Cell Communication and Signaling最新文献

{"title":"Programmed cell death protein 1 in cancer cells.","authors":"Chunlian Wei, Meijun Liu, Weifen Zhang","doi":"10.1186/s12964-025-02155-6","DOIUrl":"https://doi.org/10.1186/s12964-025-02155-6","url":null,"abstract":"<p><p>Programmed cell death protein 1 (PD-1) is frequently detected in certain subsets of tumor cells, and our understanding of PD-1 signaling consequences has expanded to include control of tumor growth, stemness and drug resistance. Nonetheless, tumor cell-intrinsic PD-1 has been comparatively underexplored in relation to PD-1 expressed on the surface of immune cells as an immune checkpoint, despite the imperative need to comprehensively elucidate the underlying mechanisms of action for achieving optimal responses in tumor immunotherapy. Here, we review the roles of the regulation and function of tumor-intrinsic PD-1 from its expression to degradation processes. Our primary focus is on unraveling its enigmatic influence on tumorigenesis and progression as proposed by recent findings, while navigating the labyrinthine network of regulatory mechanisms governing its expression and intricate functional interplay. We also discuss how the elucidation of the mechanistic underpinnings of tumor-intrinsic PD-1 expression holds the potential to explain the divergent therapeutic outcomes observed with anti-PD-1-based combination therapies, thereby furnishing indispensable insights crucial for synergistic anti-tumor strategies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"185"},"PeriodicalIF":8.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052963","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":"Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis.","authors":"Yue Zhang, Karim Katkhada, Liu Zhen Meng, Binbin Zhao, Shanlin Tong, Wiem Chaabane, Aditi Kallai, Nicholas P Tobin, Arne Östman, Alessandro Mega, Monika Ehnman","doi":"10.1186/s12964-025-02171-6","DOIUrl":"https://doi.org/10.1186/s12964-025-02171-6","url":null,"abstract":"<p><strong>Background: </strong>Mesenchymal stromal cells belong to a diverse collection of cells in different states that are poorly characterized in soft-tissue sarcomas. In this study, we explored tumor growth-regulatory signaling between differentially educated non-malignant mesenchymal stromal cells and malignant cells in pediatric rhabdomyosarcoma (RMS).</p><p><strong>Methods: </strong>Xenograft experiments demonstrated that non-malignant stromal cells influence tumor behavior. Gene expression analysis identified deregulated genes, which were further studied using cell culture assays and patient data. Clinicopathological correlations were made in a discovery cohort (N = 147) and a validation cohort (N = 101).</p><p><strong>Results: </strong>The results revealed transiently suppressive paracrine effects of orthotopic stromal cells derived from skeletal muscle. These effects were lost when the stromal cells were exposed to RMS cells, either short-term in vitro, or long-term in hindlimb muscle in vivo. High resolution microarray-based Clariom D gene expression analysis identified insulin-like growth factor binding protein 5 (IGFBP5) as the top upregulated gene in RMS cells exposed to naïve stromal cells, and effects on growth arrest, caspase 3/7 activation, and myogenic cell identity were demonstrated in functional assays. Furthermore, IGFBP5 associated with the caspase 3 substrate growth arrest specific protein 2 (GAS2), lower disease stage and favorable survival in patient cohorts.</p><p><strong>Conclusions: </strong>This study uses functional modeling and omics approaches to identify IGFBP5 as a candidate mediator of anti-tumor growth mechanisms originating from tumor-neighboring mesenchymal stromal cells. Tumors of mesenchymal origin, such as RMS, are known for their heterogeneity, and this could potentially pose a limitation to the study. However, a clinical relevance is emphasized by consistent findings across patient cohorts. These insights pave the way for novel therapeutic strategies modulating activities of stromal cell subsets at primary and metastatic sites in RMS.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"184"},"PeriodicalIF":8.