Cellular signalling最新文献

{"title":"MACC1 drives metastasis in colorectal cancer by coordinating YKT6-dependent exosome biogenesis and c-Met cargo selection","authors":"Shenghuai Hou ,&nbsp;Lingxiao Wang ,&nbsp;Chong Yang ,&nbsp;Yaoping Li ,&nbsp;Haiyi Liu","doi":"10.1016/j.cellsig.2025.112073","DOIUrl":"10.1016/j.cellsig.2025.112073","url":null,"abstract":"<div><div>Colorectal cancer metastasis remains a major cause of cancer-related mortality, with the Metastasis-Associated in Colon Cancer 1 (MACC1) protein emerging as a critical regulator of tumor progression. Although exosomes are recognized mediators of oncogenic communication, the interplay between MACC1 and exosome biology is yet to be fully explored. This study unveils a dual mechanism through which MACC1 coordinates exosome biogenesis and oncogenic cargo delivery to drive metastatic progression.</div><div>We first established clinical relevance by Pearson's demonstrating a significant correlation between MACC1 expression and exosome concentration in colorectal tumors (<em>r</em> = 0.457, <em>P</em> &lt; 0.05). Functional studies showed that MACC1-overexpressing HCT116 cells exhibited enhanced invasiveness and transmitted pro-metastatic signals via exosomes. These exosomes were significantly enriched in the c-Met oncoprotein (<em>P</em> &lt; 0.05 vs. controls) and could induce epithelial-mesenchymal transition in recipient SW480 cells, significantly enhancing their migration and invasion capacities.</div><div>Mechanistically, transcriptomic analysis identified several components of the exosome secretion machinery (YKT6, RAB22A, and VPS41) as downstream targets of MACC1. Promoter-binding assays confirmed that MACC1 directly activates the transcription of <em>YKT6</em>, a member of the Soluble N-ethylmaleimide-sensitive factor attachment protein receptor family. This protein is critical for multivesicular body-plasma membrane fusion. The transcriptional activation led to cytoplasmic accumulation of YKT6 (<em>P</em> &lt; 0.05), driving a 2.9-fold increase in exosome secretion. Crucially, YKT6-mediated exosome hypersecretion facilitated the extracellular release of c-Met-enriched vesicles, establishing a feed-forward loop for metastatic propagation.</div><div>Our findings delineate an integrated metastatic axis: MACC1 orchestrates (1) transcriptional upregulation of YKT6 to amplify exosome production, and (2) selective packaging of c-Met into exosomes that prime recipient cells for invasion. This dual regulatory mechanism highlights potential therapeutic targets for intercepting metastasis-specific exosome signaling in colorectal cancer.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112073"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902330","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":"SH3-containing guanine nucleotide exchange factor (SGEF) ameliorates pressure overload induced cardiac hypertrophy via enhancing EGFR-NRF2 mediated ferroptosis inhibition","authors":"Tao Kong,&nbsp;Shiyun Jiang,&nbsp;Rui Yao,&nbsp;Guanghui Liu,&nbsp;Yingying Li,&nbsp;Yunlong Sun,&nbsp;Lu Gao,&nbsp;Youyou Du","doi":"10.1016/j.cellsig.2025.112071","DOIUrl":"10.1016/j.cellsig.2025.112071","url":null,"abstract":"<div><div>SH3-containing guanine nucleotide exchange factor (SGEF) is reportedly associated with tumorigenesis. However, the role of SGEF in cardiovascular diseases such as cardiac hypertrophy has not been elucidated. Here, we used a pressure overload-induced cardiac hypertrophy mouse model to explore the role and underlying mechanism of SGEF in pathological cardiac hypertrophy. Adeno-associated virus 9 (AAV9) was used to deliver SGEF and shSGEF to mouse hearts to induce cardiac overexpression or knockdown of SGEF. The mice were then subjected to aortic banding surgery to establish a pathological cardiac hypertrophy model. Echocardiography was performed at 4 weeks postsurgery to evaluate cardiac function. Cardiomyocytes were stimulated with angiotensin II to establish an in vitro model. We found that SGEF was downregulated in heart tissue at 4 weeks after aortic banding (AB) and in cardiomyocytes stimulated with angiotensin II. These results show that SGEF overexpression ameliorates pressure overload-induced cardiac hypertrophy, fibrosis and dysfunction, while SGEF knockdown exacerbates pressure overload-induced cardiac hypertrophy, fibrosis and dysfunction. Moreover, SGEF overexpression relieved, whereas SGEF knockdown aggravated, cardiac oxidative stress and ferroptosis, which was confirmed by an in vitro study. Mechanistically, we found that SGEF enhanced the stability of epidermal growth factor receptor (EGFR), inhibited its ubiquitination and subsequently promoted downstream nuclear factor erythroid 2-related factor 2 (NRF2) activation, thus inhibiting ferroptosis. When we used the EGFR inhibitor osimertinib, the protective effect of SGEF on pathological cardiac hypertrophy was counteracted. Taken together, these findings indicate that SGEF protects against pressure overload-induced cardiac hypertrophy, fibrosis and dysfunction by enhancing EGFR–NRF2 signaling-mediated ferroptosis inhibition. Targeting SGE has therapeutic potential for preventing pathological cardiac hypertrophy leading to heart failure.