Mechanisms of Ageing and Development最新文献

lncRNA EPB41L4A-AS1: A promising therapeutic target for aging and age-related diseases. lncRNA EPB41L4A-AS1：一个有希望的治疗衰老和年龄相关疾病的靶点

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-10-07 DOI: 10.1016/j.mad.2025.112118

Minghui Li, Tianzi Li, Xufei Zhang, Kun Li, Ziqiang Wang

{"title":"lncRNA EPB41L4A-AS1: A promising therapeutic target for aging and age-related diseases.","authors":"Minghui Li, Tianzi Li, Xufei Zhang, Kun Li, Ziqiang Wang","doi":"10.1016/j.mad.2025.112118","DOIUrl":"https://doi.org/10.1016/j.mad.2025.112118","url":null,"abstract":"<p><p>Aging is a natural biological process characterized by progressive cellular and functional decline, significantly increasing susceptibility to age-related diseases. Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of cellular processes implicated in aging and age-related diseases. Among these, lncRNA erythrocyte membrane protein band 4.1 like 4A antisense RNA 1 (EPB41L4A-AS1) has emerged as a key player with significant dysregulation across diverse age-related diseases including cancer, Alzheimer's disease (AD), and type 2 diabetes mellitus (T2DM). This review synthesizes current evidence showing that EPB41L4A-AS1 functions primarily as a tumor suppressor in many cancers, regulates neuronal autophagy and energy metabolism in AD, and modulates inflammatory and metabolic pathways in T2DM. Mechanistically, EPB41L4A-AS1 exerts its effects-via miRNA sponging, regulating key signaling pathways (NF-κB, Rho/ROCK), influencing histone modifications, and modulating cellular metabolism (glycolysis, glutaminolysis, NAD+/ATP synthesis). The compelling evidence positions EPB41L4A-AS1 as a promising, multi-faceted therapeutic target for mitigating the burden of age-related diseases.</p>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":" ","pages":"112118"},"PeriodicalIF":5.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The stress-responsive cytokine GDF-15 and sarcopenia: A systematic review and meta-analysis on aging muscle decline 应激反应细胞因子GDF-15和肌肉减少症：衰老肌肉衰退的系统回顾和荟萃分析。

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-09-26 DOI: 10.1016/j.mad.2025.112117

Mario Virgilio Papa , Chiara Ceolin , Francesco Boschele , Raffaele Pagliuca , Giuseppe Sergi , Marina De Rui

{"title":"The stress-responsive cytokine GDF-15 and sarcopenia: A systematic review and meta-analysis on aging muscle decline","authors":"Mario Virgilio Papa , Chiara Ceolin , Francesco Boschele , Raffaele Pagliuca , Giuseppe Sergi , Marina De Rui","doi":"10.1016/j.mad.2025.112117","DOIUrl":"10.1016/j.mad.2025.112117","url":null,"abstract":"<div><h3>Background</h3><div>Given the increasing interest for Growth Differentiation Factor-15 (GDF-15) in muscle decline, this study aims to evaluate the association between circulating levels of GDF-15 and muscle mass and sarcopenia through a systematic review and meta-analysis.</div></div><div><h3>Methods</h3><div>The research, in accordance with PRISMA and MOOSE guidelines, involved PubMed, Embase, and Cochrane Libraries. Two meta-analyses were performed: (1) comparison of GDF-15 levels in sarcopenic vs non-sarcopenic individuals; (2) correlation between GDF-15 and muscle mass.</div></div><div><h3>Results</h3><div>A total of 7 studies met the inclusion criteria (total n = 2344) enrolling both adults aged ≥ 60 years (6/7 studies) and a younger cohort (42 years [IQR 31.8–51]). The first meta-analysis, based on 4 studies (n = 1393), showed significantly higher levels of GDF-15 in sarcopenic individuals (r = 0.482). The second meta-analysis, involving 4 studies (n = 1400), found a significant inverse correlation between GDF-15 and muscle mass (r = -0.221).</div></div><div><h3>Conclusions</h3><div>Sarcopenic individuals had higher circulating GDF-15. Together with the inverse correlation between GDF-15 and muscle mass observed, these findings show a small-to-moderate association between elevated GDF-15 and sarcopenic phenotypes in older adults. However, the limited number of studies and high heterogeneity for the sarcopenia comparison warrant cautious interpretation and underscore the need for larger, longitudinal investigations.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"228 ","pages":"Article 112117"},"PeriodicalIF":5.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical data-driven classification of pre-frailty reveals sex-specific patterns – Data from the Berlin Aging Study II (BASE-II) 临床数据驱动的虚弱前分类揭示了性别特异性模式——来自柏林老龄化研究II （BASE-II）的数据

