Molecular Medicine最新文献

{"title":"STMN1-IGFBP5 axis induces senescence and extracellular matrix degradation in nucleus pulposus cells: In vivo and in vitro insights.","authors":"Lei Li, Guangzhi Zhang, Zhili Yang, Zhenyu Cao, Dongxin Wang, Xuewen Kang","doi":"10.1186/s10020-025-01220-7","DOIUrl":"https://doi.org/10.1186/s10020-025-01220-7","url":null,"abstract":"<p><p>Cellular dysfunction induced by senescent nucleus pulposus (NP) cells is a key factor in the pathogenesis of intervertebral disc degeneration (IDD). Stathmin 1 (STMN1) has been proposed as a telomere-associated senescence marker implicated in senescence in many age-related diseases. Nevertheless, its role in NP cell senescence remains unclear. This study revealed that STMN1 was significantly upregulated in human degenerative and naturally aged rat NP tissue specimens. In vitro models demonstrated that STMN1 expression levels were elevated in replicative and TNF-α-induced NP senescence models. Lentiviral knockdown of STMN1 inhibited NP cell senescence, while overexpression promoted NP cell senescence, along with extracellular matrix (ECM) degradation. An in-depth mechanism indicated that insulin-like growth factor-binding protein 5 (IGFBP5), a downstream pro-senescence gene of STMN1, can induce NP cellular senescence and ECM degradation following its upregulation by STMN1. Furthermore, STMN1 knockdown reduced IGFBP5 expression and mitigated IDD development in a rat model of caudal discs puncture-induced IDD. Combined with the abovementioned results, we demonstrated for the first time that the STMN1-IGFBP5 axis can induce NP cell senescence and ECM degradation, thereby accelerating IDD development. This provides a robust foundation for the development of molecular-targeted therapies for IDD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"167"},"PeriodicalIF":6.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calpain1 inhibition enhances autophagy-lysosomal pathway and ameliorates tubulointerstitial fibrosis in Nephronophthisis.","authors":"Dantong Li, Jinglan Zhang, Xinyu Su, Yichen Yang, Jiayong Lai, Xiaoya Wei, Huamu Chen, Yaqing Liu, Haiyan Wang, Liangzhong Sun","doi":"10.1186/s10020-025-01231-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01231-4","url":null,"abstract":"<p><strong>Background: </strong>Nephronophthisis (NPH) is classified under the category of renal ciliopathies and is the most common genetic disease leading to renal failure in children. Early-onset and progressive renal tubulointerstitial fibrosis represents one of the most significant features, culminating in renal insufficiency. However, the molecular mechanism of tubulointerstitial fibrosis remains unclear. Previously, we constructed an NPH mouse model via CRISPR-Cas9. This mouse model demonstrated typical features of tubulointerstitial fibrosis. In this study, we aimed to explore the pathogenesis of tubulointerstitial fibrosis in NPH and identify early intervention targets in both the NPH models and patients.</p><p><strong>Methods: </strong>In this study, transcriptome changes in mouse kidneys were analyzed through RNA sequencing to explore the molecular mechanisms of renal tubulointerstitial fibrosis in NPH. We found an increased abundance of calpain1 in both the NPH models and patients. Pathway enrichment analysis indicated autophagy-lysosomal pathway was altered in the NPH models. Western blot, immunofluorescence or immunohistochemical staining were used to verify the expression of calpain1. We also detected autophagy activities in NPH models by lysotracker staining and transmission electron microscopy (TEM). Epithelial or mesenchymal-specific markers and Masson's trichrome staining were used to detect the status of tubulointerstitial fibrosis. Furthermore, NPH models were treated with a calpain1 inhibitor to explore the role of calpain1 in autophagy-lysosomal pathway and tubulointerstitial fibrosis.</p><p><strong>Results: </strong>The increased abundance of calpain1 impaired the autophagy-lysosomal pathway and induced tubulointerstitial fibrosis by promoting epithelial-to-mesenchymal transition. On the other hand, calpain1 inhibition could enhance the autophagy-lysosomal pathway and ameliorate the phenotypes of tubulointerstitial fibrosis in NPH models.</p><p><strong>Conclusions: </strong>Calpain1-mediated autophagy-lysosomal pathway disorder may be an important cause of tubulointerstitial fibrosis in NPH. Calpain1 may have therapeutic implications for renal tubulointerstitial fibrosis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"166"},"PeriodicalIF":6.