultured on hydrogels of different rigidities. Bleomycin induced and mechanical loading induced skin fibrosis models were established on CREB3L1 knockdown and control mice.</p><p><strong>Results: </strong>We identified a mechanosensitive fibroblast cluster that exerts contraction and ECM deposition functions in fibrotic skin, and its transcriptional identity was maintained by CREB3L1. Elevated expression of CREB3L1 was confirmed in human and mouse fibrotic skin. Further analysis showed that CREB3L1 was required for fibroblast activation, including contraction, migration, and ECM accumulation. More importantly, we revealed that matrix stiffness could alter calcium homeostasis, causing calcium influx and endoplasmic reticulum stress. The ER stress state in turn triggered the cleavage of CREB3L1, releasing its luminal domain that function as a profibrotic transcription factor. Inhibiting CREB3L1 could alleviate skin fibrosis both in vivo and in vitro.</p><p><strong>Conclusions: </strong>This study elucidates the molecular mechanism of CREB3L1 mechanosensitive activation in matrix stiffness induced skin fibrosis, and presents a promising therapeutic target for clinical translation.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular senescence and aging: molecular mechanisms and convergent pathways.","authors":"Francesca Cristiana Piritore, Michele Braggio, Arianna Minoia, Silvia Bolognin, Mattia Cominacini, Elisabetta Trabetti, Cristina Bombieri, Maria Grazia Romanelli, Luca Dalle Carbonare, Maria Teresa Valenti","doi":"10.1007/s00018-026-06317-8","DOIUrl":"10.1007/s00018-026-06317-8","url":null,"abstract":"<p><p>The frequent conceptual overlap between aging and cellular senescence has generated ambiguities in experimental approaches, biomarker usage, and therapeutic strategy development within aging research. Cellular senescence and aging are biologically distinct but interconnected processes, frequently misunderstood or used interchangeably within biomedical research and theoretical discussions. Thus, aging refers to the progressive decline in physiological integrity and function at the organismal level, while cellular senescence is a stable cell-cycle arrest triggered by various forms of stress, including DNA damage, telomere shortening, epigenetic dysregulation, and mitochondrial dysfunction. This review dissects the molecular underpinnings of both phenomena, highlighting their key differences, mechanistic overlaps, and roles in health and disease, with particular emphasis on how the accumulation of senescent cells actively contributes to age-related functional decline. In particular, we discuss emerging biomarkers and therapeutic strategies, such as senolytics and partial reprogramming. Furthermore, a deeper understanding of these processes may contribute to the identification of innovative interventions for age-related disorders, such as therapies targeting specific components of the senescence-associated secretory phenotype or selectively modulating senescent cell burden.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOC1⁺IFI30⁺ TAMs orchestrate colorectal cancer liver metastasis by coupling cholesterol biosynthesis with secretion of immunosuppressive factors.","authors":"Zheyou Cai, Yibing Chen, Lei Cui, Jine Yao, Jianghua Qiao, Weihong Sun, Haisheng Liu, Linhao Yang, Zhuang Yang, Quentin Liu, Benxin Hou, Zhengzhi Zou, Dongming Lai","doi":"10.1007/s00018-026-06338-3","DOIUrl":"10.1007/s00018-026-06338-3","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) play a crucial role in colorectal cancer (CRC) metastasis, particularly in the establishment of the liver metastatic niche. TAMs facilitate metastasis by enabling epithelial-mesenchymal transition (EMT) and suppressing anti-tumor immunity. While their roles in primary tumors have been extensively investigated, their functions at metastatic sites remain poorly understood. In this study, we analyzed the single-cell RNA sequencing data from 46 CRC patients, encompassing 402,972 cells, to identify macrophage subsets associated with liver metastasis. A distinct population of APOC1⁺ IFI30⁺ TAMs was identified and found to be significantly enriched in metastatic liver lesions. Compared to primary tumors (PT), the number of APOC1⁺ IFI30⁺ TAMs significantly increased at liver metastatic sites after CRC cells metastasized to the liver. We employed spatial transcriptomics to validate the above conclusions. These TAMs exhibited significantly enhanced immunosuppressive capacity and cholesterol synthesis metabolism. Further investigation showed that TAMs within metastatic niches reprogram the mevalonate pathway to enhance cholesterol synthesis, characterized by upregulation of key genes such as HMGCR and ACAT1/2. These TAMs act on surrounding tumor cells by secreting cholesterol and cytokines such as TNFSF12, TGFB1, MIF and LGALS9, thereby enhancing tumor adhesion and proliferation and creating an immunosuppressive microenvironment to continuously support tumor growth. Our findings provided new insights into the complex interactions among TAMs, immune cells, and tumor cells within CRC metastatic microenvironment, highlighting potential therapeutic targets to disrupt TAMs-mediated immune evasion and metastatic progression.