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-09-24 DOI: 10.1016/j.mad.2025.112114

Jeff Didier , Sébastien De Landtsheer , Maria Pires Pacheco , Ali Kishk , Jochen G. Schneider , David Goldeck , Graham Pawelec , Dominik Spira , Ilja Demuth , Thomas Sauter

{"title":"Clinical data-driven classification of pre-frailty reveals sex-specific patterns – Data from the Berlin Aging Study II (BASE-II)","authors":"Jeff Didier , Sébastien De Landtsheer , Maria Pires Pacheco , Ali Kishk , Jochen G. Schneider , David Goldeck , Graham Pawelec , Dominik Spira , Ilja Demuth , Thomas Sauter","doi":"10.1016/j.mad.2025.112114","DOIUrl":"10.1016/j.mad.2025.112114","url":null,"abstract":"<div><div>Frailty is a geriatric condition with multidimensional consequences that strongly affect older adults’ quality of life. The lack of a universal standard to describe, diagnose, and treat frailty further complicates this situation. Nowadays, multitudinous frailty assessment tools are applied depending on the regional and clinical context, adding complexity by increasing heterogeneity in the definition and characterization of frailty. Better insights into the causes and pathophysiology of frailty and its early stages are required to establish strong and accurately tailored treatment rationales for frail patients. We analysed participants aged 60 and above using cross-sectional biochemical and survey data from the Berlin Aging Study II (BASE-II, N = 1512, pre-frail=470, frail=14), applying machine-learning techniques to investigate determinants of physical frailty measured by Fried et al.’s 5-item frailty phenotype. Our findings highlight new prognostic sex-specific biomarkers of pre-frailty (the early stage of frailty) with possible clinical applications, enriching the current sex-agnostic diagnostic scores with easy monitorable physical and physiological characteristics. Low appendicular lean mass and high fat composition in men, or vitamin D deficiency and high white blood cell counts in women, emerged as strong indicators of the respective pre-frailty profiles. Because the number of fully frail individuals was extremely small (n = 14, <1 %), our findings should be interpreted as reflecting predictors of pre-frailty, not of frailty itself. We conclude that understanding the development of frailty remains a complex challenge, and that sex-specific differences must be considered by clinical geriatricians and researchers.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"228 ","pages":"Article 112114"},"PeriodicalIF":5.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human astrocytes from healthy individuals and Alzheimer’s patients respond differently to Aβ1–42 oligomers, triggering distinct paths of reactivity and senescence 健康个体和阿尔茨海默病患者的人类星形胶质细胞对Aβ1-42寡聚物的反应不同，引发不同的反应性和衰老途径。

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-09-24 DOI: 10.1016/j.mad.2025.112116

Sara Ristori , Gianmarco Bertoni , Alessandra Bigi , Cristina Cecchi , Manuela Sollazzo , Luisa Iommarini , Daniela Monti , Elisa Bientinesi