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063296","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":"Microvesicles carrying EV71 virions cross BBB through endocytic pathway to induce brain injury.","authors":"Xiaoyan Tian, Bingxin Liu, Linrun Li, Meng Yuan, Qiao You, Rui Zhang, Deyan Chen, Min Cheng, Nan Zheng, Miao He, Zhiwei Wu","doi":"10.1186/s12964-025-02195-y","DOIUrl":"https://doi.org/10.1186/s12964-025-02195-y","url":null,"abstract":"<p><p>Enterovirus 71 (EV71) is a major etiologic pathogen for hand-foot-and-mouth disease (HFMD) in young children. Severe cases of EV71 infection could lead to neurological complications and even death, while the mechanism inducing neurological complications remains poorly understood. In this study, we firstly proved that microvesicles (MVs) could carry EV71 virions and mediate a higher efficiency in infection. Utilizing an in vitro blood-brain barrier (BBB) model, we observed that MVs containing virions (MVsEV71) could cross the BBB with greater efficiency compared to EV71 alone. Through in vivo imaging, we confirmed the ability of MVs to cross the BBB. qPCR assays showed a higher copy number of EV71 in both blood and brain samples in the mice treated with MVsEV71 compared to those treated with free EV71. Also, our investigation unveiled that MVsEV71 infection of animals induced cerebral hemorrhage and more severe inflammatory infiltration in the brain compared to animals infected by EV71 in vivo. Furthermore, we found a reduction in the expression of junction proteins such as zonula occludens-1 (ZO-1) and occludin. Moreover, the uptake of MVs by brain cells was examined using chemical inhibitor to block the endocytic pathway. Our experiments elucidated that the internalization of MVs occurred via a non-clathrin-dependent mechanism and a portion of the internalized MVs proceeded to enter lysosomes. In addition, we identified damaged mitochondria as the \"cargo\" of MVs, which facilitated MVsEV71 crossing the BBB and inducing cellular apoptosis. Meanwhile, MVsEV71 crossing the BBB further induced mitochondrial damaged and activated NOX4-derived ROS pathway in U251 cells. Taken together, these findings suggested that MVs transported EV71 virions across the BBB, while damaged mitochondria facilitated this process and aggravated the brain injury. Overall, these observations provide new insights into EV71-induced neurogenic complications and present a novel therapeutic target for the treatment of viral encephalitis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"183"},"PeriodicalIF":8.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045197","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":"Hematopoietic stem cell state and fate in trained immunity.","authors":"Weinian Liao, Xiaodong Zai, Jun Zhang, Junjie Xu","doi":"10.1186/s12964-025-02192-1","DOIUrl":"https://doi.org/10.1186/s12964-025-02192-1","url":null,"abstract":"<p><p>Trained immunity serves as a de facto memory for innate immune responses, resulting in long-term functional reprogramming of innate immune cells. It enhances resistance to pathogens and augments immunosurveillance under physiological conditions. Given that innate immune cells typically have a short lifespan and do not divide, persistent innate immune memory may be mediated by epigenetic and metabolic changes in long-lived hematopoietic stem cells (HSCs) in the bone marrow. HSCs fine-tune their state and fate in various training conditions, thereby generating functionally adapted progeny cells that orchestrate innate immune plasticity. Notably, both beneficial and maladaptive trained immunity processes can comprehensively influence HSC state and fate, leading to divergent hematopoiesis and immune outcomes. However, the underlying mechanisms are still not fully understood. In this review, we summarize recent advances regarding HSC state and fate in the context of trained immunity. By elucidating the stem cell-intrinsic and extrinsic regulatory network, we aim to refine current models of innate immune memory and provide actionable insights for developing targeted therapies against infectious diseases and chronic inflammation. Furthermore, we propose a conceptual framework for engineering precision-trained immunity through HSC-targeted interventions.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"182"},"PeriodicalIF":8.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063291","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":"Acidosis-induced p38-kinase activation triggers an IL-6-mediated crosstalk of renal proximal tubule cells with fibroblasts leading to their inflammatory response.","authors":"Marie-Christin Schulz, Nathalie Wolff, Michael Kopf, Micheal Gekle","doi":"10.1186/s12964-025-02180-5","DOIUrl":"https://doi.org/10.1186/s12964-025-02180-5","url":null,"abstract":"<p><strong>Background: </strong>Local interstitial acidosis in chronic kidney disease (CKD) induces inflammatory responses and dedifferentiation of proximal tubule cells (PTCs), disrupting cellular crosstalk through cytokine and COX-2 metabolite secretion. This promotes a switch to an inflammatory fibroblast phenotype, further exacerbating inflammation and PTC dedifferentiation. p38-signaling and downstream transcription factors, including P-CREB and c-fos, contribute to these responses. This study investigates the impact of acidosis on inflammatory responses in PTCs and fibroblasts, focusing on cellular crosstalk and the role of p38-signaling.