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112071"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865784","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":"IRF2BPL inhibits proliferation, migration and invasion of osteosarcoma cells by inhibiting FOSL2-mediated PI3K/AKT pathway activation","authors":"Wenda Liu ,&nbsp;Kezhou Xia ,&nbsp;Xinghan Huang,&nbsp;Zhun Wei,&nbsp;Zicheng Wei,&nbsp;Weichun Guo","doi":"10.1016/j.cellsig.2025.112068","DOIUrl":"10.1016/j.cellsig.2025.112068","url":null,"abstract":"<div><h3>Background</h3><div>Interferon regulatory factor 2-binding protein-like protein (IRF2BPL) is a nuclear protein susceptible to degradation and phosphorylation. It modulates downstream protein expression and facilitates ubiquitin-mediated proteolysis. Although IRF2BPL has been investigated in various biological systems, its functional role in osteosarcoma pathogenesis remains poorly understood.</div></div><div><h3>Methods</h3><div>We analyzed publicly available databases to evaluate IRF2BPL expression in osteosarcoma tissues and its prognostic significance. In vitro functional assays, including CCK-8, wound healing, and Transwell experiments, were conducted to examine IRF2BPL's effects on osteosarcoma cell proliferation, migration, and invasion. RNA sequencing (RNA-seq) and co-immunoprecipitation (Co-IP) assays were used to investigate IRF2BPL's molecular mechanisms. A subcutaneous xenograft tumor model was generated to validate its role in vivo.</div></div><div><h3>Results</h3><div>IRF2BPL is downregulated in osteosarcoma and correlates with patient survival. Overexpression of IRF2BPL suppresses osteosarcoma cell proliferation, migration, and invasion, whereas its silencing enhances these processes, both in vitro and in vivo. Mechanistic studies revealed that IRF2BPL influences osteosarcoma progression by regulating the FOSL2/PI3K/AKT/mTOR axis via ubiquitin-mediated degradation.</div></div><div><h3>Conclusion</h3><div>In summary, our study demonstrates that IRF2BPL is downregulated in osteosarcoma and serves as a prognostic marker. Functional assays confirmed that IRF2BPL suppresses tumor cell proliferation, migration, and invasion, while its silencing exerts the opposite effect. Mechanistically, IRF2BPL regulates the FOSL2/PI3K/AKT/mTOR axis through ubiquitin-mediated degradation, highlighting its potential as a therapeutic target in osteosarcoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112068"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879593","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":"The cGAS-STING pathway in age-related ocular diseases: Mechanisms and therapeutic opportunities","authors":"Zilin Shang ,&nbsp;Di Qin ,&nbsp;Xiangnan Liu,&nbsp;Hui Li,&nbsp;Chang Liu,&nbsp;Rui Zhang,&nbsp;Tongyi Sun,&nbsp;Zhifang Pan,&nbsp;Weiguo Feng,&nbsp;Xinguo You","doi":"10.1016/j.cellsig.2025.112069","DOIUrl":"10.1016/j.cellsig.2025.112069","url":null,"abstract":"<div><div>The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial component of the innate immune system, which senses abnormal double-stranded DNA in the cytoplasm and induces the type I interferon and pro-inflammatory cytokines expression. In cellular senescence, the cGAS-STING signaling pathway triggers the senescence-associated secretory phenotype, thereby exacerbating the senescence phenomenon and leading to age-related ocular diseases, including age-related macular degeneration and diabetic retinopathy. Herein, we outline the structure of cGAS-STING signaling pathway and its association with cellular senescence, and discuss the mechanism of behavior between cGAS-STING and ocular aging-related diseases. Finally, we summarize the relevant inhibitors of the cGAS-STING signaling pathway, thereby offering a novel direction for exploring the mechanism of ocular aging-related inflammatory diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112069"},"PeriodicalIF":3.7,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865782","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":"NSUN2 