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral tissue BDNF expression is affected by promoter IV defect and enriched environments in mice: negative hippocampus-intestine and positive thymus-serum-muscle correlations.","authors":"Janet Wang, William Schupp, Kazuko Sakata","doi":"10.1186/s10020-025-01196-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01196-4","url":null,"abstract":"<p><strong>Background: </strong>Brain-derived neurotrophic factor (BDNF) expression is reduced in the brain of various central nervous system (CNS) disorders, but its relation to peripheral expression remains unclear. This study aimed to determine peripheral BDNF expression affected by BDNF promoter IV defect and enriched environment treatment (EET). Promoter IV defect is associated with CNS disorders and chronic stress, whereas EET increases hippocampal BDNF expression and ameliorates CNS dysfunctions.</p><p><strong>Methods: </strong>Enzyme-linked immunosorbent assay measured BDNF protein levels in eleven regions (hippocampus, frontal cortex, heart, lung, liver, spleen, intestine, kidney, intestine, thymus, muscle, serum) in wild-type and knock-in promoter IV (KIV) mice with or without 3 weeks of EET provided after weaning.</p><p><strong>Results: </strong>Knock-in promoter IV resulted in BDNF levels significantly decreased in muscle, but significantly increased in intestine, liver, thymus, and serum, which suggests compensatory upregulation of other promoters in those tissues. EET increased BDNF levels in muscle and serum of KIV mice and thymus of wild-type mice, suggesting EET's beneficial effects in muscle motor and adaptive immune regulation. EET increased hippocampal BDNF levels in both genotypes, which significantly negatively correlated with intestine BDNF levels, suggesting its role in the brain-gut axis. EET reduced wild-type heart BDNF levels, possibly through parasympathetic regulation. Significant positive BDNF correlations were observed among serum-muscle, serum-thymus, lung-spleen, and intestine-liver, suggesting inter-organ interaction and regulation of BDNF. Partial Least Squares discriminant analyses (PLS-DA) identified that variations in BDNF levels in intestine, liver, frontal cortex, and serum contribute most to classify promoter IV defect, and those in hippocampus, serum, heart, thymus, and liver contribute most to classify EET effects.</p><p><strong>Conclusion: </strong>This is the first study to demonstrate how genetic and environmental factors affect BDNF expression in peripheral tissues, highlighting the complex BDNF correlations across organ systems and suggesting usefulness of multivariate BDNF analyses for detecting promoter IV defect and enriched environment effects. Elucidation of BDNF's role and regulatory mechanisms in peripheral organ systems may help better our understanding of its connection to CNS disorders and their treatments.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"164"},"PeriodicalIF":6.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electron-beam FLASH whole brain irradiation induced a unique changes of intestinal flora.","authors":"Feifei Gao, Wei Cheng, Yanxi Ma, Boyi Yu, Xinle Lang, Xiaodong Jin, Jianxin Wang, Xianhong Liu, Cuixia Di, Hui Wang, Fei Ye, Ting Zhao, Weiqiang Chen, Qiang Li","doi":"10.1186/s10020-024-01053-w","DOIUrl":"https://doi.org/10.1186/s10020-024-01053-w","url":null,"abstract":"<p><strong>Background: </strong>Whole-brain radiotherapy (WBRT) is an important way to treat multiple metastases. Ultra-high dose rate (FLASH) can avoid neurotoxicity caused by conventional irradiation, it has attracted much attention. This study aims to study the difference of irradiation-induced intestinal flora between conventional dose rate and FLASH WBRT.</p><p><strong>Methods: </strong>WBRT with 10 Gy was performed with electron-beam conventional irradiation (2 Gy/s) and electron-beam FLASH (eFLASH) irradiation (230 Gy/s). The intestinal feces and whole brain of mice were isolated after behavioral evaluation at 1st, 3rd and 10th weeks post-irradiation. HE staining and immunofluorescence were used to access the level of brain damage. The differences in intestinal microbes and transcription levels were detected by 16S rRNA gene sequencing and transcriptome sequencing, respectively.