</p><p><strong>Methods: </strong>HK-2 (human PTCs) and CCD-1092Sk (human fibroblasts) were exposed to acidic or control media in mono- and coculture for 30 min, 3 h, or 48 h. Protein expression of IL-6, phosphorylated (P-) and total CREB, P- and total SRF, c-fos, and P- and total p38 was analyzed by western blot. IL-6 secretion was measured using ELISA. The impact of p38 and IL-6 receptor activity was assessed by pharmacological intervention.</p><p><strong>Results: </strong>In coculture, acidosis initially caused a transient decrease in IL-6 secretion but significantly increased IL-6 levels after 48 h. Acidosis induced intracellular IL-6 expression in HK-2 cells within 3 h independent of culture conditions, with sustained IL-6 protein increase after 48 h only in coculture. Acidosis also enhanced P-CREB and c-fos expression in coculture during the first 3 h. Regardless of culture conditions, acidosis increased IL-6, c-fos, and P-SRF expression in CCDSK cells after 48 h. P-CREB and COX-2 expression were elevated in CCDSK in coculture. Acidosis-mediated effects on IL-6, P-CREB, and P-SRF expression were p38-dependent in both cell lines. Finally, we assessed the pH-dependency of IL-6 action and found that IL-6 addition increased COX-2 expression via the IL-6 receptor in acidic but not control media. Thus, acidosis enhances IL-6 secretion and potentiates its receptor-mediated biological effects.</p><p><strong>Conclusion: </strong>This study identifies IL-6 as a key mediator of tubule-fibroblast crosstalk in an acidic milieu, promoting inflammatory processes. Acidosis induces IL-6 expression, secretion, and biological effects, with p38 kinase as a crucial mediator. If validated in vivo, these findings could enhance understanding of CKD and support early interventions.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"180"},"PeriodicalIF":8.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058402","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":"NETs activate the GAS6-AXL-NLRP3 axis in macrophages to drive morphine tolerance.","authors":"Qingyan Tian, Haiyue Guo, Mengyao Zhang, Kunmao Jiang, Fan Hu, Yan Xu, Li Wan, Xiaokai Zhou, Yinbing Pan, Wentao Liu, Chun-Yi Jiang","doi":"10.1186/s12964-025-02181-4","DOIUrl":"https://doi.org/10.1186/s12964-025-02181-4","url":null,"abstract":"<p><strong>Background: </strong>The development of morphine tolerance presents a major clinical challenge in the effective management of severe pain. This study aims to explore the mechanisms underlying morphine tolerance from a novel perspective, with the ultimate goal of uncovering new insights and identifying promising therapeutic targets for its treatment.</p><p><strong>Methods: </strong>C57BL/6J mice were used in the tail-flick test to evaluate morphine tolerance. Neutrophils derived from mouse bone marrow were employed to investigate the mechanisms underlying morphine-induced NETs formation. Bone marrow-derived macrophages (BMDMs) were harvested from the femur and tibia to study the role of NETs-induced inflammation in analgesic tolerance. Proinflammatory cytokines were measured using Western blotting and real-time PCR. The levels of NETs and the TLR7/9-NLRP3-related signaling pathway were assessed through Western blotting, real-time PCR, and ELISA. Confocal laser scanning microscopy was utilized to visualize NETs in the dorsal root ganglion (DRG) and in cells.</p><p><strong>Results: </strong>Our experiments demonstrated that the levels of NETs in the plasma of patients using morphine for analgesia, as well as in morphine-tolerant animals, were significantly elevated. Genetic elimination of Pad4, neutrophil depletion, and treatment with DNase 1 and RNase A to disrupt NETs formation all effectively alleviated morphine tolerance. These findings indicate that NETs play a critical role in the development of morphine tolerance. Mechanistically, we discovered that morphine-induced NETs can be engulfed by macrophages through the GAS6-AXL axis, which subsequently triggers the activation of the TLR7/TLR9-mediated NLRP3 inflammasome, leading to significantly increased levels of IL-1β and IL-18, and ultimately contributing to tolerance. Deletion of Axl, Gas6, or Nlrp3 each significantly improved morphine tolerance. Furthermore, in the murine model, treatment with the IL-1 receptor antagonist anakinra and the IL-18 decoy receptor IL-18BP prevented the development of morphine tolerance.