Cellular signalling最新文献

{"title":"Mechanistic insights into homocysteine-induced coronary microcirculatory dysfunction post-MI: The pivotal role of LncMEG3/miR-223/NLRP3 signaling axis.","authors":"Jingan Rao, Congcong Ding, Xiao Huang, Junpei Li, Jine Liu, Zikang Cheng, Huihong Zeng, Biming Zhan, Xiaoshu Cheng","doi":"10.1016/j.cellsig.2025.112164","DOIUrl":"https://doi.org/10.1016/j.cellsig.2025.112164","url":null,"abstract":"<p><strong>Background: </strong>Hyperhomocysteinemia (HHcy) is known to exacerbate coronary microvascular dysfunction in patients experiencing acute myocardial infarction (AMI). However, the precise mechanisms underlying the exacerbation of injury by HHcy remain to be fully elucidated.</p><p><strong>Methods: </strong>HHcy models were established in C57/BL6 mice and human coronary artery endothelial cells (HCAECs). Transcriptome sequencing identified differentially expressed non-coding RNAs (ncRNAs) and proteins in myocardial infarction (MI) mice with HHcy. Cardiac function and tissue morphology were assessed using small animal ultrasound imaging and hematoxylin-eosin (H&E) staining. CD31 immunofluorescence staining and ink staining were employed to evaluate microvascular density and microcirculatory function. The scratch wound healing assay was utilized to determine endothelial cell migration capacity. Quantitative real-time PCR and Western blot analysis was performed to investigate the impact of HHcy on the long non-coding RNAs (lncRNA) MEG3/microRNA-223/NLRP3 signaling pathway in vivo and in vitro.</p><p><strong>Results: </strong>Both in vivo and in vitro studies demonstrated that HHcy could exacerbate cardiac and endothelial cell injury following MI or hypoxia through the lncRNA MEG3/microRNA-223/NLRP3 signaling pathway. HHcy suppressed miR-223 expression by upregulating lncRNA MEG3 levels, which subsequently increased NLRP3 expression and aggravated cell pyroptosis. Microcirculatory disorders arising from impaired coronary microvascular function significantly contributed to the decline in cardiac function. Targeting lncRNA MEG3 silencing or NLRP3 inhibition could attenuate the exacerbation of cardiac damage and microcirculatory dysfunction induced by HHcy after myocardial infarction.</p><p><strong>Conclusion: </strong>HHcy exacerbates cardiac injury and microcirculatory dysfunction post-myocardial infarction through the lncRNA MEG3/microRNA-223/NLRP3 signaling pathway.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112164"},"PeriodicalIF":3.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the hnRNPK/miR-133a-3p/UCP2 axis: a novel regulatory circuit governing porcine skeletal muscle satellite cell fate","authors":"Yongjie Xu ,&nbsp;Xiaofang Cheng ,&nbsp;Mengjia Zhang ,&nbsp;Jiahua Guo ,&nbsp;Kejin Ren ,&nbsp;Kaili Zhou ,&nbsp;Tianyu Li ,&nbsp;Yuxi Wang ,&nbsp;Quanxi Li ,&nbsp;Tiantian Meng ,&nbsp;Cencen Li ,&nbsp;Pengpeng Zhang ,&nbsp;Haixia Xu","doi":"10.1016/j.cellsig.2025.112160","DOIUrl":"10.1016/j.cellsig.2025.112160","url":null,"abstract":"<div><h3>Objective</h3><div>MicroRNAs (miRNAs) post-transcriptionally regulate gene expression by targeting mRNA 3’UTRs, critically influencing skeletal muscle development. While miR-133a-3p is implicated in myogenesis, its regulatory interplay with RNA-binding proteins (RBPs) in porcine skeletal muscle satellite cells (PSCs) remains unexplored. This study elucidates the functional role and molecular mechanism of miR-133a-3p through a novel hnRNPK/miR-133a-3p/<em>UCP2</em> axis in PSCs.</div></div><div><h3>Methods</h3><div>RT-qPCR and western blot were used for gene expression analysis. miR-133a-3p mimic and miR-133a-3p inhibitor were conducted to overexpression and knockdown the expression of miR-133a-3p in PSCs, respectively. The hnRNPK overexpression vector was designed using the pcDNA3.1(+) vector. 5-ethynyl-2′-deoxyuridine (EdU) assays were conducted for cell proliferation. Immunofluorescence detection was employed for cell differentiation analysis. The dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and biotin-labeled miRNA pull-down assays were utilized for regulatory mechanism analysis of hnRNPK/miR-133a-3p/ <em>UCP2</em>.