Cellular & Molecular Biology Letters最新文献

{"title":"GPD2 inhibition impairs coagulation function via ROS/NF-κB/P2Y12 pathway.","authors":"Jiajie Chen, Guifeng Xu, Zhipeng Xie, Shaoxia Xie, Wenwei Luo, Shilong Zhong, Weihua Lai","doi":"10.1186/s11658-025-00759-x","DOIUrl":"10.1186/s11658-025-00759-x","url":null,"abstract":"<p><strong>Background: </strong>Coronary heart disease (CHD) remains a global health threat. As antiplatelet therapy constitutes the cornerstone of CHD management, ticagrelor has been universally endorsed as a first-line agent in major clinical guidelines. However, the therapeutic efficacy of ticagrelor is compromised by interindividual variability in bleeding risk. Notably, while inherited genetic variations account for part of this heterogeneity, the dynamic regulatory role of modifiable epigenetic mechanisms-particularly DNA methylation in mediating platelet reactivity-remains inadequately characterized, presenting a critical knowledge gap in optimizing precision antiplatelet strategies.</p><p><strong>Methods: </strong>We utilized the 850k methylation array to measure DNA methylation levels in blood samples from 47 healthy controls and 93 patients with CHD. Subsequently, epigenome-wide association study (EWAS), summary data-based Mendelian randomization (SMR), and heterogeneity in dependent instruments (HEIDI) analyses were applied to pinpoint critical methylation sites that influence gene expression, platelet function recovery, and bleeding risk. After developing a targeted cellular model using the CRISPR-dCas9-DNMT3A/Tet1CD-U6-sgRNA system and integrating with transcriptomic sequencing data, we conducted mechanistic cellular experiments to elucidate how these methylation sites affect platelet function recovery and bleeding risk. The findings were further validated through animal studies.</p><p><strong>Results: </strong>Integrated analysis of EWAS and SMR-HEIDI revealed that hypermethylation at CpG site cg03230175 within the GPD2 gene promoter region was significantly associated with decreased GPD2 gene expression (P = 1.76E-18), delayed platelet functional recovery (P = 9.02 × 10<sup>-3</sup>), and elevated hemorrhagic risk (P = 2.71 × 10<sup>-2</sup>). Transcriptomic studies indicated that GPD2 gene (cg03230175) methylation affects mitochondrial function, nuclear factor kappa B (NF-κB) signaling pathway, reactive oxygen species metabolic process, and G protein-coupled receptor (GPCR) ligand binding. Cellular experiments demonstrated that the GPD2 gene (cg03230175) methylation inhibits coagulation function by suppressing reactive oxygen species (ROS) production, NF-κB activation, and P2Y12 gene expression (P2Y12 receptor plays a pivotal role in platelet activation, thrombus formation, and the pathogenesis of thrombotic disorders). The animal study results confirmed that GPD2 enzyme inhibition can indeed prolong the clotting time in mice.</p><p><strong>Conclusions: </strong>GPD2 gene (cg03230175) methylation resulted in reduced gene expression levels, inhibited mitochondrial energy metabolism, decreased ROS levels, and affected P2Y12 gene expression through the NF-κB pathway, ultimately leading to inhibition of coagulation function. Registry: The Impact of Genotype on Pharmacokinetics and Antiplatelet Effects of Ticagrelor in Healthy Chinese ","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"84"},"PeriodicalIF":9.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Posttranslational modifications of YAP/TAZ: molecular mechanisms and therapeutic opportunities.","authors":"Zhenxiong Zhang, Peiheng He, Li Yang, Jun Gong, Renyi Qin, Min Wang","doi":"10.1186/s11658-025-00760-4","DOIUrl":"10.1186/s11658-025-00760-4","url":null,"abstract":"<p><p>Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), are critical effectors of the Hippo pathway, as well as other biochemical and biophysical signals. Through their interaction with DNA-binding partners, YAP/TAZ can modulate the transcription of many genes critical for organ size regulation and tissue homeostasis maintenance. Aberrant expression or activation of YAP/TAZ is implicated in the pathogenesis of many cancers and noncancerous diseases. Notably, their functional outputs demonstrate remarkable diversity, with context-dependent roles emerging across distinct disease models and tissue microenvironments. Posttranslational modifications (PTMs) exert profound impacts on the stability, subcellular localization, and function of YAP/TAZ. The canonical Hippo pathway-mediated phosphorylation and ubiquitination have been well characterized as mechanisms that downregulate YAP/TAZ stability and transcriptional activity. Recent studies have identified novel phosphorylation sites, atypical ubiquitination patterns, along with ubiquitin-like modifications, glycosylation, methylation, acetylation, and lactylation on YAP/TAZ. These PTMs exhibit dynamic regulation in response to microenvironmental stimuli, providing molecular insights into the context-dependent functional versatility of YAP/TAZ. This review systematically synthesizes current understanding of YAP/TAZ PTM networks and discusses their therapeutic implications.