promotes osteosarcoma metastasis via stabilizing UBE2S mRNA in an m5C-dependent manner","authors":"Yu Chen ,&nbsp;Ranran Sun ,&nbsp;Liwen Liu ,&nbsp;Chao Li ,&nbsp;Yun Wang ,&nbsp;Chengxin Chen ,&nbsp;Guizhen Zhang ,&nbsp;Dongdong Song ,&nbsp;Guangying Cui ,&nbsp;Zhigang Ren ,&nbsp;Detao Yin ,&nbsp;Wenhua Xue","doi":"10.1016/j.cellsig.2025.112065","DOIUrl":"10.1016/j.cellsig.2025.112065","url":null,"abstract":"<div><div>5-methylcytosine (m5C) is a prevalent posttranscriptional RNA modification that participates in the initiation and progression of various cancers. NSUN2 is the primary RNA methyltransferase responsible for catalyzing the formation of m5C. However, its regulatory role and potential mechanism in osteosarcoma are still unclear. Here, we demonstrated that the NSUN2 expression was markedly upregulated in osteosarcoma tissues and cell lines. Clinically, increased NSUN2 expression was associated with poor prognosis. Functional studies revealed that NSUN2 significantly promoted metastasis and epithelial-mesenchymal transition (EMT) in osteosarcoma. Mechanistically, integrated analysis based on RNA sequencing and expression correlation identified UBE2S as a downstream target gene of NSUN2, while NSUN2 enhanced the stabilization of <em>UBE2S</em> mRNA in an m5C-dependent manner. More importantly, UBE2S overexpression reversed the inhibition of cell invasion and EMT induced by NSUN2 knockdown. Moreover, UBE2S interacted with and ubiquitinated β-catenin, enhancing its stability and activation. Interestingly, osteosarcoma patients with dual-high expression of NSUN2 and UBE2S exhibited shorter overall survival. In summary, our study revealed that NSUN2 facilitated metastasis by enhancing the UBE2S/β-catenin axis, suggesting a potential therapeutic approach for osteosarcoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112065"},"PeriodicalIF":3.7,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871707","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":"LncRNA ZNF295-AS1 modulates nasopharyngeal carcinoma progression via the miR-762/HDAC6 axis-mediated autophagy","authors":"Qiaozhi Jin ,&nbsp;Ziyuan Chen ,&nbsp;Si Ouyang ,&nbsp;Jianhua Xu ,&nbsp;Shengnan Ye","doi":"10.1016/j.cellsig.2025.112064","DOIUrl":"10.1016/j.cellsig.2025.112064","url":null,"abstract":"<div><div>Long non-coding RNAs (lncRNAs) and autophagy play pivotal roles in the pathogenesis of nasopharyngeal carcinoma (NPC), yet the mechanisms underlying lncRNA-mediated autophagy regulation in NPC remain largely unknown. This study aimed to identify critical autophagy-related lncRNAs in NPC and to elucidate the functional role and molecular mechanisms of ZNF295-AS1 in modulating autophagy and tumor progression. We systematically screened for autophagy-associated lncRNAs by analyzing the NPC gene expression dataset GSE12452 from the GEO database, employing integrated differential expression analysis coupled with machine learning techniques. Subsequently, we constructed a co-expression network of lncRNAs and autophagy-related genes using bioinformatics tools. The expression and clinical implications of ZNF295-AS1 and its target HDAC6 were validated through a combination of RNA in situ hybridization, quantitative RT-PCR, immunohistochemistry, and functional assays conducted in NPC cell lines and xenograft models. We assessed autophagic flux using fluorescence dual-reporter assays, Western blotting, and transmission electron microscopy, while investigating the role of miR-762 in regulatory mechanisms via molecular interaction assays. Our results highlight that ZNF295-AS1 is a novel autophagy-associated lncRNA that is positively correlated with HDAC6 and is downregulated in NPC tissues, with low expression levels being associated with poor prognosis. Overexpression of ZNF295-AS1 was found to inhibit NPC cell proliferation, migration, and invasion, while disrupting autophagic flux and leading to an accumulation of p62 and LC3B-II; these effects were reversed by HDAC6 knockdown and miR-762 overexpression. Mechanistically, ZNF295-AS1 functions as a competing endogenous RNA, sponging miR-762 and thus relieving the repression of HDAC6, ultimately influencing autophagy and tumor progression. In conclusion, ZNF295-AS1 is implicated in the regulation of autophagy and malignancy in NPC through the miR-762/HDAC6 axis, suggesting its potential as a novel diagnostic and therapeutic target in NPC management.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112064"},"PeriodicalIF":3.