</div></div><div><h3>Results</h3><div>Transcriptional profiling revealed miR-133a-3p upregulation during PSCs differentiation. Gain- and loss-of-function assays demonstrated that miR-133a-3p suppresses proliferation but promotes differentiation; its inhibition yielded opposite effects. Comprehensive mechanistic studies (dual-luciferase, RIP, and biotin pull-down assays) identified hnRNPK as a direct binding partner of miR-133a-3p. Subsequent validation confirmed UCP2 as a downstream target, with hnRNPK attenuating miR-133a-3p-mediated <em>UCP2</em> repression. Notably, hnRNPK antagonized miR-133a-3p's pro-differentiation effects, revealing its role as a negative myogenesis regulator.</div></div><div><h3>Conclusion</h3><div>Collectively, we report a novel hnRNPK/miR-133a-3p/<em>UCP2</em> axis governing mitochondrial gene expression and PSCs differentiation. This work advances understanding of RBP-miRNA interaction in post-transcriptional myogenic regulation and provides new targets for muscle biology and regenerative medicine.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112160"},"PeriodicalIF":3.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study on the molecular mechanism of KPNA2 regulation of myocardial ischemia/delayed reperfusion injury through mitophagy.","authors":"Ende Tao, Zhe Tao, Fudon Wang, Songjie Bai, Songqing Lai, Xiaogui Li, Yang Bai, Chengtao Peng, Li Wan","doi":"10.1016/j.cellsig.2025.112157","DOIUrl":"https://doi.org/10.1016/j.cellsig.2025.112157","url":null,"abstract":"<p><p>This study investigates the role of Karyopherin Subunit Alpha 2 (KPNA2) in myocardial ischemia/delayed reperfusion (I/dR) injury and its underlying molecular mechanisms. Using SD rat I/dR models and cell hypoxia/reoxygenation (H/R) models, we found that KPNA2 expression was significantly upregulated following I/dR treatment, leading to mitophagy dysfunction and myocardial cell damage. Mechanistic studies revealed that the transcription factor Paired box 6 (PAX6) promotes KPNA2 expression by binding to its promoter, while KPNA2 protein directly interacts with Phosphate Cytidylyltransferase 1 Alpha (PCYT1A). This KPNA2-PCYT1A interaction significantly inhibited mitophagy activity, as evidenced by the downregulation of key mitophagy molecules such as PINK1 and Parkin, along with a decreased LC3-II/LC3-I ratio and accumulation of p62 protein. In animal experiments, PAX6 inhibition downregulated KPNA2/PCYT1A expression, restored mitophagy function, alleviated myocardial injury, and improved cardiac function. This study, for the first time, elucidates a novel mechanism by which the PAX6-KPNA2-PCYT1A signaling axis regulates mitophagy in myocardial I/dR injury, providing potential targets for clinical treatment.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112157"},"PeriodicalIF":3.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3 contributes to osimertinib resistance in non-small cell lung cancer cell lines by regulating CDC25A and AURKB mRNA stability","authors":"Ryusuke Suzuki ,&nbsp;Minoru Terashima ,&nbsp;Akihiko Ishimura ,&nbsp;Makiko Meguro-Horike ,&nbsp;Shin-ichi Horike ,&nbsp;Sasithorn Wanna-udom ,&nbsp;Takahisa Takino ,&nbsp;Takeshi Suzuki","doi":"10.1016/j.cellsig.2025.112156","DOIUrl":"10.1016/j.cellsig.2025.112156","url":null,"abstract":"<div><div>Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is used as a first-line therapy for non-small cell lung cancer (NSCLC) harboring <em>EGFR</em> mutations. Nevertheless, the emergence of acquired drug resistance poses a significant challenge, leading to poor clinical outcomes. METTL3, a key methyltransferase responsible for N6-methyladenosine (m6A) modification of RNA, has been implicated in cancer development and progression across various cancer types. In this study, we explored the role of METTL3 in acquired resistance to osimertinib and assessed its potential as a therapeutic target. Using <em>METTL3</em> knockdown <em>EGFR</em>-mutated NSCLC cell lines, we found that downregulation of METTL3 suppressed the acquisition of osimertinib resistance. Microarray analysis and qRT-PCR revealed that <em>CDC25A</em> and <em>AURKB</em> are downstream target genes of METTL3, with METTL3 facilitating the stabilization of their mRNAs. Downregulation of these METTL3 target genes also attenuated osimertinib resistance. Furthermore, we evaluated the effects of combining osimertinib with either a METTL3 inhibitor or a CDC25A inhibitor, both of which increased drug efficacy by promoting apoptosis. Collectively, this study highlights the involvement of METTL3 in the initial acquisition of osimertinib resistance and the therapeutic potential of targeting the METTL3-mediated regulatory pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112156"},"PeriodicalIF":3.