</p><p><strong>Conclusions: </strong>This study identifies morphine-induced NETs as a key contributor to morphine tolerance, with the GAS6-AXL-TLR7/9 axis emerging as a potential therapeutic target. Strategies focused on disrupting NETs and modulating this axis may offer a promising approach to combat morphine tolerance.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"181"},"PeriodicalIF":8.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11992818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040864","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 network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia.","authors":"Valeria Bica, Veronica Venafra, Giorgia Massacci, Simone Graziosi, Sara Gualdi, Gessica Minnella, Federica Sorà, Patrizia Chiusolo, Maria Elsa Brunetti, Gennaro Napolitano, Massimo Breccia, Dimitrios Mougiakakos, Martin Böttcher, Thomas Fischer, Livia Perfetto, Francesca Sacco","doi":"10.1186/s12964-025-02185-0","DOIUrl":"https://doi.org/10.1186/s12964-025-02185-0","url":null,"abstract":"<p><strong>Background: </strong>About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose alternative effective strategies for cancer patients.</p><p><strong>Methods: </strong>To achieve this goal, we developed a novel multi-step strategy, which integrates high sensitive mass spectrometry-based phosphoproteomics with network-based analysis. This strategy builds context-specific networks recapitulating the signaling rewiring upon drug treatment in therapy-resistant and sensitive cells.</p><p><strong>Results: </strong>We applied this strategy to elucidate the BCR::ABL1-independent mechanisms that drive relapse upon therapy discontinuation in chronic myeloid leukemia (CML) patients. We built a signaling map, detailing - from receptor to key phenotypes - the molecular mechanisms implicated in the control of proliferation, DNA damage response and inflammation of therapy-resistant cells. In-depth analysis of this map uncovered novel therapeutic vulnerabilities. Functional validation in patient-derived leukemic stem cells revealed a crucial role of acquired FLT3-dependency and its underlying molecular mechanism.</p><p><strong>Conclusions: </strong>In conclusion, our study presents a novel generally applicable strategy and the reposition of FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for CML relapsed patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"179"},"PeriodicalIF":8.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058830","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":"Zinc finger DHHC-type palmitoyltransferase 13-mediated S-palmitoylation of GNA13 from Sertoli cell-derived extracellular vesicles inhibits autophagy in spermatogonial stem cells.","authors":"Heran Cao, Huihui Gao, Yan Li, Long Li, Shujuan Liu, Tianqi Jin, Yang Wang, Ye Gong, Shuiqiao Yuan, Wuzi Dong","doi":"10.1186/s12964-025-02177-0","DOIUrl":"https://doi.org/10.1186/s12964-025-02177-0","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) originating from testicular somatic cells act as pivotal intermediaries in cell signaling crosstalk between spermatogenic cells and the testicular microenvironment. The intricate balance between palmitoylation and depalmitoylation governs the positioning of protein cargos on the membrane, thereby influencing cellular activities by concentrating these proteins in EVs for delivery to recipient cells. Here, we reveal that GNA13 undergoes specific S-palmitoylation at Cys14 and Cys18 residues in Sertoli cells (SCs), a modification essential for its localization to the plasma membrane. We identify DHHC13, a member of the zinc finger DHHC-type palmitoyltransferase family that catalyzes protein S-palmitoylation, as the enzyme responsible for this critical post-translational modification. Additionally, GNA13 palmitoylation is indispensable for its selective enrichment in EVs emanating from SCs. Intriguingly, we discovered the presence of palmitoylated GNA13 in SC-derived EVs significantly downregulates autophagy levels in spermatogonial stem cells (SSCs), and the inhibition of GNA13 palmitoylation attenuates its interaction with ARHGEF12 which leads to diminished RhoA activity and consequent elevation of autophagy in SSCs. Our results illuminate the crucial role of DHHC13-mediated GNA13 S-palmitoylation in modulating autophagy levels in SSCs through SCs-derived EVs, suggesting that PM-GNA13-EV may serve as a potential candidate for further exploration in addressing fertility-related challenges during spermatogenesis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"178"},"PeriodicalIF":8.