</p><p><strong>Results: </strong>eFLASH irradiation significantly reduced radiation neurotoxicity and had a long-term protective effect on cognitive function and learning and memory ability. Compared with conventional irradiation, eFLASH irradiation not only up-regulated the expression of genes related to neuronal regeneration and digestive system, but also induced more abundant intestinal microflora, especially the \"probiotics\" such as Lachnospiraceae and others, which were proved to play a role in radiation protection, increased significantly after eFLASH irradiation. The up-regulated microbiota after eFLASH irradiation was significantly positively correlated with genes related to neuronal development and regeneration, while significantly negatively correlated with genes related to inhibitory synapses. Additionally, conventional irradiation down-regulated microbial metabolism-related pathways, while FLASH did not.</p><p><strong>Conclusions: </strong>In summary, we explored the unique gut microbiota changes induced by eFLASH WBRT for the first time, providing a theoretical basis for exploring the mechanism of action of FLASH.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"165"},"PeriodicalIF":6.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer.","authors":"Zhiyong Wang, Cheng Yu, Gengchen Xie, Kaixiong Tao, Zhijie Yin, Qing Lv","doi":"10.1186/s10020-025-01182-w","DOIUrl":"https://doi.org/10.1186/s10020-025-01182-w","url":null,"abstract":"<p><strong>Background: </strong>Mitophagy, essential for cellular homeostasis, is involved in eliminating damaged mitochondria and is associated with cancer progression and chemoresistance. The specific impact of mitophagy on microsatellite instability-high (MSI-H) colorectal cancer (CRC) is still under investigation. Ubiquitination, a post-translational modification, is essential for controlling protein stability, localization, and function. This study identifies USP14, a deubiquitinating enzyme, as a key regulator of mitophagy in MSI-H CRC.</p><p><strong>Methods: </strong>A deubiquitinating enzyme (DUBs) siRNA library screening identified USP14 as a key regulator of mitophagy. Tissue samples from patients were analyzed using immunohistochemistry and Western blot. USP14 knockdown cell lines were generated using lentiviral transfection. Protein interactions between USP14 and BAG4 were confirmed by co-immunoprecipitation, while quantitative PCR was used to measure gene expression. Mitochondrial proteins were extracted to analyze mitophagy, and flow cytometry was used to assess apoptosis. Finally, a mouse xenograft model was employed to study USP14's role in tumor growth and oxaliplatin sensitivity.</p><p><strong>Results: </strong>Screening reveals that USP14 inhibits mitophagy and CRC (MSI-H) show high USP14 expression which correlates with poor prognosis. Functional analyses reveal that knocking down USP14 reduces tumor growth, and increases sensitivity to oxaliplatin. Mechanically, USP14 inhibits mitophagy by K48-deubiquitinating and stabilizing BAG4 at K403, which prevents the recruitment of Parkin to damaged mitochondria. The significant clinical relevance of USP14, BAG4, and PRKN are proved in tumor tissues.</p><p><strong>Conclusions: </strong>The study highlights the USP14/BAG4/PRKN axis as a critical pathway in CRC (MSI-H), suggesting that targeting USP14 could inhibit tumor progression and improve chemotherapeutic outcomes. These findings underscore the importance of ubiquitination and mitophagy in cancer biology, indicating a potential therapeutic target for MSI-H CRC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"163"},"PeriodicalIF":6.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BACH1 deficiency improves placental angiogenesis via SLC25A51-mediated mitochondrial NAD⁺ transport in intrahepatic cholestasis of pregnancy.","authors":"Shengpeng Li, Weiying Zhu, Zhixuan Xing, Dan Chen, Huimin Zhao, Yanli Zhang, Wenlong Zhang, Jiaojiao Sun, Yaxian Wu, Ling Ai, Qingfeng Pang","doi":"10.1186/s10020-025-01215-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01215-4","url":null,"abstract":"<p><strong>Background: </strong>Placental angiogenesis is particularly important in the treatment of intrahepatic cholestasis of pregnancy (ICP). Although BACH1 has been implicated in angiogenesis associated with cardiovascular diseases, its specific role and underlying mechanisms in ICP remain unclear. This study aims to investigate the role of BACH1 in ICP.