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KIF2C regulates macrophage M2 polarization and DLBCL progression by regulating the STAT3/IL-10 axis","authors":"Li Qian ,&nbsp;Rongfeng Shi ,&nbsp;Juanjuan Yang ,&nbsp;Jianguo Zhang","doi":"10.1016/j.cellsig.2025.112155","DOIUrl":"10.1016/j.cellsig.2025.112155","url":null,"abstract":"<div><div>KIF2C is an oncogene highly expressed in various malignancies, but its role in diffuse large B-cell lymphoma (DLBCL) remains unclear. In this study, THP-1 cells were stimulated to differentiate into M0, M1, and M2 macrophages using the culture medium of OCI-LY3 DLBCL cells. KIF2C expression was upregulated during M2 polarization. Knockdown or overexpression of KIF2C in THP-1 cells revealed that KIF2C promoted M2 but not M1 polarization. Whether in the co-culture of THP-1_M0 cells with altered KIF2C levels and OCI-LY3 cells, or in OCI-LY3 cells with altered KIF2C levels. KIF2C knockdown inhibited OCI-LY3 proliferation, migration, and invasion, and promoted apoptosis. In contrast, KIF2C overexpression enhanced M2 polarization and tumor-promoting behaviors. Mechanistically, KIF2C knockdown reduced p-STAT3 (Tyr705) levels in macrophages. Application of STAT3 agonist colivelin TFA restored IL-10 expression and M2 polarization. KIF2C knockdown in tumor cells inhibited their growth and viability, both <em>in vitro</em> and in a subcutaneous xenograft model, in which M2 macrophage polarization, IL-10 expression, and tumor progression were reduced. These findings suggest that KIF2C in macrophages and/or tumor cells regulates DLBCL-associated M2 macrophage polarization and tumor progression through the STAT3/IL-10 axis, highlighting KIF2C as a potential therapeutic target in DLBCL.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112155"},"PeriodicalIF":3.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROCK2 promotes renal cell carcinoma progression by functioning as an RNA-binding protein regulating the PAI-1/NLRP3 axis and senescence escape","authors":"Zhengdong Hong ,&nbsp;Yinghui Zeng ,&nbsp;Qiang Zhou ,&nbsp;Hong Han ,&nbsp;Xiaoke Guo ,&nbsp;Weibin Zhu ,&nbsp;Cunlong Zhu ,&nbsp;Xin Luo ,&nbsp;Yuting Zhou ,&nbsp;Yiqian Wang","doi":"10.1016/j.cellsig.2025.112154","DOIUrl":"10.1016/j.cellsig.2025.112154","url":null,"abstract":"<div><div>Renal cell carcinoma (RCC) is an aggressive malignancy with limited treatment options at advanced stages. Although the incidence of RCC is increasing globally, the molecular mechanisms driving its progression remain poorly understood. In this study, we demonstrate that ROCK2 promotes RCC progression through post-transcriptional regulation of PAI-1. RNA sequencing and cytokine profiling of ROCK2-knockdown RCC cells revealed a significant decrease in PAI-1 expression. Overexpression of PAI-1 restored NLRP3 inflammasome activation, inhibited cellular senescence, and enhanced mitochondrial fission and autophagy, effects that were abolished by the NLRP3 inhibitor MCC950. In vivo, PAI-1 overexpression promoted tumor growth and suppressed both apoptosis and senescence, while NLRP3 inhibition reversed these effects. RNA immunoprecipitation assays confirmed that ROCK2 directly binds to PAI-1 mRNA, suggesting a post-transcriptional regulatory mechanism. Collectively, these results support a model in which ROCK2 facilitates RCC progression by stabilizing PAI-1 mRNA, thereby activating the NLRP3 inflammasome, inhibiting cellular senescence, and promoting mitochondrial remodeling, suggesting that the ROCK2/PAI-1/NLRP3 axis may serve as a potential therapeutic target for RCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112154"},"PeriodicalIF":3.