Cellular and Molecular Life Sciences最新文献

{"title":"Lithocholic acid ameliorates ulcerative colitis via the PXR/TLR4/NF-κB/NLRP3 signaling pathway and gut microbiota modulation.","authors":"Yaoyao Liu, Jie Gao, Lu Chen, Yanfang Chen, Jingjing Jiang, Hong Chen, Li Ma","doi":"10.1007/s00018-025-05834-2","DOIUrl":"10.1007/s00018-025-05834-2","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, closely linked to dysbiosis of gut microbiota and imbalances in bile acids. Lithocholic acid (LCA), a secondary bile acid, plays a crucial role in maintaining gut health; however, its specific therapeutic potential in UC remains to be fully elucidated. This study investigates the efficacy of LCA in alleviating UC and explores the underlying mechanisms, particularly focusing on the PXR/TLR4/NF-κB/NLRP3 signaling pathway and gut microbiota modulation. Using a dextran sulfate sodium (DSS)-induced colitis model, our findings demonstrate that LCA administration significantly alleviates colitis symptoms, evidenced by reduced disease activity index (DAI), increased colon length, improved intestinal barrier function, and decreased colonic inflammation. Mechanistically, LCA activates the pregnane X receptor (PXR), which inhibits TLR4-mediated NF-κB/NLRP3 inflammasome activation, leading to reduced colonic inflammation and lower levels of pro-inflammatory cytokines. Furthermore, LCA remodels gut microbiota by promoting beneficial bacterial growth, such as Akkermansiaceae, Lactobacillaceae and Muribaculaceae, while suppressing pathogenic and opportunistic pathogens, including Enterobacteriaceae and Bacteroidaceae. The gut microbiota-dependent effects of LCA were corroborated through antibiotic treatment and fecal microbiota transplantation (FMT) experiments. Notably, the absence of intestinal flora affected PXR expression and activity, modifying the aforementioned effects. Overall, our findings reveal that LCA ameliorates experimental colitis by regulating the PXR/TLR4/NF-κB/NLRP3 signaling cascade and modulating gut microbiota composition. This study underscores LCA's potential as a targeted therapeutic strategy and a promising microbiota-focused approach for managing UC, offering new insights into the role of bile acids in intestinal health and disease management.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"336"},"PeriodicalIF":6.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991613","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":"pVHL regulates protein stability of the TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation.","authors":"Caixia Wang, Xiaozhi Rong, Haifeng Zhang, Bo Wang, Yan Bai, Yonghua Sun, Chengtian Zhao, Jianfeng Zhou","doi":"10.1007/s00018-025-05852-0","DOIUrl":"10.1007/s00018-025-05852-0","url":null,"abstract":"<p><p>The Wnt/β-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. TCF/LEF transcription factors play a pivotal role in this pathway, acting as repressors by recruiting co-repressors in the absence of Wnt signals, and as activators via β-catenin binding in the presence of Wnt signaling. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Using cultured cells and zebrafish as in vitro and in vivo models, we demonstrated that the von Hippel-Lindau protein (pVHL), the substrate recognition component of an E3 ubiquitin ligase complex, regulates the stability of TCF/LEF proteins. Unexpectedly, pVHL directly binds to TCF/LEF and promotes their proteasomal degradation independent of its E3 ubiquitin ligase activity. Notably, a human homologue of pVHL, the pVHL-like protein (pVHLL), which lacks the capability to assemble an E3 ligase complex with Elongin B/C, RBX1, and CUL2, similarly downregulates TCF/LEF protein levels. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent function of pVHL and uncover a novel mechanistic regulation of Wnt/β-catenin signaling.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"335"},"PeriodicalIF":6.