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte CD146 and soluble CD146 promote hepatic stellate cell activation via the integrin αvβ1-p38 MAPK signaling axis to drive liver fibrosis.","authors":"Bingqing Yang, Chenxue Hou, Rongcai Ye, Jingya Yin, Yixue Shu, Xiaoyan Cheng, Lei Sun, Kun Yang, Quan Sun, Yue Li, Wen Xie, Qi Wang","doi":"10.1007/s00018-026-06324-9","DOIUrl":"10.1007/s00018-026-06324-9","url":null,"abstract":"<p><p>During chronic liver injury, hepatocytes promote liver fibrosis by interacting with hepatic stellate cells (HSCs). However, the key intracellular factors that regulate intercellular communication in hepatocytes remain poorly understood. Although cluster of differentiation 146 (CD146) is predominantly recognized as an endothelial cell marker, our study found that CD146 is substantially upregulated in hepatocytes under fibrotic stress and may play an independent role in transcellular signaling. This study aimed to elucidate the functions and underlying mechanisms of hepatocyte CD146 in liver fibrosis. We evaluated CD146 expression in liver tissues and serum soluble CD146 (sCD146) levels in patients with liver fibrosis and mouse models. Hepatocyte-specific CD146-overexpressing mice (AAV8-CD146) were generated and fed either a normal chow diet (NCD) or a high-fat diet (HFD); hepatocyte-specific CD146 knockout mice (CD146^Alb-Cre) were subjected to carbon tetrachloride (CCl₄)-induced fibrosis. Comprehensive molecular, biochemical, and histological analyses were performed to systematically assess the role of CD146 in the initiation and progression of liver fibrosis. A co-culture system of hepatocytes and HSCs was also established to investigate the paracrine regulatory effects of CD146 on HSCs. The levels of sCD146 were positively correlated with the progression and severity of chronic liver disease. A diagnostic model incorporating sCD146 and other serological markers showed improved diagnostic performance for decompensated cirrhosis. Compared with healthy controls, hepatocyte CD146 expression was markedly upregulated in liver tissues from patients with cirrhosis and fibrotic mice. Under HFD conditions, hepatocyte-specific CD146 overexpression exacerbated hepatic inflammation and fibrosis in mice, whereas hepatocyte-specific CD146 deletion significantly attenuated CCl₄-induced liver fibrosis. Transforming growth factor-β1 (TGF-β1) induced CD146 upregulation in hepatocytes and increased the release of sCD146. Released sCD146 bound to integrin αvβ1 on the surface of HSCs, activated the p38 mitogen-activated protein kinase (p38 MAPK) pathway, and promoted HSC activation and type I collagen production. These findings identify hepatocyte-derived CD146/sCD146 as a TGF-β1-inducible mediator of hepatocyte-HSC communication that promotes liver fibrosis through the CD146/sCD146-integrin αvβ1-p38 MAPK signaling axis. They also support serum sCD146 as a potential non-invasive biomarker for advanced chronic liver disease.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The formin Fhod3 is required for sarcomere reassembly after mitosis in postnatal cardiomyocytes.","authors":"Shuhei Sakaguchi, Yohko Kage, Eka Adip Pradipta, Ayako Miura, Koji Furukawa, Ryu Takeya","doi":"10.1007/s00018-026-06340-9","DOIUrl":"10.1007/s00018-026-06340-9","url":null,"abstract":"<p><p>Fhod3, a member of the formin family of proteins that regulate actin polymerization, is essential for the organization of cardiac sarcomeres during embryonic cardiogenesis. We previously demonstrated that the perinatal deletion of Fhod3 in mice results in lethality with disorganized sarcomeres, whereas the deletion in the adult period is non-lethal and does not affect sarcomere morphology. To clarify the underlying mechanism of this developmental stage-dependent outcome, we examined the effects of Fhod3 depletion in primary cultured cardiomyocytes derived from Fhod3^flox neonates. Long-range time-lapse imaging throughout the entire culture period revealed that Fhod3 depletion around birth using muscle creatine kinase-Cre caused sarcomere disruption only in cells that had undergone mitosis and not in cells that had not