{"title":"Human astrocytes from healthy individuals and Alzheimer’s patients respond differently to Aβ1–42 oligomers, triggering distinct paths of reactivity and senescence","authors":"Sara Ristori , Gianmarco Bertoni , Alessandra Bigi , Cristina Cecchi , Manuela Sollazzo , Luisa Iommarini , Daniela Monti , Elisa Bientinesi","doi":"10.1016/j.mad.2025.112116","DOIUrl":"10.1016/j.mad.2025.112116","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by cognitive decline, amyloid-β (Aβ) plaques, and neurofibrillary tangles. Aβ<sub>1–42</sub> oligomers exert neurotoxic and pro-inflammatory effects. Astrocytes maintain brain homeostasis, and their dysfunction contributes to AD progression. This study investigates the impact of Aβ<sub>1–42</sub> oligomers on primary human astrocytes from healthy individuals and AD patients. Our findings show that astrocytes from both groups internalise Aβ<sub>1–42</sub> oligomers. In healthy astrocytes, internalisation enhances proteasome activity, whereas in AD astrocytes, it reduces it. Aβ<sub>1–42</sub> oligomers induce calcium dyshomeostasis and mitochondrial membrane potential alterations in both groups. Interestingly, oligomers induce apoptosis in a subset of healthy astrocytes, while surviving ones become reactive and hyperproliferative, releasing neuroinflammatory and neurotrophic molecules. Conversely, Aβ<sub>1–42</sub> drives AD astrocytes into senescence, characterised by increased β-galactosidase activity, p14<sup>ARF</sup> expression, senescence-associated secretory phenotype (SASP), and heterochromatin foci. Importantly, conditioned media from Aβ<sub>1–42</sub>-treated AD astrocytes, but not from healthy ones, cause death of differentiated SH-SY5Y neuron-like cells, suggesting that senescent astrocytes contribute to neurotoxicity. These findings reveal differential astrocytic responses to Aβ<sub>1–42</sub> oligomers, emphasising the importance of astrocyte senescence in AD pathogenesis. This research offers insight into cellular mechanisms underlying AD and may support the development of innovative therapeutic strategies for neurodegenerative diseases.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"228 ","pages":"Article 112116"},"PeriodicalIF":5.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Increased mTOR signaling secondary to a human ILK missense variant inhibits nephrogenesis with decreased metabolism 继发于人类ILK错义变异的mTOR信号增加抑制代谢降低的肾发生。

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-09-19 DOI: 10.1016/j.mad.2025.112115

Xiangyue Hu , Dana Kablawi , Wout F.J. Feitz , Kirsten Y. Renkema , Nine V.A.M. Knoers , Norman D. Rosenblum

{"title":"Increased mTOR signaling secondary to a human ILK missense variant inhibits nephrogenesis with decreased metabolism","authors":"Xiangyue Hu , Dana Kablawi , Wout F.J. Feitz , Kirsten Y. Renkema , Nine V.A.M. Knoers , Norman D. Rosenblum","doi":"10.1016/j.mad.2025.112115","DOIUrl":"10.1016/j.mad.2025.112115","url":null,"abstract":"<div><div>Nephrogenesis is critical to mammalian kidney function throughout life. Decreased nephron formation, an embryonic process dependent on ureteric-mesenchymal tissue interactions, is a fundamental feature of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) and an antecedent to adult-onset cardiovascular and renal disease. Yet, mechanisms controlling the number of nephrons formed during embryogenesis are largely undefined. Here, we elucidated deleterious effects of increased mTOR signaling on murine nephrogenesis. A rare human genetic missense variant (<em>ILK</em><sup><em>T173I</em></sup>) in Integrin-Linked Kinase (<em>ILK</em>) was identified in a human CAKUT cohort. Replacement of the mouse <em>ILK</em><sup><em>WT</em></sup> allele with <em>Ilk</em><sup><em>T173I</em></sup> caused increased kidney mTOR signaling, low nephron number, and decreased ureteric branching, the latter of which was rescued by rapamycin. Transcriptomic analysis of sorted embryonic kidney cells suggested that elevated mTOR signaling is limited to non-ureteric mesenchyme, a finding that was substantiated by immunostaining in situ. Maturation of nephrogenic cells in <em>Ilk</em><sup><em>T173I</em></sup>-knock-in kidneys was decreased as demonstrated by nephrogenic-specific markers, morphologic analysis, and proliferation of nephrogenic progenitors. Metabolic profiling of non-ureteric cells demonstrated decreased oxidative ATP production. Together, our data revealed a deleterious role of excessive mTOR signaling downstream of <em>ILK</em><sup><em>T173I</em></sup> by inhibiting maturation, cell proliferation and metabolism in the nephrogenic cell lineage.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"228 ","pages":"Article 112115"},"PeriodicalIF":5.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disentangling tau, glymphatic dysfunction and astrocytic activation in amyloid-positive Alzheimer's disease 淀粉样蛋白阳性阿尔茨海默病中Tau蛋白、淋巴功能障碍和星形细胞激活的分离。

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-09-17 DOI: 10.1016/j.mad.2025.112113

Hsin-I. Chang , Shih-Wen Chen , Shu-Hua Huang , Shih-Wei Hsu , Chen-Chang Lee , Chung-Guei Huang , Chi-Wei Huang , Chiung-Chih Chang