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991652","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":"A key spectral tuning site of UV-sensitive vertebrate non-visual opsin Opn5.","authors":"Takahiro Yamashita, Kazuyuki Asamoto, Kengo Fujii, Chihiro Fujiyabu, Hideyo Ohuchi, Yoshinori Shichida","doi":"10.1007/s00018-025-05879-3","DOIUrl":"10.1007/s00018-025-05879-3","url":null,"abstract":"<p><p>Opsins are photoreceptive proteins responsible for visual and non-visual photoreceptions in animals. In general, vertebrates have multiple visual and non-visual opsins whose spectral sensitivities range from the UV to the red region. Among these opsins, Opn5 has been widely identified in vertebrates from fishes to primates and functions as a non-visual opsin in various tissues, including the retina and brain. Vertebrate Opn5 has been characterized as a UV-sensitive bistable opsin. Thus, Opn5 provides one of the molecular mechanisms determining the short wavelength limit that vertebrates can detect. In this study, we searched for the amino acid residue responsible for the UV light sensitivity of Opn5. Our mutational analysis revealed that Opn5 acquired visible light sensitivity by the substitution of Lys91 with an amino acid other than an arginine or tyrosine residue. In addition, the mutations at Lys91 altered the preferential binding of the retinal isomers in Opn5. Therefore, the conservation of Lys91 among vertebrate Opn5 proteins would be necessary to enable Opn5 to work as the shortest wavelength sensor in various tissues.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"334"},"PeriodicalIF":6.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944805","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":"DDX60 protects ischemic myocardial injury and heart dysfunction by improving mitochondrial function via promoting Arl2 mRNA translation.","authors":"Tianyou Yuan, Changzuan Zhou, Yifan Long, Xiaoqiang Chen, Longzhe Gao, Ya Li, Songwen Chen, Xiaofeng Lu, Juan Xu, Xiaoyu Wu, Genqing Zhou, Shaowen Liu, Wenyi Yang, Yong Wei, Lidong Cai","doi":"10.1007/s00018-025-05839-x","DOIUrl":"10.1007/s00018-025-05839-x","url":null,"abstract":"<p><p>Mitochondrial dysfunction is increasingly recognized as a pivotal driver of cardiomyocyte apoptosis and cardiac deterioration following myocardial infarction (MI). This study identifies a significant upregulation of DDX60 in cardiomyocytes under hypoxic conditions. Elevated DDX60 levels enhance mitochondrial function and attenuate cardiomyocyte apoptosis in vitro, whereas its knockdown induces the opposite effects. In vivo, cardiomyocyte-specific DDX60 knockout markedly exacerbates mitochondrial dysfunction and apoptosis, accelerating post-MI cardiac remodeling and functional decline. Furthermore, we found that Arl2 knockdown partially negates the protective effects of DDX60 overexpression on ATP production and apoptosis. Conversely, adeno-associated virus-9 (AAV9)-mediated Arl2 overexpression partially restores cardiac function, reduces infarct size, and rescues mitochondrial integrity in DDX60 CKO mice post-MI. Mechanistically, DDX60 forms a translational complex with eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) that enhances Arl2 mRNA translation, a process essential for mitochondrial homeostasis. Collectively, these findings establish DDX60 as a key regulator of cardioprotection post-MI by enhancing Arl2 translation, highlighting its potential as a therapeutic target for ischemic heart disease.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"332"},"PeriodicalIF":6.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944858","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":"Modeling of kidney allograft rejection using hiPSC-derived kidney organoids and HLA-mismatched PBMCs: an in vitro co-culture system.","authors":"Sun Woo Lim, Sheng Cui, Xianying Fang, Do Hyun Na, Hanbi Lee, Yoo Jin Shin, Hyunhye Kang, Eun-Jee Oh, Byung Ha Chung","doi":"10.1007/s00018-025-05867-7","DOIUrl":"10.1007/s00018-025-05867-7","url":null,"abstract":"<p><p>The aim of this study is to establish an in vitro co-culture system to model allograft rejection using kidney organoids system derived from human induced pluripotent stem cells (hiPSCs). We co-cultured kidney organoids derived from wild-type hiPSCs with HLA-mismatched peripheral blood mononuclear cells (PBMCs) from healthy controls (HC) for 24 h. To assess allogeneic rejection modeling, we measured the expression of HLA molecules, (HLA-ABC and HLA-DR), and evaluated cellular damage in the kidney organoids. Additionally, we