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862157","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":"Melatonin reverses lenvatinib resistance in HCC by regulating the ATF4-NRF1 pathway mediated by ceramide synthase 6","authors":"Xiao Wu ,&nbsp;Huiya Ying ,&nbsp;Jun Xu ,&nbsp;Weimin Cai,&nbsp;Xiangting Zhang,&nbsp;Dandan Zhu,&nbsp;Ziqiang Xia,&nbsp;Yixiao Wang,&nbsp;Qian Zhao,&nbsp;Ruoru Zhou,&nbsp;Yuan Zeng,&nbsp;Fujun Yu","doi":"10.1016/j.cellsig.2025.112067","DOIUrl":"10.1016/j.cellsig.2025.112067","url":null,"abstract":"<div><div>The tyrosine kinase inhibitor lenvatinib is a first-line drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its efficacy is significantly compromised by the development of drug resistance. Gaining insights into the molecular mechanisms underlying lenvatinib resistance could offer novel strategies to enhance and prolong therapeutic responses. In this study, we established lenvatinib-resistant HCC cells and identified melatonin as a potential therapeutic agent to reverse lenvatinib resistance. We found that the key lipid metabolism gene CERS6 was significantly upregulated in lenvatinib-resistant cells, suggesting its involvement in mediating resistance to lenvatinib in HCC. Notably, the combination of lenvatinib and melatonin treatment, along with CERS6 knockdown, effectively overcame resistance by suppressing HCC cell proliferation and promoting cell death. Further investigations revealed pronounced endoplasmic reticulum (ER) stress in HCC cells treated with melatonin. Mechanistically, melatonin treatment reduced the expression levels of p-PERK, p-eIF2α, and ATF4, proteins associated with the activation of the ER stress response pathway. Additionally, the mitochondrial biogenesis-related PGC1α-NRF1-TFAM signaling cascade was altered, along with changes in mitochondrial morphology. Our findings demonstrate that the combination of lenvatinib and melatonin effectively mitigates lenvatinib resistance in HCC cells, offering a promising strategy to address drug resistance in clinical HCC management.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112067"},"PeriodicalIF":3.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862158","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":"SIRT3 mitigates osteoarthritis by suppressing ferroptosis through activating AMPK signaling pathway","authors":"Weiyu Tian ,&nbsp;Zijing Yang ,&nbsp;Mingkai Yu ,&nbsp;Tao Ma ,&nbsp;Zefan Guo ,&nbsp;Wenhao Weng ,&nbsp;Xuanchen Ren ,&nbsp;Wenxuan Li ,&nbsp;Weishan Wang ,&nbsp;Nannan Pang ,&nbsp;Zhendong Zhang","doi":"10.1016/j.cellsig.2025.112063","DOIUrl":"10.1016/j.cellsig.2025.112063","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is characterized by cartilage degeneration and inflammatory environments that promote chondrocyte death via mechanisms including ferroptosis. SIRT3-AMPK activation inhibits inflammatory and catabolic responses in chondrocytes. However, its potential effect on chondrocyte ferroptosis remains unclear.</div></div><div><h3>Objective</h3><div>This study aimed to elucidate the effects of SIRT3 on ferroptosis in chondrocytes under inflammatory conditions and the underlying mechanisms involving the AMPK/mTOR signaling pathway.</div></div><div><h3>Methods</h3><div>Mendelian randomization was used to analyze the epidemiological relationship between SIRT3 expression and the occurrence of knee OA. ATDC5 cells were treated with IL-1β, TNF-α, or ferroptosis agonist/antagonist. SIRT3 was overexpressed in ATDC5 cells. The effects of SIRT3 on extracellular matrix metabolism, mitochondrial function, and ferroptosis were detected by Western blot, immunofluorescence, JC-1 staining, quantitative real-time PCR, and Alcian blue staining. In vivo experiments were conducted using mice subjected to destabilization of the medial meniscus to mimic OA. Then, micro-CT, histological analyses, and protein expression detections were conducted.</div></div><div><h3>Results</h3><div>Mendelian randomization identified SIRT3 expression as a protective factor in the development of knee OA. In vitro, IL-1β and TNF-α induced ferroptosis and oxidative stress in ATDC5 cells while down-regulating SIRT3. Treatment with the ferroptosis agonist Erastin or the antagonist Fer-1 resulted in decreased or increased protein levels of SIRT3, respectively. SIRT3 overexpression mitigated the degradation of the extracellular matrix, alleviated oxidative stress, modulated mitochondrial functions, and prevented ferroptosis in ATDC5 cells under IL-1β treatment in vitro. Furthermore, the effects of SIRT3 may be mediated by the AMPK/mTOR signaling pathway. In vivo, SIRT3 overexpression mitigated OA severity, evidenced by improved joint integrity and reduced cartilage degradation.