</p><p><strong>Methods: </strong>The study used clinical samples and two distinct mouse models of ICP to validate BACH1 alterations in ICP through immunohistochemistry (IHC), immunofluorescence (IF), and western blot (WB) analyses. Subsequently, global BACH1-knockout mice were employed to investigate the phenotypic effects of BACH1 deficiency on ICP progression. The molecular mechanisms underlying the regulatory role of BACH1 in ICP were further elucidated using multi-omics approaches (e.g., transcriptomics and proteomics), combined with dual-luciferase reporter assays and electrophoretic mobility shift assays (EMSA).</p><p><strong>Results: </strong>The expression of BACH1 was significantly upregulated in ICP, and its expression level positively correlated with clinicopathological indicators of ICP. Experiments using BACH1-knockout mice demonstrated that BACH1 deletion effectively ameliorated ICP-related placental tissue damage and significantly enhanced the expression levels of angiogenesis markers such as vascular endothelial growth factor (VEGF). Mechanistic investigations indicated that BACH1 deficiency activated the transcriptional expression of solute carrier family 25 member 51 (SLC25A51), thereby promoting the mitochondrial transport of nicotinamide adenine dinucleotide (NAD⁺), restoring mitochondrial function, and improving the activities of electron transport chain complexes I, II, and IV. Notably, BACH1 deficiency promoted taurocholic acid (TCA)-induced proliferation of human umbilical vein endothelial cells (HUVECs), whereas this phenotype could be reversed by shRNA-mediated knockdown of SLC25A51. Further studies confirmed that administration of the specific BACH1 inhibitor HPPE effectively alleviated TCA-induced suppression of HUVECs proliferation.</p><p><strong>Conclusions: </strong>BACH1 may suppress placental angiogenesis by inhibiting the transcriptional expression of SLC25A51, making it a potential therapeutic target. Specifically, pharmacological inhibition of BACH1 could provide a targeted therapeutic strategy for placental angiogenesis associated with ICP.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"162"},"PeriodicalIF":6.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate immune training in the neonatal response to sepsis.","authors":"Jaimar C Rincon, Dayuan Wang, Valerie E Polcz, Evan L Barrios, Marvin L Dirain, Ricardo F Ungaro, Dina C Nacionales, Leilani Zeumer-Spataro, Feifei Xiao, Philip A Efron, Lyle L Moldawer, Guoshuai Cai, Shawn D Larson","doi":"10.1186/s10020-025-01179-5","DOIUrl":"https://doi.org/10.1186/s10020-025-01179-5","url":null,"abstract":"<p><p>Neonates, especially those born prematurely, are highly vulnerable to infection-induced mortality. Numerous observational and immunological studies in newborns have shown that live attenuated vaccines have beneficial, non-specific effects (NSEs) against secondary infections to unrelated pathogens. These beneficial effects have been attributed to trained immunity, and emergency granulopoiesis plays an essential role. However, trained immunity has been shown to affect multiple myeloid subsets and how trained immunity influences the host protective response is still undefined. Here we show that Bacillus-Calmette-Guérin (BCG) vaccination improves survival to polymicrobial sepsis by simultaneously reprogramming broad aspects of myelopoiesis. Specifically, BCG vaccination expands multiple myeloid subsets, including the lineage (Lin)^-Sca- 1⁺c-kit⁺ (LSK) and granulocytic-macrophage progenitors (GMPs), and increases CD11b⁺Gr1⁺ cell number, as well as their oxidative metabolism and capacity to stimulate T-cell proliferation in response to sepsis. Single-cell RNA sequencing of neonatal splenocytes suggests that BCG-vaccination changes the broad transcriptional landscape of multiple myeloid subsets. The result is the maturation of various neutrophil and monocyte subsets, stimulation of antimicrobial processes, and suppression of inflammatory pathways and myeloid-derived suppressor cell transcription. These findings reveal that BCG administration early after birth fundamentally reorganizes the myeloid landscape to benefit the subsequent response to polymicrobial infection.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"159"},"PeriodicalIF":6.