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996209","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":"Unraveling the role of hypoxia-inducible factors in cutaneous melanoma: from mechanisms to therapeutic opportunities.","authors":"Arianna Bellazzo, Barbara Montico, Roberto Guerrieri, Francesca Colizzi, Agostino Steffan, Jerry Polesel, Elisabetta Fratta","doi":"10.1186/s12964-025-02173-4","DOIUrl":"https://doi.org/10.1186/s12964-025-02173-4","url":null,"abstract":"<p><p>Hypoxia is a common feature of solid malignancies, including cutaneous melanoma (CM). Hypoxia-inducible factor (HIF)-1α and HIF-2α orchestrate cellular responses to hypoxia and coordinate a transcriptional program that promote several aggressive features in CM, such as angiogenesis, epithelial-mesenchymal transition, metastasis formation, metabolic rewiring, and immune escape. BRAF^V600E, which is the most frequent mutation observed in CM patients, usually increases HIF-α signaling not only in hypoxia, but also in normoxic CM cells, enabling HIF-1α and HIF-2α to continuously activate downstream molecular pathways. In this review, we aim to provide a comprehensive overview of the intricate role and regulation of HIF-1α and HIF-2α in CM, with a brief focus on the complex interactions between HIF-α subunits and non-coding RNAs. We also discuss HIF-α-mediated cellular responses in normoxia along with the mechanisms that allow HIF-α subunits to maintain their stability under normal oxygen conditions. Finally, we resume available evidence on potential therapeutic approaches aimed at targeting HIF-1α and/or HIF-2α.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"177"},"PeriodicalIF":8.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060428","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":"REST contributes to renal fibrosis through inducing mitochondrial energy metabolism imbalance in tubular epithelial cells.","authors":"Yingxian Yang, Shuiqin Gong, Chun Zhou, Wang Xin, Shaozong Qin, Mengying Yao, Qigang Lan, Wenhao Liao, Jinghong Zhao, Yinghui Huang","doi":"10.1186/s12964-025-02166-3","DOIUrl":"10.1186/s12964-025-02166-3","url":null,"abstract":"<p><strong>Background: </strong>Renal fibrosis represents the final common pathological manifestation of chronic kidney disease (CKD), yet the underlying mechanism remains elusive, and there is still a lack of effective targeted therapeutic strategy. Although previous research indicated that repressor element 1-silencing transcription factor (REST) contributed to acute kidney injury (AKI) in renal tubular epithelial cells (RTECs), its specific contribution to renal fibrosis and associated mechanisms remains largely unexplored.</p><p><strong>Methods: </strong>Renal biopsies from CKD patients were collected to evaluate the expression of REST. Kidney-specific Rest conditional knockout (Cdh16-Cre/Rest^flox/flox) mice were generated and employed unilateral ureter obstruction (UUO) models to investigate the role of REST in renal fibrosis. RNA sequencing was performed to elucidate the mechanism. Mitochondrial function was evaluated by transmission electron microscopy (TEM), reactive oxygen species (ROS), oxygen consumption rates (OCR), extracellular acidifcation rate (ECAR) and adenosine triphosphate (ATP). The severity of renal fibrosis was assessed through Western blot, immunofluorescent staining and immumohistochemical staining. Bioinformatic prediction, dual luciferase reporter gene assay, point mutation and chromatin immunoprecipitation (ChIP) assay were utilized to clarify the molecular mechanism.</p><p><strong>Results: </strong>REST was significantly up-regulated in the kidney tissues from CKD patients, UUO-induced fibrotic mouse models and TGF-β1-incubated RTECs. Notably, kidney-specific knockout of Rest prominently alleviated renal fibrosis by improving mitochondrial energy metabolism and restoring fatty acid oxidation. Mechanically, REST disturbed mitochondrial energy metabolism through repressing the transcription of oxoglutarate dehydrogenase-like (OGDHL) via directly binding to its promotor region. Further, pharmacological inhibition of REST using the specific REST inhibitor, X5050, significantly ameliorated the progression of renal fibrosis both in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our explorations revealed the upregulation of REST in renal fibrosis disrupts mitochondrial energy metabolism through transcriptionally suppressing OGDHL, which may act as a promising therapeutic target for renal fibrosis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"176"},"PeriodicalIF":8.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813051","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}