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms by which Ac-SDKP regulates HSP27 via the p38MAPK/mTOR autophagy pathway to ameliorate pulmonary fibrosis","authors":"Wenli Li ,&nbsp;Shuoqian Ma ,&nbsp;Lu Liu ,&nbsp;Yi He ,&nbsp;Wenxin Guo ,&nbsp;Ye Qian ,&nbsp;Jin Wang ,&nbsp;Liyan Zhu ,&nbsp;Haijing Deng","doi":"10.1016/j.cellsig.2025.112151","DOIUrl":"10.1016/j.cellsig.2025.112151","url":null,"abstract":"<div><h3>Objectives</h3><div>The main objective of this study was to investigate whether the antifibrotic tetrapeptide <em>N</em>-acetyl-serinyl-aspartyl-lysinyl-proline (Ac-SDKP) affects the p38MAPK/mTOR autophagy pathway by regulating heat shock protein 27 (HSP27)-mediated autophagy during the treatment of silicosis-related fibrosis to investigate the antifibrotic effect of Ac-SDKP.</div></div><div><h3>Methods</h3><div>In this study, we employed TGF-β1-induced human non-small cell lung cancer cells (A549), mouse embryonic fibroblasts (MEFs), and a silica-induced rat model of silicosis-related fibrosis. HSP27 interference vectors and LV-<em>Hspb1</em> vectors were constructed, and the expression levels of relevant proteins were detected after lentiviral interference plasmid infection.</div></div><div><h3>Results</h3><div>Ac-SDKP significantly reduced the area of silicosis nodules, alpha-smooth muscle actin (α-SMA), heat shock protein 27 (HSP27), p38 mitogen-activated protein kinase (p-p38MAPK/p38MAPK), mechanistic target of rapamycin (p-mTOR/mTOR), and SQSTM1/p62; increased the ratio of light chain 3 beta II/I (LC3B-II/I); and mitigated silica-induced lung fibrosis. The p38MAPK inhibitor SB203580 further enhanced the effects of Ac-SDKP. Following lentiviral transfection to overexpress HSP27, Ac-SDKP was able to rescue the autophagy deficiency induced by HSP27 overexpression.</div></div><div><h3>Conclusions</h3><div>This study revealed that Ac-SDKP ameliorates pulmonary fibrosis <em>via</em> the p38MAPK/mTOR-dependent autophagy pathway during silicosis treatment and exerts a cytoprotective effect by enhancing autophagic flux through the inhibition of HSP27 expression. Understanding this mechanism may contribute to the development of novel therapeutic strategies for the prevention of silicosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112151"},"PeriodicalIF":3.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomal circ_0008803 drives lung cancer cell migration and invasion via NF-κB activation","authors":"Zhenhua Chen ,&nbsp;Leyi Li ,&nbsp;Jing Teng ,&nbsp;Jiahui Chen ,&nbsp;Shuaibin Wang ,&nbsp;Ziyuan Chen ,&nbsp;Wei Chen ,&nbsp;Yichen Lin ,&nbsp;Yulin Hu ,&nbsp;Yue Shang ,&nbsp;Jinxian He ,&nbsp;Chengwei Zhou ,&nbsp;Xiaodan Meng","doi":"10.1016/j.cellsig.2025.112152","DOIUrl":"10.1016/j.cellsig.2025.112152","url":null,"abstract":"<div><div>Exosomes facilitate intercellular communication and play a critical role in tumor development. Circular RNA (circRNA), a major component of exosomes, is involved in cancer metastasis through exosome-mediated delivery. This study identified a novel non-small-cell lung cancer (NSCLC)-associated circRNA, circ_0008803 in exosomes. We found that circ_0008803 promoted the migration and invasion of NSCLC cells in vitro and facilitated tumor growth in vivo. Using confocal microscopy, we observed that circ_0008803 was encapsulated in exosomes and transported to recipient cells. Upon release into recipient cells, circ_0008803 competitively bound to miR-432-5p, which upregulated the expression of transformer 2 beta homolog (TRA2B). Concurrently, circ_0008803 interacted with the ELAV-like RNA-binding protein 1 (ELAVL1) and promoted the translocation of ELAVL1 from the nucleus to the cytoplasm. The circ_0008803-ELAVL1 complex further interacted with the 3’untranslated region (3’UTR) of TRA2B, enhancing the stability of TRA2B in the cytoplasm. Through these mechanisms, the upregulated TRA2B activated the NF-κB pathway, thereby promoting the migration and invasion of recipient cells. Furthermore, elevated serum exosomal circ_0008803 levels correlated with advanced NSCLC stages and distant metastasis. In summary, this study highlights circ_0008803 as a novel exosomal circRNA implicated in NSCLC metastasis, providing mechanistic insights and underscoring its potential as a diagnostic biomarker.