Cell Communication and Signaling最新文献

{"title":"AIM2 activation mediated by RIPK1/3-dependent mitochondrial DNA release drives Aβ_1-40-Induced retinal pigment epithelium injury.","authors":"Xiaoxu Huang, Tongqi Li, Guanran Zhang, Jieqiong Chen, Tong Li, Shiqi Yang, Qiyu Bo, Xiaohuan Zhao, Xiaoling Wan, Xinyue Zhu, Bo Yu, Xiaodong Sun, Junran Sun","doi":"10.1186/s12964-025-02294-w","DOIUrl":"10.1186/s12964-025-02294-w","url":null,"abstract":"<p><strong>Background: </strong>The retinal pigment epithelium (RPE) degeneration and subsequent retinal atrophy are hallmarks of age-related macular degeneration (AMD). Amyloid-beta (Aβ), the primary component of amyloid plaques in Alzheimer's disease (AD), is also present within drusen and is considered a critical factor contributing to RPE degeneration in AMD. Recent findings indicate that Aβ-induced inflammation plays a role in RPE degeneration. The aim of this study was to explore the molecular players and the precise mechanisms involved in this process, particularly the potential role of the absent in melanoma 2 (AIM2)-like receptors (ALRs) inflammasome.</p><p><strong>Methods: </strong>An animal model of Aβ_1-40-induced RPE injury was established. Fundus photography, electrophysiology and hematoxylin-eosin staining were used to evaluate the morphological and functional RPE damage. Transcriptome sequencing was used to detect the differentially expressed genes between Aβ_1-40 group and control group. The transcriptional and protein expression levels of AIM2 pathway and RIPK family members were detected. Adeno-associated virus vector 2/2 (AAV2/2)-shAIM2 was constructed to knockdown AIM2 expression in mice RPE cells. Aβ_1-40-treated ARPE-19 cells and hRPE cells were employed to analyze the regulatory effects of RIPK family on mitochondrial DNA (mtDNA) release and AIM2 pathway activation.</p><p><strong>Results: </strong>Aβ induces RPE damage through stimulation of AIM2 inflammasome and augmentation of caspase-1 and interleukin-1β (IL-1β). Knocking down AIM2 inhibits the release of inflammatory cytokines and alleviates the degeneration of the retina and RPE. Simultaneously, Aβ triggers the activation of RIPK1/RIPK3 kinases, as manifested by heightened protein expression and phosphorylation. Inhibiting RIPK1/RIPK3 phosphorylation dampens AIM2 inflammasome activity and curtails IL-1β secretion. Mechanistically, RIPK1/RIPK3 inhibition attenuates Aβ-induced Drp1(S616) hyperphosphorylation, consequently reducing mitochondrial fission and the efflux of mitochondrial DNA (mtDNA) into the cytosol. The diminished mtDNA release is responsible for attenuated AIM2 activation and subsequent inactivation of the stimulator of interferon genes (STING)/nuclear factor-kappa-B (NF-κB) signaling cascade.</p><p><strong>Conclusions: </strong>Our study is the first to validate AIM2's contribution in Aβ-induced RPE pathology and underscore the significance of the RIPK1/RIPK3-induced mtDNA release in modulating inflammatory responses, shedding light on the underlying mechanisms and potential therapeutics of AMD.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"301"},"PeriodicalIF":8.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340670","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":"STING-ΔN, a novel splice isoform of STING, modulates innate immunity and autophagy in response to DNA virus infection.","authors":"Jian Deng, Sheng-Nan Zheng, Jing Zhang, Cheng-Hao Li, Tao Li, Pei-Hui Wang","doi":"10.1186/s12964-025-02305-w","DOIUrl":"10.1186/s12964-025-02305-w","url":null,"abstract":"<p><strong>Background: </strong>Stimulator of interferon (IFN) genes (STING) is a central adaptor protein in the cGAS-STING signaling pathway, orchestrating the production of type I interferons (IFNs) in response to cytosolic DNA detection, a crucial mechanism in antiviral defense. However, further investigation is needed to understand how post-transcriptional regulation, particularly alternative splicing, modulates STING activity.</p><p><strong>Methods: </strong>We identified a novel alternatively spliced isoform of STING, termed STING-∆N, resulting from exon 3 skipping. We examined STING-∆N expression in various human tissues and cell lines and assessed its role in cGAS-STING signaling using RT-qPCR, luciferase reporter assays, SDD-AGE, immunofluorescence, and immunoblot analysis. We evaluated the influence of STING-∆N on HSV-1 proliferation and STING-induced autophagy by viral plaque assay and immunoblotting. To unravel the mechanistic role of STING-∆N, we further investigated its interaction with STING, TBK1, and 2'3'-cGAMP and its effect on the STING-TBK1 complex using co-immunoprecipitation and 2'3'-cGAMP pull-down assay.