</div></div><div><h3>Conclusions</h3><div>SIRT3 inhibits ferroptosis and regulates mitochondrial function via the AMPK/mTOR signaling pathway, thereby alleviating OA. Targeting the SIRT3-AMPK axis presents a promising therapeutic method for OA treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112063"},"PeriodicalIF":3.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862159","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":"Osteocyte dysregulation in periodontitis: Pathological mechanisms and therapeutic potential","authors":"Luyao Si ,&nbsp;Xinxin Tian ,&nbsp;Longfei Tian ,&nbsp;Kai Yang","doi":"10.1016/j.cellsig.2025.112062","DOIUrl":"10.1016/j.cellsig.2025.112062","url":null,"abstract":"<div><div>Periodontitis, a chronic inflammatory disease driving alveolar bone destruction, is critically mediated by osteocyte dysregulation. This review synthesizes current evidence revealing that osteocyte-derived RANKL and sclerostin actively promote osteoclastogenesis while suppressing osteoblast activity, directly accelerating bone resorption. Osteocyte apoptosis, ferroptosis, and senescence further exacerbate inflammation through cytokine cascades (e.g., IL-6, TNF-α) and impair regenerative capacity. Therapeutically, targeting osteocytes with anti-RANKL (e.g., denosumab) or anti-sclerostin antibodies (e.g., romosozumab) significantly reduces osteoclast activation and bone loss in preclinical models, while activation of the Notch signaling pathway enhances osteocyte survival and promotes bone formation. Collectively, these findings highlight osteocyte-centered signaling as a promising therapeutic avenue for restoring bone homeostasis and underscore the need for further research to translate these mechanisms into clinical interventions for periodontitis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112062"},"PeriodicalIF":3.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858988","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":"PZR: Advances in research from cellular signaling Hub to emerging therapeutic targets","authors":"Heng Ping Wang ,&nbsp;WanLi Sha ,&nbsp;Ying Fu ,&nbsp;Huiyan Wang","doi":"10.1016/j.cellsig.2025.112061","DOIUrl":"10.1016/j.cellsig.2025.112061","url":null,"abstract":"<div><div>Protein Zero Related (PZR) is a type I transmembrane glycoprotein encoded by the <em>MPZL1</em> gene and a member of the immunoglobulin superfamily (IgSF). Despite sharing 46 % sequence homology in its extracellular domain with myelin P0 protein (MPZ), PZR exhibits distinct functional specialization. It undergoes alternative splicing to generate three isoforms (PZR, PZRa, PZRb) with tissue-specific expression patterns, predominantly enriched in cardiovascular, renal, and pancreatic tissues, and localized to cell-cell contact sites and migration-associated domains, consistent with its roles in adhesion and motility.</div><div>Functionally, PZR serves as a multifunctional signaling hub, acting as both a receptor for concanavalin A (ConA) and a regulator of SH2 domain-containing protein tyrosine phosphatase-2 (SHP-2) and Src family kinases. ConA binding triggers c-Src activation, leading to PZR autophosphorylation and subsequent recruitment of SHP-2. Its intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) further mediate interactions with Src kinases and SHP-2, driving oncogenesis, immunomodulation, and antiviral responses. Post-translational modifications, including phosphorylation and glycosylation, enhance its protein-binding capacity, enabling broad influence over physiological and pathological processes, particularly in tumor microenvironment signaling and cellular fate regulation. Initially implicated in Noonan syndrome and schizophrenia, recent studies highlight PZR as a critical regulator of cancer cell adhesion and migration, with dysregulation accelerating disease progression. This review systematically analyzes the structural and functional properties of PZR, explores its disease-associated molecular mechanisms, and integrates emerging evidence to propose PZR as a promising therapeutic target. By delineating its signaling networks and pathophysiological roles, we provide a framework for advancing diagnostic and therapeutic strategies targeting PZR-related disorders.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112061"},"PeriodicalIF":3.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144852436","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}