{"title":"Disentangling tau, glymphatic dysfunction and astrocytic activation in amyloid-positive Alzheimer's disease","authors":"Hsin-I. Chang , Shih-Wen Chen , Shu-Hua Huang , Shih-Wei Hsu , Chen-Chang Lee , Chung-Guei Huang , Chi-Wei Huang , Chiung-Chih Chang","doi":"10.1016/j.mad.2025.112113","DOIUrl":"10.1016/j.mad.2025.112113","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) features tau pathology, neurodegeneration, and cognitive decline. Dysfunction of the glymphatic system, which clears pathological proteins, and astrocytic activation may exacerbate neurodegeneration. We investigated the interplay among tau accumulation, glymphatic dysfunction, and astrocytic activation in amyloid PET-positive AD patients using diffusion tensor image analysis along the perivascular space (DTI-ALPS) as a glymphatic biomarker. Our cohort comprised 157 AD patients and 117 cognitively unimpaired controls. We measured DTI-ALPS, plasma GFAP, hippocampal volume, and cognitive scores at two time points. [F18]Florzolotau PET quantified tau burden. Regression analyses assessed associations between biomarkers and cognitive decline, and mediation analysis tested GFAP’s role in tau-driven neurodegeneration. We also compared topographical distributions of DTI-ALPS and GFAP using tau PET and gray matter images. Tau burden emerged as the strongest predictor of cognitive decline, while DTI-ALPS showed no significant cognitive association. GFAP mediated the link between tau burden and hippocampal atrophy, implicating astrocytic activation in tau-driven neurodegeneration. Regional analyses revealed GFAP associations in anterior cingulate and medial temporal areas, contrasting with DTI-ALPS patterns in parasagittal and lateral prefrontal regions. These findings underscore tau burden as the driver of cognitive decline, with astrocytic activation mediating neurodegeneration; glymphatic dysfunction minimally impacts cognition.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"228 ","pages":"Article 112113"},"PeriodicalIF":5.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Defective mitochondrial quality control in the aging of skeletal muscle 骨骼肌老化过程中线粒体质量控制缺陷。

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-09-08 DOI: 10.1016/j.mad.2025.112112

Emanuele Marzetti , Riccardo Calvani , Helio José Coelho-Junior , Francesco Landi , Anna Picca

{"title":"Defective mitochondrial quality control in the aging of skeletal muscle","authors":"Emanuele Marzetti , Riccardo Calvani , Helio José Coelho-Junior , Francesco Landi , Anna Picca","doi":"10.1016/j.mad.2025.112112","DOIUrl":"10.1016/j.mad.2025.112112","url":null,"abstract":"<div><div>Age-related skeletal muscle decline is a major contributor to frailty, functional impairment, and loss of independence in advanced age. This process is characterized by selective atrophy of type II fibers, impaired excitation–contraction coupling, and reduced regenerative capacity. Emerging evidence implicates mitochondrial dysfunction as a central mechanism in the disruption of muscle homeostasis with age. Beyond ATP production, mitochondria orchestrate redox signaling, calcium handling, and apoptotic pathways, which are increasingly compromised in aged muscle due to chronic oxidative stress and defective quality control. High-resolution respirometry has revealed intrinsic, lifestyle-independent declines in mitochondrial respiratory capacity, while large-scale phenotyping and transcriptomic profiling have established robust associations between mitochondrial integrity, physical performance, and mobility. These findings have prompted a paradigm shift from static descriptions of mitochondrial decline toward dynamic analyses of mitochondrial signaling networks and stress adaptability. Several quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy, and vesicle trafficking, emerge as critical regulators of myocyte integrity. Understanding how these systems deteriorate with age will be pivotal for developing therapeutic targets to preserve muscle function, mitigate sarcopenia, and extend health span.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"228 ","pages":"Article 112112"},"PeriodicalIF":5.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Histone modifications: Key players in Alzheimer's disease 组蛋白修饰：阿尔茨海默病的关键因素

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-09-02 DOI: 10.1016/j.mad.2025.112102

Kun Li , Xiaolin Qiu , Qiqi Yang , Ziqiang Wang

引用次数: 0

ABI3BP deficiency alleviates Ang II-induced VSMC senescence through the Nrf2 signalling pathway ABI3BP缺失通过NRF2信号通路缓解angii诱导的VSMC衰老

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-08-30 DOI: 10.1016/j.mad.2025.112104

Aiqiu Mao , Qiang Tu , Huaqiang Xie , Xiaoying Wang , Yuhan Liu , Yan Ding , Zheng Cao