</p><p><strong>Results: </strong>STING-∆N shares an identical C-terminal sequence (aa 121-379) with STING but lacks a 120-amino acid N-terminal region encoding three conserved transmembrane (TM) domains. STING-∆N is expressed in various human tissues and cell lines. STING-∆N significantly suppressed IFN activation induced by cGAS, 2'3'-cGAMP, and STING. STING-∆N also reduced type I and III IFN induction in response to double-stranded DNA, HPV, and HSV-1. Additionally, STING-∆N promoted HSV-1 replication and inhibited STING-induced autophagy. Mechanistically, STING-∆N interacts with 2'3'-cGAMP, STING, and TBK1, sequestering their binding and disrupting the formation of the 2'3'-cGAMP-STING and STING-TBK1 complexes.</p><p><strong>Conclusions: </strong>STING-∆N acts as a potent negative regulator of the cGAS-STING pathway, revealing a previously unrecognized regulatory mechanism by which alternative splicing modulates immune responses to DNA viruses. These findings suggest that STING-∆N could be a promising therapeutic target for modulating immune responses in viral infections, autoimmune diseases, and cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"299"},"PeriodicalIF":8.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340672","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":"Prevalence and clinical relavance of germline mutations in Chinese patients with pancreatic cancer.","authors":"Yu Jiang, Dan Li, Yang Liu, Jiejie Qin, Hao Chen, Jun Zhang, Yijin Gu, Baiyong Shen, Jiabin Jin","doi":"10.1186/s12964-025-02281-1","DOIUrl":"10.1186/s12964-025-02281-1","url":null,"abstract":"<p><strong>Introduction: </strong>The prevalence and clinical significance of germline sequence variations in unselected Chinese pancreatic cancer (PC) patients remain underexplored.</p><p><strong>Methods: </strong>This retrospective study analyzed PC patients (not selected for age or family history) who underwent germline cancer predisposition gene analysis from January 2019 to December 2023 at Ruijin Hospital. Comparative data were sourced from The Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP) database. Germline P/LP variants were classified using MSK's Precision Oncology Knowledge Base, and their clinical relevance and potential for genotype-directed therapy were evaluated.</p><p><strong>Results: </strong>Sequencing of 1812 unselected Chinese PC cases (1088 [60.0%] male; mean [SD] age, 65.3 [9.5] years) identified 185 pathogenic and Likely pathogenic germline variants (P/LP GVs) in 174 patients (9.3%, 95% CI 8.0%-10.7%), with 43.1% affecting known pancreatic cancer susceptibility genes. Patients with P/LP GVs were diagnosed 2.68 years younger (p < 0.001) than those without. Besides the known PC predisposition genes, DNMT3A emerge as novel potential susceptibility genes for PC. OncoKB classification showed 54.0% had P/LP GVs with therapeutic implications, occurring in 94 out of 1,812 (5.2%) Chinese PC patients. Collectively, P/LP GVs in homologous recombination genes constituted 95.7% (n = 90) of all therapeutically actionable GVs. After adjustment, patients with P/LP GVs exhibited significantly improved overall survival (OS) than those without (HR = 0.7107, 95% CI: 0.5390-0.9373, p = 0.0156). Among patients with P/LP GVs, 119 had de novo metastases. Those with OncoKB level 1 variants had better OS than those without. Additionally, patients received genotype directed chemo or targeted therapies had much better improved survival.</p><p><strong>Conclusion: </strong>In this cohort, 5.2% of PC patients possessed therapeutically relevant P/LPGVs. Germline testing may provide prognostic benefits and is crucial for therapy selection, particularly in metastatic PC patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"300"},"PeriodicalIF":8.