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"83"},"PeriodicalIF":9.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-monotonic response of macrophages to mechanical stretch impacts skin wound healing.","authors":"Qian Wei, Fangzhou Du, Jinjiang Cui, Jiangen Xu, Yuchen Xia, Shikai Li, Qiong Deng, Xiaoyu Xu, Jingzhong Zhang, Shuang Yu","doi":"10.1186/s11658-025-00764-0","DOIUrl":"10.1186/s11658-025-00764-0","url":null,"abstract":"<p><strong>Background: </strong>The skin is subjected to constant mechanical stress in both healthy and wounded states. Macrophages play crucial roles in skin homeostasis and in all stages of the wound healing process. However, the effects of static mechanical stretch (MS) on macrophages and the subsequent consequences on skin cells remain largely unclear.</p><p><strong>Methods: </strong>We applied static MS at amplitudes of 7%, 15%, and 21% to macrophages derived from THP-1 using a customized cell-stretching device, thoroughly investigating its impacts on viability, polarization, secretome, and underlying signaling pathways. Recognizing the substantial influence of the macrophage secretome on neighboring cells, we collected conditioned medium from macrophages exposed to MS (MS-CM) and evaluated its effects on keratinocytes, fibroblasts, and endotheliocytes.</p><p><strong>Results: </strong>Macrophages exhibited a non-monotonic biological response to MS across the range of 7-21%, resulting in similar non-monotonic effects of MS-CM on the behaviors skin cell behaviors. The most significant effects were observed when macrophages were subjected to 15% MS. The 15% MS promoted macrophage viability and polarization toward the M2 phenotype, leading to increased release of anti-inflammatory cytokines and growth factors, as well as activation of the mechanotransduction pathways Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Consistent with these findings, 15% MS-CM enhanced the migration of keratinocytes, endotheliocytes, and fibroblasts, and promoted in vitro tube formation and fibroblast activation. In contrast, both 7% and 21% MS showed a similar tendency but with less pronounced or insignificant effects. Additionally, in a full-thickness wound model, the application of concentrated 15% MS-CM demonstrated additional beneficial effects on wound healing by enhancing angiogenesis and dermal reconstitution.</p><p><strong>Conclusions: </strong>Our observation of the non-monotonic macrophage response to MS provides a foundation for elucidating how macrophages may translate mechanical cues into paracrine signals that influence skin function and wound healing dynamics.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"82"},"PeriodicalIF":9.2,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional humanization of 15-lipoxygenase-1 (Alox15) protects mice from dextran sodium sulfate induced intestinal inflammation.","authors":"Florian Reisch, Marjann Schäfer, Dominika Labuz, Halina Machelska, Sabine Stehling, Gerhard P Püschel, Michael Rothe, Dagmar Heydeck, Hartmut Kuhn","doi":"10.1186/s11658-025-00756-0","DOIUrl":"10.1186/s11658-025-00756-0","url":null,"abstract":"<p><strong>Background: </strong>Mammalian arachidonic acid lipoxygenases (ALOXs) have previously been implicated in the pathogenesis of inflammatory disease, and pro- as well as anti-inflammatory activities have been reported. The human genome involves six functional ALOX genes and each of them encodes for a functionally distinct enzyme. ALOX15 is one of these isoforms and the majority of mammalian ALOX15 orthologs including mouse Alox15 convert arachidonic acid to its 12-hydroperoxy derivative. In contrast, human ALOX15 forms 15-hydroperoxy arachidonic acid instead. This difference in the catalytic properties of the two mammalian ALOX15 orthologs may be of biological relevance since arachidonic acid 15-lipoxygenating ALOX-isoforms exhibit an improved biosynthetic capacity for pro-resolving mediators. We recently generated Alox15 knock-in mice, which homozygously express a humanized Alox15 mutant (Leu353Phe) instead of the wildtype enzyme. These animals should be protected from the development of inflammatory symptoms in whole animal inflammation models if the biosynthesis of pro-resolving mediators plays a major role.