{"title":"ABI3BP deficiency alleviates Ang II-induced VSMC senescence through the Nrf2 signalling pathway","authors":"Aiqiu Mao , Qiang Tu , Huaqiang Xie , Xiaoying Wang , Yuhan Liu , Yan Ding , Zheng Cao","doi":"10.1016/j.mad.2025.112104","DOIUrl":"10.1016/j.mad.2025.112104","url":null,"abstract":"<div><div>Vascular aging is a critical independent risk factor for cardiovascular disease (CVD), yet its precise molecular mechanisms remain poorly understood. In this study, we generated an ABI3BP knockout mouse to investigate the role of ABI3BP deficiency in angiotensin II (Ang II)-induced vascular aging. The results demonstrated that ABI3BP was highly expressed in AngII-induced senescent vascular smooth muscle cell (VSMC) and vascular tissues, with significantly increased expression also observed in the blood vessels of naturally aged mice. Downregulation of ABI3BP expression using siRNA significantly inhibited Ang II-induced senescence of VSMC. ABI3BP knockout ameliorated Ang II-induced vascular aging in mice, reduced the secretion of senescence-associated inflammatory factors IL-6 and TNF-α, alleviated senescence-induced accumulation of collagen in the vascular media and thickening of the vascular intima, and effectively suppressed Ang II-induced elevation of blood pressure. Further investigations revealed that these protective effects might be mediated through enhanced expression of Nrf2 and its downstream anti-aging factors. Silencing Nrf2 with siRNA attenuated the protective effects of ABI3BP downregulation on vascular aging. Overall, these findings demonstrate that ABI3BP downregulation inhibits VSMC senescence by enhancing the activity of the Nrf2-mediated antioxidant defense pathway, thereby attenuating the progression of vascular aging.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"228 ","pages":"Article 112104"},"PeriodicalIF":5.1,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DKK3, regulated by FOXF1-EZH2 axis, takes action on tubular epithelial cells senescence to trigger glomerular endothelial cells ferroptosis involving in renal fibrosis DKK3受FOXF1-EZH2轴调控，作用于小管上皮细胞衰老，触发肾小球内皮细胞铁上沉，参与肾纤维化。

IF 5.1 3区医学

Mechanisms of Ageing and Development Pub Date : 2025-08-28 DOI: 10.1016/j.mad.2025.112103

Huiling Cao , Yanxia Chen , Jinjing Huang, Weiping Tu, Ben Ke, Xiangdong Fang

{"title":"DKK3, regulated by FOXF1-EZH2 axis, takes action on tubular epithelial cells senescence to trigger glomerular endothelial cells ferroptosis involving in renal fibrosis","authors":"Huiling Cao , Yanxia Chen , Jinjing Huang, Weiping Tu, Ben Ke, Xiangdong Fang","doi":"10.1016/j.mad.2025.112103","DOIUrl":"10.1016/j.mad.2025.112103","url":null,"abstract":"<div><div>Chronic kidney disease (CKD) can be accelerated by renal fibrosis. Dickkopf-3 (DKK3) plays a role in regulating renal fibrosis, while tubular cell senescence contributes to fibrosis development. Here, the role and mechanism of DKK3 on senescence and renal fibrosis were evaluated. We demonstrated that in CKD patients and Unilateral Ureteral Obstruction (UUO) mice, downregulation of FOXF1 and upregulation of DDK3 was observed, of which expression patterns exhibited negative association. Reinforced FOXF1 protected against H<sub>2</sub>O<sub>2</sub>-triggered tubular cell damage, fibrosis, and senescence, which was reversed by DKK3 overexpression. In UUO mice, FOXF1 depletion worsened renal fibrosis and senescence. Mechanistically, FOXF1 was identified to be a transcriptional activator of EZH2 to mediated epigenetic silence of DKK3 via H3K27me3 levels. Moreover, exosomal DKK3 from tubular cells controlled Endothelial to Mesenchymal Transition, oxidative stress and ferroptosis in MRGECs. Overall, our data reveal that the FOXF1-EZH2-DKK3 axis controls tubular cell senescence. Exosome-borne DKK3 influences lipid peroxidation in glomerular endothelial cells, inducing ferroptosis and advancing renal fibrosis, which provides new therapeutic targets for CKD treatment.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"228 ","pages":"Article 112103"},"PeriodicalIF":5.1,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0