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340671","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 neuroinflammatory interactions between microglia and astrocytes in a human iPSC-based coculture platform.","authors":"Iisa Tujula, Tanja Hyvärinen, Johanna Lotila, Julia Rogal, Dimitrios Voulgaris, Lassi Sukki, Kaisa Tornberg, Katri Korpela, Henna Jäntti, Tarja Malm, Anna Herland, Pasi Kallio, Susanna Narkilahti, Sanna Hagman","doi":"10.1186/s12964-025-02304-x","DOIUrl":"10.1186/s12964-025-02304-x","url":null,"abstract":"<p><strong>Background: </strong>Microglia and astrocytes are central mediators of neuroinflammation in several neurodegenerative diseases. Their intricate crosstalk and contributions to pathogenesis remain elusive, highlighting the need for innovative in vitro approaches for investigating glial interactions in neuroinflammation. This study aimed to develop advanced human-based glial coculture models to explore the inflammatory interactions of microglia and astrocytes in vitro.</p><p><strong>Methods: </strong>Human induced pluripotent stem cell (iPSC)-derived microglia and astrocytes were cultured both in conventional culture dishes and in a microfluidic coculture platform. This platform features separate compartments for both cell types, enabling the creation of distinct microenvironments with spontaneous migration of microglia toward astrocytes through interconnecting microtunnels. To induce inflammatory activation, glial cultures were stimulated with lipopolysaccharide (LPS), a combination of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), or interferon-γ (IFN-γ) for 24 h. Glial activation and interactions were analyzed with immunocytochemistry, the secretion of inflammatory factors from the culture media was measured, and microglial migration was quantified.</p><p><strong>Results: </strong>Microglia-astrocyte cocultures were generated in both conventional cultures and the microfluidic platform. Inflammatory stimulation with LPS and TNF-α/IL-1β elicited cell type-specific responses in microglia and astrocytes, respectively. LPS stimulation of cocultures induced lower secretion of several inflammatory mediators, suggesting dampening of microglial inflammatory responses when cocultured with astrocytes. Notably, inflammatory interaction between glial cells was demonstrated by increased level of IL-10 after TNF-α/IL-1β stimulation in cocultures compared with monocultures. The microfluidic coculture platform enabled the parallel study of microglial migration, glial activation and phagocytic function, thereby facilitating the investigation of glial responses within distinct inflammatory microenvironments. Furthermore, glial inflammatory responses and interactions were demonstrated in the controlled microenvironments of the microfluidic coculture platform. The inflammatory coculture environment was associated with elevated levels of complement component C3, emphasizing the intricate interplay between microglia and astrocytes.</p><p><strong>Conclusions: </strong>Our results depict an elaborate inflammatory interaction between iPSC-derived microglia and astrocytes via reciprocal molecular signaling. Importantly, the microfluidic coculture platform established in this study provides a more functional and advanced setup for investigating inflammatory glial interactions in vitro.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"298"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337211","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":"UHRF1 phase separation mediates stable inheritance of DNA methylation and promotes the proliferation of prostate cancer cells.","authors":"Zhean Li, Yihan Wang, Ziqi Yu, Yujia Luo, Yixiang Zhao, Erfei Xue, Junfeng Zhan, Huimin Lu, Fei Sun","doi":"10.1186/s12964-025-02309-6","DOIUrl":"10.1186/s12964-025-02309-6","url":null,"abstract":"<p><p>The primary epigenetic alteration in the development of prostate cancer (PC) is aberrant methylation of the promoter region of tumor suppressor genes. Maintaining DNA methylation activity requires ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1). Through its SET and RING-associated (SRA) domain, UHRF1 identifies methylated cytosine-phosphate-guanine sequences and binds DNA methyltransferase 1 (DNMT1) directly to replicated DNA foci. Nevertheless, the modality used by UHRF1 to regulate gene networks in PC cells precisely and efficiently is unknown. Research has indicated that epigenetic modification is significantly influenced by the phase separation of epigenetic regulators. Thus, the purpose of this work was to find