analyzed the distribution of T cells and their subsets within the co-cultured PBMCs. The immunosuppressive effect of tacrolimus was also evaluated in this co-culture system. Transcriptomic analysis, conducted using RNA sequencing, identified molecules associated with allogeneic rejection. When kidney organoids were co-cultured with alloreactive PBMCs for 24 h, HLA-ABC and HLA-DR expression significantly increased in kidney organoid cells. Additionally, kidney organoids showed reduced cell viability and increased apoptosis compared to syngeneic controls, as assessed by flow cytometry and Annexin V/PI staining. However, treatment with tacrolimus reduced HLA expression in a dose-dependent manner, highlighting the diminished alloimmune responses. Further analysis of PBMC subsets revealed shifts in T helper (TH) and cytotoxic T cell (TC) populations under allogeneic conditions, including increased effector TH and TC cells. Transcriptomic analysis through RNA sequencing identified 256 differentially expressed genes (DEGs), with notable immune-related pathways such as NF-kappa B and TNF signaling involved in allograft rejection. These results provide evidence that a co-culture system with allogeneic kidney organoids and PBMCs can potentially model transplant rejection in vitro.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"333"},"PeriodicalIF":6.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944749","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 transcriptional regulation of NUPR1 expression by MYC is implicated in the regulation of ferroptosis in human spermatogonial stem cells.","authors":"Junxiao Yang, Yueling Zhang, Jiakun Deng, Chunyun Li, Wei Chen, Yinghong Cui, Haibin Zhang","doi":"10.1007/s00018-025-05818-2","DOIUrl":"10.1007/s00018-025-05818-2","url":null,"abstract":"<p><p>Non-obstructive azoospermia (NOA) is a leading cause of male infertility, characterized by impaired spermatogenesis. Recent studies suggest that ferroptosis, an iron-dependent form of cell death, may contribute to testicular dysfunction, however, its role in NOA remains underexplored. In this study, we investigated the roles of NUPR1 and MYC in regulating ferroptosis in human spermatogonial stem cells (SSCs) and evaluated their potential as therapeutic targets for NOA. Single-cell RNA sequencing of testicular tissues from NOA and obstructive azoospermia (OA) patients revealed distinct cellular populations, with UMAP clustering showing a significant reduction in germ cells in NOA samples. High-dimensional weighted gene co-expression network analysis (hdWGCNA) identified two key modules (red and green-yellow) that were associated with spermatogonia. Integrative analysis of scRNA-seq, microarray datasets, and ferroptosis-related genes identified NUPR1 as a key regulatory gene. Immunofluorescence analysis demonstrated NUPR1 co-localization with SSC markers PLZF and UCHL1, and its expression was significantly lower in the testes of NOA patients compared to fertile controls. NUPR1 knockdown in SSCs led to increased ROS levels, lipid peroxidation, and Fe²⁺ accumulation, along with decreased expression of key ferroptosis markers such as GPX4, NRF2, and KEAP1, cycloheximide chase assays further demonstrated that NUPR1 depletion accelerates the degradation of GPX4 and NRF2, confirming NUPR1's role in ferroptosis regulation. Moreover, chromatin immunoprecipitation (ChIP) assays showed that MYC binds directly to the NUPR1 promoter, suggesting MYC's involvement in regulating ferroptosis through NUPR1. These findings identify NUPR1 and MYC as critical regulators of ferroptosis in SSCs, providing novel insights into the molecular mechanisms of NOA and suggesting potential therapeutic strategies targeting ferroptosis for male infertility.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"331"},"PeriodicalIF":6.