</p><p><strong>Methods: </strong>To explore whether functional humanization of mouse Alox15 might impact the pathogenesis of inflammatory diseases we tested Alox-KI mice in comparison with wildtype control animals in two whole animal inflammation models (dextran sodium sulfate induced colitis, Freund's complete adjuvant induced paw edema). In these experiments we quantified the severity of inflammatory symptoms during the acute phase of inflammation and during the resolution period.</p><p><strong>Results: </strong>We found that Alox15 knock-in mice are strongly protected from the development of inflammatory symptoms in the dextran sodium sulfate colitis model when the loss of body weight was used as major readout parameter. Quantification of the colon tissue oxylipidomes revealed that the colon concentrations of resolvin D5 were elevated in Alox15-KI mice and thus, this mediator might contribute to the protective effect induced by our genetic manipulation. However, other specialized pro-resolving mediators, such as maresin-2, neuroprotectin-1, and lipoxins, may not play a major role for the protective response. In the Freund's complete adjuvant induced paw edema inflammation model no protective effect was observed.</p><p><strong>Conclusions: </strong>Taken together, our data suggest that humanization of the reaction specificity of mouse Alox15 (Leu353Phe mutation) exhibits differential effects in two mouse inflammation models.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"81"},"PeriodicalIF":9.2,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 SARS-CoV-2 envelope PDZ binding motif acts as a virulence factor disrupting host's epithelial cell-cell junctions.","authors":"Flavio Alvarez, Guilherme Dias de Melo, Florence Larrous, Lauriane Kergoat, Batiste Boëda, Vincent Michel, Danielle Seilhean, Magali Tichit, David Hing, David Hardy, Etienne Kornobis, Hervé Bourhy, Nicolas Wolff, Célia Caillet-Saguy","doi":"10.1186/s11658-025-00758-y","DOIUrl":"10.1186/s11658-025-00758-y","url":null,"abstract":"<p><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), disrupts the alveolar epithelial barrier and exacerbates airway inflammation, leading to acute respiratory failure. The Envelope (E) protein is key to virulence, notably through its PDZ-binding motif (PBM), which interacts with host PDZ proteins, affecting signaling pathways and pathogenicity. This study investigates the PBM's role in virulence by generating PBM-deficient mutant viruses and assessing their impact in vitro and in vivo. The mutants showed delayed replication and reduced cytopathic effects in vitro. In vivo, infected hamsters exhibited less weight loss, lower viral loads, and reduced inflammation, indicating attenuated pathogenicity. Histological analysis confirmed milder airway damage. Additionally, PBM-deficient viruses had impaired interactions with tight junction proteins like ZO-1, a PDZ-containing protein essential for epithelial integrity. Although the PBM played a key role in airway pathology, its impact on neuroinvasion was minimal during the acute phase of infection. Thus, the E protein PBM plays a critical role in SARS-CoV-2's fitness, virulence, and pathogenicity, through the disruption of cell junctions and inflammation, underscoring its potential as a therapeutic target.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"80"},"PeriodicalIF":9.2,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stem cell-secreted KGF ameliorates acute lung injury via the Gab1/ERK/NF-κB signaling axis.","authors":"Shuning Xin, Yan Ding, Tong Yu, Yunmei Fu, Yong Cui, Hongguang Nie","doi":"10.1186/s11658-025-00757-z","DOIUrl":"10.1186/s11658-025-00757-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The epithelial sodium channel (ENaC) situated in the apical membrane of alveolar epithelial type 2 (AT2) cells is beneficial to edematous fluid reabsorption in acute lung injury (ALI). Recently, mesenchymal stem cells (MSCs), particularly their secretome, has emerged as a novel approach for treating pulmonary diseases. Among these secreted factors, keratinocyte growth factor (KGF) plays a critical role in mediating alveolar epithelial repair during ALI by enhancing epithelial cell proliferation, restoring epithelial integrity, and alleviating pulmonary edema, making it a promising candidate for therapeutic strategies. This study primarily focused on