out if UHRF1 phase separation is a mechanism for PC cells to inherit DNA methylation in a stable manner. We evaluated the correlation between UHRF1 expression level and PC development, as well as used PC cell lines to study the mechanism of UHRF1 phase separation driving the progression of PC. The results of this study demonstrated that UHRF1 formed phase-separated droplets by its SRA motif and intrinsically disordered region 3. Furthermore, UHRF1 formed nuclear condensates at the promoter region of multiple cancer-related genes and recruited DNMT1 to allow epigenetic gene silencing that led to malignant proliferation of PC cells. These results revealed that phase separation of UHRF1 is crucial for PC pathogenesis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"297"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337212","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":"Evidence for a JAK2/STAT3 proinflammatory and vasculogenic mimicry interrelated molecular signature in adipocyte-derived mesenchymal stromal/stem cells.","authors":"Carolane Veilleux, Marie-Ève Roy, Alain Zgheib, Michel Desjarlais, Borhane Annabi","doi":"10.1186/s12964-025-02298-6","DOIUrl":"10.1186/s12964-025-02298-6","url":null,"abstract":"<p><strong>Background: </strong>During obesity, the excessive accumulation of fat in tissue promotes dysregulated hormonal and cytokine homeostasis that triggers chronic inflammation, which is, in part, associated with an increased incidence of some cancers. This protumoral inflammatory environment is further exacerbated through the secretome of mature adipocytes, which promotes tumor angiogenesis. Emerging studies suggest that human adipocyte-derived mesenchymal stromal/stem cells (ADMSCs) may contribute to a complementary process supporting local angiogenesis termed vasculogenic mimicry (VM). The molecular mechanisms linking ADMSCs to VM and inflammation remain poorly understood.</p><p><strong>Methods: </strong>ADMSC 3D capillary-like structures were generated upon seeding on Cultrex. Structure analysis was performed using WIMASIS. Total RNA was extracted using TRIzol and RT-qPCR was performed to assess gene expression or screen RT² PCR arrays. Transient gene silencing was performed by transfecting cells with a specific siRNA against STAT3. Protein lysates were harvested and used for Western blotting. Realtime cell migration was performed with the xCELLigence system.</p><p><strong>Results: </strong>Our findings revealed that in vitro priming of ADMSCs with Cultrex led to the formation of 3D capillary-like structures and the acquisition of an inflammatory molecular signature. VM-derived ADMSCs share a common proinflammatory molecular signature similar to that induced in 2D ADMSC monolayers by tumor necrosis factor (TNF)-alpha and are characterized by upregulated expression of COX2, CCL2, CCL5, CXCL5, CXCL8, IL-6, SNAI1, and MMP9. Interestingly, pharmacological inhibition or gene silencing of the JAK2/STAT3 signaling pathway reduced chemotactic cell migration, in vitro VM and the expression of proinflammatory and invasive biomarkers.</p><p><strong>Conclusions: </strong>Overall, we provide novel evidence that inhibiting JAK2/STAT3-regulated VM can also alter the acquisition of a proinflammatory signature and prevent the contribution of ADMSCs to alternative tumor neovascularization processes.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"291"},"PeriodicalIF":8.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334530","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 Src family kinase inhibitor drug Dasatinib and glucocorticoids display synergistic activity against tongue squamous cell carcinoma and reduce MET kinase activity.","authors":"Ali N A Hmedat, Jessica Doondeea, Daniel Ebner, Stephan M Feller, Marc Lewitzky","doi":"10.1186/s12964-025-02129-8","DOIUrl":"10.1186/s12964-025-02129-8","url":null,"abstract":"<p><strong>Background: </strong>Tongue squamous cell carcinoma (TSCC) is an aggressive cancer associated with a poor prognosis and limited treatment options, necessitating new drug targets to improve therapeutic outcomes. Our current work studies protein tyrosine kinases as well-known targets for successful cancer therapies. It focuses on Src family kinases (SFK), which are known to play a critical role in some head and neck tumors.