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944852","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":"Molecular components of the FPR2/ALX pathway participate in astrocyte-neuron resolution responses to afford maneb-induced toxicity.","authors":"Oriana N Benzi Juncos, Natalia P Alza, José L Cordero, Nelson P Barrera, Gabriela A Salvador","doi":"10.1007/s00018-025-05841-3","DOIUrl":"https://doi.org/10.1007/s00018-025-05841-3","url":null,"abstract":"<p><p>Environmental toxicants such as maneb (MB), a dithiocarbamate pesticide, trigger progressive neuronal death, probably due to the imbalance in inflammation/resolution mechanisms, resulting in the onset of neurodegeneration. The inflammation/resolution balance is governed by G protein-coupled receptor (GPCR) signaling, but it has been poorly described in the Central Nervous System (CNS), since resolution GPCR ligands are negligible and elusive lipid compounds. These mediators are mainly synthesized by lipoxygenases (ALOX) from arachidonic acid (AA) and docosahexaenoic acid (DHA) released by specific phospholipases A2 (PLA2). Thus, we aimed to characterize the molecular components of resolution involved in neuron-astrocyte communication in response to MB-induced toxicity. The metabolomics study showed significant changes in 20 metabolites in neurons and 43 in astrocytes as a response to MB treatment. Major phospholipids' content (phosphatidylcholine - PC - and phosphatidylethanolamine) was reduced in both cell types with a simultaneous increase in lysophospholipids. In silico analysis revealed the upregulation of a Group IID secretory phospholipase A2 (sPLA2-IID), and the fatty acid profile showed increased neuronal DHA content and decreased AA and DHA levels in astrocytes. In addition, increased DHA esterified-PC content in neurons exposed to MB was observed. Astrocyte secretome and its lipid extract protected neurons against MB-induced toxicity. This neuroprotective effect was abolished by blocking AA and DHA oxygenation by ALOX-15 and associated with the activation of the formyl peptide receptor 2 (FPR2/ALX), probably mediated by lipoxin A4. Moreover, a neuronal lipid ligand induced astrocyte proliferation through this GPCR. Our study suggests that molecular components of the FPR2/ALX pathway participate in both the neuroprotection exerted by astrocytes and astrocytic proliferative signals shaped by neurons under MB toxicity.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"327"},"PeriodicalIF":6.2,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944831","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":"Heterogeneity of radial spoke components in Tetrahymena cilia.","authors":"Marta Bicka, Avrin Ghanaeian, Corbin Black, Ewa Joachimiak, Anna Osinka, Sumita Majhi, Anna Konopka, Ewa Bulska, Khanh Huy Bui, Dorota Wloga","doi":"10.1007/s00018-025-05871-x","DOIUrl":"https://doi.org/10.1007/s00018-025-05871-x","url":null,"abstract":"<p><p>Radial spokes, RS1, RS2, and RS3, are T-shaped, multiprotein complexes that transmit regulatory signals from the central apparatus to outer doublet complexes, including dynein arms. Radial spokes, especially RS3, differ in their morphology, protein composition, and RS base-docked IDAs. Spokes' defects alter cilia beating frequency, waveform, and amplitude, leading, in humans, to primary ciliary dyskinesia and male infertility. The role of the particular spokes remains unclear. Ciliate Tetrahymena thermophila has three RSP3 paralogs and two or three paralogs of some other RSPs. Using multiple complementary approaches, we demonstrated that Tetrahymena forms RS1 and RS2 subtypes, each with a core composed of various RSP3 paralogs and one type of RSP3-less RS3. We elucidated proteomes of RS1 and RS2 subtypes, RS3, and identified novel RS proteins, including enzymatic proteins involved in local regulation of ADP/ATP levels, the guanylate nucleotide pathway, and protein phosphorylation, whose presence further diversifies RSs' properties and likely functions.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"329"},"PeriodicalIF":6.2,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944808","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":"Melatonin attenuates intervertebral disc degeneration by restoring mitochondrial homeostasis through PGC-1α signaling pathway.","authors":"Tao Lan, Wenhan Yang, Bin Yan, Weizhuang Guo, Yuantao Zhang","doi":"10.1007/s00018-025-05877-5","DOIUrl":"https://doi.org/10.1007/s00018-025-05877-5","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP) and poses a substantial economic burden worldwide. Mitochondrial dysfunction, associated with oxidative stress and