investigating the impact of KGF secreted from MSC on ALI, and clarifying its specific mechanism in regulating the expression of ENaC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Lipopolysaccharide (LPS)-stimulated primary mouse AT2 cells were treated with KGF in vitro, and western blots along with immunofluorescence assays were performed to investigate the regulatory mechanism of KGF on ENaC protein expression. To further confirm the role of mouse bone marrow MSC-derived KGF, co-culture experiments with AT2 cells and either MSC or MSC with KGF knockdown (MSC-siKGF) were conducted. In vivo, an ALI model was established in mice by LPS-induced lung injury. The therapeutic effects of tail vein-injected MSC or MSC-siKGF were assessed using hematoxylin-eosin staining, lung wet/dry weight ratio, and alveolar fluid clearance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In primary mouse AT2 cells, KGF stimulation effectively restored the reduction of growth factor receptor-bound protein 2-associated binding protein 1 (Gab1) and α/γ-ENaC protein levels induced by LPS. KGF inhibited the activation of the LPS-induced extracellular regulated protein kinases (ERK) and nuclear factor-kappaB (NF-κB) signaling pathway. Treatment with the ERK pathway inhibitor PD98059 reversed the LPS-induced reduction in ENaC protein levels but had no effect on Gab1 levels. In addition, PD98059 suppressed LPS-induced activation of the NF-κB signaling pathway. Further analysis revealed that LPS stimulation weakened the interaction between the NF-κB p65 subunit and inhibitor kappaB (IκB), while KGF enhanced this interaction and inhibited the nuclear translocation of p65. Both KGF and the NF-κB inhibitor QNZ reversed the LPS-induced downregulation of ENaC protein levels and gene expression. Furthermore, both agents effectively restored the functional activity of ENaC channels. Co-culture with MSCs increased Gab1 protein levels, inhibited ERK/NF-κB signaling activation, and suppressed p65 nuclear translocation in LPS-treated AT2 cells, whereas these effects were attenuated in cells co-cultured with MSC-siKGF. In an ALI mouse model, tail-vein injection of MSCs alleviated lung injury and pulmonary edema, while the therapeutic effects of MSC-siKGF were weaker they were partly restored by the combination of QNZ.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusi","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"79"},"PeriodicalIF":9.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: A novel mechanism for A-to-I RNA-edited CYP1A1 in promoting cancer progression in NSCLC.","authors":"Zhipeng Wang, Yan Wu, Ziqi Ding, Xinru Xiao, Yanhua Huang, Zhiguang Liu, Qian Zhang","doi":"10.1186/s11658-025-00755-1","DOIUrl":"10.1186/s11658-025-00755-1","url":null,"abstract":"","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"78"},"PeriodicalIF":9.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AKT and DUBs: a bidirectional relationship.","authors":"Valentina Serratore, Maria Lucibello, Donatella Malanga, Giuseppe Viglietto, Carmela De Marco","doi":"10.1186/s11658-025-00753-3","DOIUrl":"10.1186/s11658-025-00753-3","url":null,"abstract":"<p><p>The serine/threonine kinase Akt is crucial for cell physiology and can also contribute to pathology if its activation and regulation is disturbed. This kinase phosphorylates several substrates involved in mechanisms that are altered in human disease. AKT is regulated by several post-translational modifications (PTMs), including ubiquitination/deubiquitination. Ubiquitination can both target AKT to the proteasome and promote its activation. The interplay with the deubiquitination mechanism plays a crucial role in almost all biological activities of AKT. Information on the mechanisms of AKT deubiquitination and its key players has evolved rapidly in recent years along with the development of potential targeting strategies, although many of them are still unclear. Nevertheless, AKT in turn regulates various deubiquitinases (DUBs), suggesting further targeting strategies for human diseases. In this review, we aim to provide an up-to-date overview of the dual relationship between AKT and DUBs with respect to potential translational aim.