</p><p><strong>Methods: </strong>Western blot analyses of phospho-tyrosine protein patterns in 34 TSCC lines facilitated the investigation of SFK as contributors to these phosphorylations. The SFK inhibitors PP2 and Dasatinib were utilized to determine SFK contributions to cell motility and survival. A high-throughput screen with 1600 FDA-approved drugs was performed with three TSCC lines to discover drugs that act synergistically with Dasatinib against TSCC cell viability. Glucocorticoids emerged as potential candidates and were further investigated in 2D culture and by 3D soft agar colony formation. Dexamethasone was chosen as the major tool for our analyses of synergistic effects of Dasatinib and glucocorticoids on TSCC lines. Effects on the cell cycle were investigated by flow cytometry and expression levels of cell cycle regulators. Senescence was analyzed by senescence-associated β galactosidase detection and p27Kip1 protein expression. Autophagy was measured by Acridine Orange staining.</p><p><strong>Results: </strong>A panel of 34 TSCC lines showed a surprisingly homogenous pTyr-protein pattern and a prominent 130 kDa pTyr-protein. Inhibition of SFK activity greatly reduced overall pTyr-protein levels and p130Cas tyrosine phosphorylation. It also impaired TSCC viability in 2D cell culture and 3D soft agar colony formation. A high-throughput drug combination screen with Dasatinib identified glucocorticoids as promising candidates for synergistic activity. Dasatinib and Dexamethasone combination treatment showed strong synergistic effects on Src and p130Cas phosphorylation and led to reduced p130Cas expression. Dexamethasone also suppressed phosphorylation of the MET kinase and its key substrate Gab1. On the cellular level, Dasatinib combination with glucocorticoids led to G1 cell cycle arrest, appeared to increase senescence and enhanced autophagy. This was also reflected by effects on cell cycle regulatory proteins, including CDKs and cyclins.</p><p><strong>Conclusion: </strong>This work is the first to show a strong synergistic activity of Dasatinib in combination with clinically used glucocorticoids in solid tumors. Furthermore, the tyrosine kinase MET and its effector protein Gab1 are newly identified glucocorticoid targets. Given the extensive research on MET as a drug target in various cancers, our findings have the potential to advance future cancer treatments.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"293"},"PeriodicalIF":8.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334434","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":"Mitochondrial dysfunction in the regulation of aging and aging-related diseases.","authors":"Xianhong Zhang, Yue Gao, Siyu Zhang, Yiqi Wang, Xinke Pei, Yufei Chen, Jinhui Zhang, Yichen Zhang, Yitian Du, Shauilin Hao, Yujiong Wang, Ting Ni","doi":"10.1186/s12964-025-02308-7","DOIUrl":"10.1186/s12964-025-02308-7","url":null,"abstract":"<p><p>Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"290"},"PeriodicalIF":8.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334532","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":"Role of DEAD/DEAH-box helicases in immunity, infection and cancers.","authors":"Rex Devasahayam Arokia Balaya, Saptami Kanekar, Shreya Kumar, Richard K Kandasamy","doi":"10.1186/s12964-025-02225-9","DOIUrl":"10.1186/s12964-025-02225-9","url":null,"abstract":"<p><p>DEAD/DEAH-box helicases (DDX) are integral RNA-binding proteins within the RNA helicase superfamily 2 (SF2), characterized by distinct DEAD (Asp-Glu-Ala-Asp) and DEAH (Asp-Glu-Ala-His) motifs. These motifs delineate two subfamilies: DEAD-box (DDX) and DEAH-box (DHX). DEAD-box proteins predominantly facilitate localized non-processive RNA duplex destabilization, whereas DEAH-box helicases mediate processive RNA translocation and unwinding. This functional dichotomy is attributed to Asp-to-His substitution in the DEAH motif, which modulates ATP hydrolysis and conformational dynamics. DEAD-box helicases have been implicated in critical cellular processes, including translation, splicing, and RNA decay. In contrast, DEAH-box proteins play pivotal roles in splicing, ribosome biogenesis, and RNA export. DEAD/DEAH-box helicases play crucial roles in various cellular processes, and their regulation is primarily governed by post-translational modifications (PTMs) and protein-protein