apoptosis, is linked to various degenerative diseases. Melatonin has emerged as a potential therapeutic agent for preventing IVDD because of its capacity to regulate cellular rhythms. The impact of melatonin on mitochondrial dysfunction and its underlying mechanisms is not yet fully understood. Firstly, Cell Counting Kit-8 (CCK-8) assay was used to evaluate nucleus pulposus (NP) cell viability treated with melatonin and advanced oxidation protein products (AOPP). Then, Western blotting, immunofluorescence and tunnel staining were employed to explore the underlying mechanisms in vitro. Next, a needle-punctured rat model followed by radiographic analysis and immunohistochemical staining was used to evaluate the potential effect of melatonin in vivo. This study demonstrated that AOPP triggered oxidative stress, exacerbated mitochondrial injury, and increased NP cell apoptosis. Additionally, melatonin enhanced mitochondrial function and protected NP cells from oxidative injury. Further studies demonstrated that melatonin enhanced mitochondrial biogenesis and modulated mitochondrial dynamics and mitophagy via the Peroxisome proliferator-activated receptorγcoactivator 1α (PGC-1α) signaling pathway, maintaining mitochondrial homeostasis and thereby decreasing excessive apoptosis and extracellular matrix (ECM) degradation. A PGC-1α inhibitor lessened melatonin's effect on the mitochondrial quality system, weakening its protective function in NP cells against oxidative stress. Furthermore, in vivo experiments confirmed that melatonin slowed the progression of IVDD. These findings provide a theoretical basis for treating IVDD by targeting mitochondrial dysfunction and modulating the mitochondrial quality control system. Melatonin could be an effective treatment for IVDD.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"330"},"PeriodicalIF":6.2,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944448","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":"Interrogating the regulatory epigenome of cellular senescence.","authors":"Dimitris-Foivos Thanos, Orestis A Ntintas, Emmanouil I Athanasiadis, Angelos Papaspyropoulos, Russell Petty, Vassilis G Gorgoulis","doi":"10.1007/s00018-025-05848-w","DOIUrl":"https://doi.org/10.1007/s00018-025-05848-w","url":null,"abstract":"<p><p>Chromatin, the spatial organizer of genomic DNA, is hierarchically folded into higher-order structures to facilitate DNA compaction, enabling genome surveillance. Understanding the organization and function of the three-dimensional (3D) genome is critical to profile chromatin accessibility and functional interactions that govern gene regulation across multiple biological processes, including aging and one of its hallmarks, cellular senescence. Cellular senescence constitutes a defensive stress response to various intrinsic and extrinsic stimuli, preserving cellular and organismal homeostasis through a generally irreversible cell cycle arrest. In this review article we discuss epigenetic alterations occurring to DNA and chromatin that drive and fuel the onset of this complex phenomenon. As such, we describe major large-scale chromatin events, including the formation of higher-order chromatin structures and the 3D spatial alterations of the genome that occur during senescence. We also discuss global heterochromatin loss, deficiencies in nuclear lamins, the depletion of core histones and their modifications, as well as the epigenetic regulation of the senescence-associated secretory phenotype (SASP), all of which serve key roles in the epigenome of senescent cells. To clearly demonstrate the significance of epigenetic modifications, data from a computational meta-analysis are presented, aiming to further underpin key epigenetic mechanisms occurring in senescent cells. Last, we highlight promising epigenetic modulators implemented in therapeutic strategies for senescent cell detection and elimination, possibly leading to significant clinical advances against various age-related diseases as well as the delay and prevention of the aging onset.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"328"},"PeriodicalIF":6.2,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944854","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}