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"77"},"PeriodicalIF":9.2,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FRMD8 inhibits tumor metastasis in BRCA1-associated TNBC by negatively regulating tmTNF-α.","authors":"Jun Xu, Xiaoyu Yang, Peng Shu, Wei Wang, Haibo Wu, Zhe Wang","doi":"10.1186/s11658-025-00754-2","DOIUrl":"10.1186/s11658-025-00754-2","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC), particularly in patients with metastasis, is associated with limited treatment options and shorter survival times. In this study, through library screening and animal experiments, we identified that the low expression of FERM domain-containing protein 8 (FRMD8) in breast cancer type 1 susceptibility protein (BRCA1)-mutant breast cancer cells (TNBC subtype), significantly enhances the metastatic potential of tumor cells to various organs. Further functional experiments revealed that FRMD8^low inhibited the cleavage of tmTNF-α (transmembrane TNF-α) and promoted the expression of surface tmTNF-α. We also identified that the mechanism by which FRMD8 regulates tmTNF-α is related to the inhibition of inactive rhomboid protein 2 (iRHOM2) degradation, which acts mainly through the endocytic pathway. Furthermore, FRMD8^low/iRHOM2^low greatly facilitated the in vivo metastasis of TNBC. Finally, we found that combined treatment with paclitaxel and etanercept reversed the expression of FRMD8 and iRHOM2, concomitantly inhibiting the metastatic potential in vivo. This study explores how FRMD8 influences TNF-α processing and the metastatic behavior of breast cancer, providing insights into molecular dynamics that could guide future therapeutic strategies to improve outcomes in patients with breast cancer.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"76"},"PeriodicalIF":9.2,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term treatment with benzodiazepines and related Z-drugs exacerbates breast cancer: clinical evidence and molecular mechanisms.","authors":"Wei-Chung Vivian Yang, Yen-Yi Lin, Jeak Ling Ding, Chin-Sheng Hung, Phung-Anh Nguyen, Bo-Xiang Zhang, Tsung-Han Hsieh, Shu-Chun Chang","doi":"10.1186/s11658-025-00752-4","DOIUrl":"10.1186/s11658-025-00752-4","url":null,"abstract":"<p><strong>Background: </strong>Benzodiazepines (Diazepam) and related Z-drugs (Zolpidem), henceforth referred to as BZDRs, are widely used for clinical treatment of insomnia and anxiety disorders. BZDRs act on GABA type A receptors to inhibit neurotransmitters. We previously demonstrated that prolonged clinical use of BZDRs exacerbates the risk of breast cancer (BRCA).</p><p><strong>Methods: </strong>By biomedical, health informatics platform analyses and in vivo studies, we explored clinical association between BZDR usage and BRCA development and advancement. Furthermore, by retrospective studies on patient clinical data and in vitro empirical analyses of the impact of BZDR on BRCA cells, and together with ingenuity pathway analysis (IPA) analyses, we validated the signaling pathways and identified potential intermolecular crosstalk involved.</p><p><strong>Results: </strong>Clinical data showed that BRCA patients on long term treatment with BZDRs suffered increased mortality rate (p = 0.034). Studies on patient samples indicated that among 16 GABA receptors examined, GABRA3 (a pro-tumorigenic player) was significantly upregulated by BZDRs, which advanced BRCA disease. To support our clinical findings, we examined in vivo, the impact of BZDRs on BRCA advancement using MDA-MB231 cells to mediate metastasis in mice model. Our results show that BZDRs indeed promoted cancer advancement to the lungs and localized in the tibia. Using BRCA cell lines, we revealed the molecular-cellular effects of prolonged treatment with BZDRs in vitro. We showed significant metastasis indicated by increased cancer cell migration and invasion, which correlated well with our clinical observations. We discovered that BZDR-mediated GABRA3 stimulation was associated with downregulation of anti-tumorigenic extracellular matrix (ECM) molecules (S100B, COL6A6 and VIT) and upregulation of pro-tumorigenic FBN3 in BRCA cells. Notably, GABRA3-shRNA and GABRA3-CRISPR/Cas9 disrupted the abovementioned dynamics dramatically and suppressed BRCA cell invasion induced by BZDRs. Bioinformatics analyses highlighted molecular pathways showing interplay between GABRA3 and ECMs, which presumably exacerbated BZDR-induced BRCA progression via immune modulators.</p><p><strong>Conclusions: </strong>Long-term clinical use of BZDRs significantly increased the mortality rate of BRCA patients. We provide in vivo and in vitro evidence confirming that BZDRs promote BRCA advancement. We revealed that BZDR-mediated BRCA signaling pathways through GABRA3-ECMs, which promotes metastasis, probably through immune modulation and changes in the tumor microenvironment.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"75"},"PeriodicalIF":9.2,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}