undergone mitosis, suggesting that sarcomere breakdown by Fhod3 deletion occurs after mitosis. To verify this, we varied the timing of Fhod3 deletion using a tamoxifen-inducible αMHC-MerCreMer line. Cells treated with tamoxifen from day 1 in vitro (DIV1) exhibited a disruption of sarcomeres, similar to that observed in the Fhod3-depleted cells by MCK-Cre around birth. In contrast, cells treated from DIV9, when postnatal mitosis was almost complete, showed organized sarcomere despite Fhod3 depletion. Thus, in the presence of Fhod3, sarcomere reassembly after mitosis was successful, whereas it failed in the absence of Fhod3, indicating the indispensable role of Fhod3 in sarcomere reorganization after mitosis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis reveals impaired Müller glia-mediated intercellular communication and photoreceptor pathology in USH1C retinal organoids.","authors":"Nicole Wenck, Mark Zorin, Qiang Wang, Selina Kröll, Anna Justen, Katharina Hay, Christof Rickert, Maria Méndez-Lago, Sivarajan Karunanithi, Dimitra Athanasiou, Kalliopi Ziaka, Pietro De Angeli, Katarina Stingl, Susanne Kohl, Michael E Cheetham, Thomas Mittmann, Kerstin Nagel-Wolfrum","doi":"10.1007/s00018-026-06321-y","DOIUrl":"10.1007/s00018-026-06321-y","url":null,"abstract":"<p><p>Usher syndrome type 1, caused by pathogenic variants in the USH1C gene, leads to congenital deafness and progressive retinal degeneration resulting in vision loss. While auditory deficits can be compensated by cochlea implants and hearing aids, no treatment exists to prevent retinal degeneration. Here, we generated retinal organoids from induced pluripotent stem cells of two USH1C patients to elucidate the cellular and molecular mechanisms driving ocular pathogenesis. Single-cell RNA sequencing of healthy and USH1C retinal organoids identified differential expression of genes related to phototransduction in photoreceptors, as well as alterations in cell adhesion and canonical Wnt signaling in Müller glia cells. Analysis of intercellular communication revealed an overall reduced signaling efficiency, particularly affecting Müller glia-mediated retinal adhesion processes. Morphological characterization of organoids confirmed transcriptome changes by showing degeneration of the outer limiting membrane and loss of adherens junction architecture. Moreover, photoreceptors revealed increased levels of apoptosis, as well as morphological and functional changes related to phototransduction. Our results demonstrate that disruption of Müller glia signaling contributes to an overall loss of retinal integrity, providing novel insights into USH1C pathogenesis and offering targets for therapeutic interventions.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein D acts as a chaperone of Aβ peptide delaying its assembly into amyloid aggregates.","authors":"Jorge Mondejar-Duran, Antonio Díaz-Quintana, Maria D Ganfornina, Diego Sanchez","doi":"10.1007/s00018-026-06339-2","DOIUrl":"10.1007/s00018-026-06339-2","url":null,"abstract":"<p><p>The accumulation of amyloid-β (Aβ) peptides is at the root of Alzheimer's disease (AD), where oligomeric forms of Aβ disrupt brain physiology before any sign of dementia. Intense research has been directed to extrinsic molecules that modulate Aβ aggregation. However, more knowledge is needed about endogenous mechanisms maintaining Aβ homeostasis in a healthy brain. The Lipocalin Apolipoprotein D (ApoD) displays neuroprotective functions, many of which rely on managing lipids in cell membranes or lipoprotein particles. ApoD is upregulated in the aging brain and AD and is present in amyloid-β plaques. However, the functional relationship of ApoD with Aβ peptides aggregation needs to be studied. Using aggregation and ligand binding assays guided by molecular dynamics modeling, in this work we demonstrate that human ApoD is able to interact with Aβ, both in monomeric or aggregated states. Multiple binding sites in ApoD, including its hydrophobic ligand-binding pocket, are demonstrated between ApoD and Aβ by fluorescence titration, and these diverse interactions delay the aggregation process and reduce the number of large aggregates. Modeling the dynamics of interactions in sub-stoichiometric ApoD/Aβ ratios predicts that ApoD decreases the probability of switching to the β-stranded structure required for Aβ oligomerization. Our findings reveal Aβ as a novel ligand category for ApoD and therefore place this Lipocalin as an important element of the endogenous control of Aβ. ApoD is able to chaperon Aβ monomers from their origin in cellular membranes, preventing their progression towards amyloid plaques.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}