interactions (PPIs), particularly within their N- and C-terminal sequences. Despite extensive research, significant knowledge gaps persist regarding their regulation, cofactor roles, substrates, PPIs, mutation effects, and involvement in signaling cascades. Mutations in DEAD domains have been associated with dysregulated immune signaling and have been implicated in various cancers, underscoring their importance in disease pathogenesis. Specific helicases, including DDX3, DDX5, DDX6, and DDX41, have been extensively studied for their roles in immune response regulation, antiviral defense, and cellular stress response. This review critically examines the DEAD-box helicases involved in cell cycle regulation and their inhibitors, as well as those that regulate the Toll-like receptor signaling pathway. Furthermore, we provide comprehensive insights into the phosphorylation-based regulation of major DDX members, with a particular focus on DDX3X, DDX21, and DDX42 in various cancers. Elucidating the molecular mechanisms, regulatory influences, and therapeutic potential of DEAD/DEAH-box helicases is of paramount importance, particularly in the fields of infectious diseases and immune modulation. This review provides current knowledge and identifies critical areas for future research, aiming to advance our understanding of these essential molecular machines and their potential as therapeutic targets.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"292"},"PeriodicalIF":8.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334533","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":"Differential impact of hepatitis delta virus replication and expression of viral antigens on the cellular kinome profile.","authors":"Keerthihan Thiyagarajah, Mirco Glitscher, Kai-Henrik Peiffer, Eberhard Hildt","doi":"10.1186/s12964-025-02290-0","DOIUrl":"10.1186/s12964-025-02290-0","url":null,"abstract":"<p><strong>Background: </strong>An infection with hepatitis D virus (HDV) is considered the most extreme form of viral hepatitis. Infection with HDV elicits strong increases in inflammation and hepatic injury, therefore pushing liver cirrhosis and development of hepatocellular carcinoma (HCC). Despite this, little is known on how HDV influences the host-cell's equilibrium. As the pathogenesis is majorly driven by host-responses, a deep understanding is required in terms of how signalling cascades are modulated by the virus in order to identify targets for preventive and therapeutic strategies. Accordingly, this study aims to establish the kinome profile for HDAg-expressing and HDV-replicating cells which could serve as base for future research characterizing HDV-host interaction.</p><p><strong>Methods: </strong>We performed kinome profiling in Huh7 cells ectopically expressing the two HDV protein isoforms S- and LHDAg or replicating HDV genomes. Significantly deregulated kinases were identified using an array-based screening.</p><p><strong>Results: </strong>The different HDAg isoforms revealed a differential impact on the overall signalling landscape predominantly in nucleoplasm. Enrichment analyses indicated that HDAg and HDV-replication elicit kinomic changes overlapping with footprints of several diseases such as viral carcinogenesis and HCC. The responsible kinases therefore present promising targets of intervention. Moreover, pathways of innate immunity, inflammation, growth-factor-response yet also distinct modulatory signalling cascades were identified. Most prominently, the MAPK- and PI3K-Akt-cascades were affected by all experimental conditions. Within these cascades AKT1, GSK3A and PRKACA were identified as the most influential hits. A hierarchical pathway map of identified deregulated kinases indicated major changes in inflammatory processes, cell cycle control and metabolic control.</p><p><strong>Conclusions: </strong>A detailed analysis of the impact of HDV on the cellular kinome was established. Based on this, host-factors, single hits and even entire signalling cascades were identified. These advance understanding of HDV life cycle, and support development of novel therapeutics, yet also help to assess pathogenic processes.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"294"},"PeriodicalIF":8.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334529","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}