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112152"},"PeriodicalIF":3.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constitutive expression of cardiomyocyte Klf9 precipitates metabolic dysfunction and spontaneous cardiomyopathy.","authors":"Chandni Thakkar ,&nbsp;Saleena Alikunju ,&nbsp;Aishwarya Venkatasubramanian ,&nbsp;Dorothy D'Mello ,&nbsp;Hussain Abbas ,&nbsp;Zhi Yang ,&nbsp;Ivessa Andreas ,&nbsp;Nazish Sayed ,&nbsp;Maha Abdellatif ,&nbsp;Danish Sayed","doi":"10.1016/j.cellsig.2025.112146","DOIUrl":"10.1016/j.cellsig.2025.112146","url":null,"abstract":"<div><div>Adaptation of gene expression is the earliest response during work overload to maintain cardiac homeostasis and function. We reported a novel function of Krüppel-like factor (Klf) 9 in mediating metabolic adaptations in response to Dexamethasone in cardiomyocytes. Klf9 expression decreases in hearts undergoing cardiac hypertrophy and failure, suggesting that differential regulation of Klf9 could be contributing to the pathogenesis. Here, we present the characterization of a conditional (αMHC-Cre) Klf9 knock-in (Klf9KI) mouse. Constitutive expression of exogenous Klf9 results in spontaneous cardiac dysfunction and the onset of failure by 8 weeks of age, and an early mortality by 12–14 weeks, suggesting that Klf9 dysregulation is sufficient for maladaptation. Transcriptome data from 1-week-old Klf9KI hearts show dysregulation of genes involved in lipid, carbohydrate, and glutathione metabolism, and transcripts of transport, transcription, and motor proteins. At 4 weeks and 8 weeks, we observe a differential expression of genes involved in innate immunity and extracellular matrix, along with metabolic and contractile signaling. These data correlate with the untargeted metabolome analysis, showing dysregulation in metabolites of lipid and fatty acids, glutathione, purine and pyrimidines, and sucrose metabolic pathways. Functional data in Klf9KI hearts show a decrease in mitochondrial ETC complex activity and ATP production, and an increase in ROS. Structural mitochondrial defects include distortion and sparse cristae in Klf9KI vs. Wt-Cre hearts. In conclusion, we show that Klf9 is critical for metabolic adaptations in postnatal heart development. Constitutive expression of Klf9 results in metabolic maladaptation, which precipitates dysfunction, early onset of heart failure, and death.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112146"},"PeriodicalIF":3.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TYROBP facilitates metastatic progression in pancreatic cancer through CTSZ-driven glycolytic rewiring and macrophage recruitment","authors":"Dingwen Zhong ,&nbsp;Yonghui Liao ,&nbsp;Xianyu Huang ,&nbsp;Wenhui Chen ,&nbsp;Jiaxin Liu ,&nbsp;Xinsong Fu","doi":"10.1016/j.cellsig.2025.112142","DOIUrl":"10.1016/j.cellsig.2025.112142","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains intractable because metastasis outruns intervention. Here we define TYROBP—a microglial adaptor previously unlinked to PDAC—as a pivotal metastatic driver. Transcriptomic mining and validation across paired human specimens revealed pronounced TYROBP up-regulation that trended with poorer survival. Gain- and loss-of-function studies showed that TYROBP potentiates PDAC cell migration and invasion without influencing proliferative indices in vitro or subcutaneous tumor growth in vivo. Mechanistically, transcription factor SP1 occupies a promoter motif (P1) to enforce TYROBP expression; TYROBP then complexes with cathepsin Z (CTSZ), enhancing CXCL8-mediated tumor-associated macrophage recruitment and activating a pAKT–CD44 axis independent of epithelial-to-mesenchymal transition while simultaneously accelerating glycolysis. The flavonoid baicalein engages TYROBP directly, abrogates CTSZ/pAKT/CD44 signaling, and curtails hepatic metastasis in mice without systemic toxicity. TYROBP knock-down blunts dissemination, whereas enforced TYROBP expression exacerbates metastasis—effects reversed by baicalein. Thus, the SP1-TYROBP-CTSZ axis licenses PDAC metastasis, and baicalein-mediated TYROBP inhibition offers a tractable therapeutic strategy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112142"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}