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surfactant protein D alleviates chondrocytes senescence by upregulating SIRT3/SOD2 pathway in osteoarthritis.","authors":"Huanyu Jiang, Yantao Zhang, Piyao Ji, Jianghua Ming, Yaming Li, Yan Zhou","doi":"10.1186/s10020-025-01221-6","DOIUrl":"https://doi.org/10.1186/s10020-025-01221-6","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is an age-related degenerative disease that affects bones and joints. The hallmark pathogenesis of OA is associated with chondrocyte senescence. Surfactant protein D (SP-D) is a member of the innate immune proteins family, which can inhibit the immune inflammatory response of chondrocytes. However, the effect of SP-D on chondrocyte senescence phenotype is poorly studied. The present study investigated the phenotypic regulation of OA chondrocyte senescence mediated by SP-D and explored the underlying molecular mechanism.</p><p><strong>Methods: </strong>In this study, an in vitro senescence chondrocyte model was generated by subjecting chondrocytes to IL-1β treatment. Furthermore, the expression of aging-related biomarkers and mitochondrial functions in SP-D overexpressing chondrocytes was observed. Co-immunoprecipitation was conducted to verify the association between SP-D and the identifed proteins within chondrocytes. Moreover, a rat OA model was established by destabilization of the medial meniscus surgery, and the effect of SP-D on reversing the aging phenotype of OA cartilage was investigated.</p><p><strong>Results: </strong>The results indicated that SP-D significantly decreased senescence and enhanced mitochondrial functions in senescent chondrocytes. The RNA-sequencing analysis revealed that the SIRT3/SOD2 pathway predominantly modulated the effect of SP-D on alleviating senescence. In addition, SP-D overexpression mitigated chondrocyte senescence, suppressed senescence-associated secretory phenotype (SASP) secretion and ameliorated mitochondrial damage. In the rat OA model, SP-D inhibited aging-related pathological changes by upregulating SIRT3/SOD2 pathway, thereby protecting the cartilage tissue integrity.</p><p><strong>Conclusion: </strong>These findings indicate that SP-D modulates the inhibition of chondrocyte senescence by upregulating SIRT3/SOD2 pathway. These data indicate that targeting SP-D and the SIRT3/SOD2 pathway might be a promising therapeutic strategy for OA.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"161"},"PeriodicalIF":6.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMSB10 drives prostate cancer aggressiveness via immune microenvironment regulation.","authors":"Haoran Xia, Jiaxin Ning, Xiaoxiao Guo, Hongchen Song, Xuanhao Li, Xuan Wang","doi":"10.1186/s10020-025-01211-8","DOIUrl":"https://doi.org/10.1186/s10020-025-01211-8","url":null,"abstract":"<p><p>Thymosin β10 (TMSB10) has emerged as a key player in the progression of prostate cancer, significantly influencing the tumor immune microenvironment. Pan-cancer analysis from The Cancer Genome Atlas (TCGA) revealed that TMSB10 is upregulated across multiple cancer types, particularly in prostate cancer, where high TMSB10 expression correlates with poorer patient outcomes. Functional assays using prostate cancer cell lines LNCaP and DU145 showed that TMSB10 silencing suppresses cell proliferation, migration, and invasion, while overexpression enhances these oncogenic processes. Furthermore, co-culture experiments demonstrated that TMSB10 overexpression skews macrophage polarization, decreasing the population of M1-type macrophages while increasing M2-type macrophages. This shift reduces immune cell cytotoxicity and alters cytokine secretion, highlighting TMSB10's role in immune evasion. These findings establish TMSB10 as a pivotal factor in prostate cancer biology, promoting tumor aggressiveness and modulating the immune response within the tumor microenvironment. TMSB10 presents a promising therapeutic target for prostate cancer, offering new avenues for treatments aimed at altering the tumor immune landscape. This research also provides a foundation for further exploration of TMSB10's role in other cancers.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"160"},"PeriodicalIF":6.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exogenous TSG-6 treatment alleviates DSS-induced colitis in mice by modulating Pou2f3 and promoting tuft cells differentiation.","authors":"Shaopeng Yang, Yuqi Li, Rongwei Ruan, Jiangping Yu, Bo Zhu, Haibin Lou, Xiaolan Zhang, Shi Wang","doi":"10.1186/s10020-025-01230-5","DOIUrl":"https://doi.org/10.1186/s10020-025-01230-5","url":null,"abstract":"<p><strong>Background: </strong>Whereas intestinal epithelial barrier dysfunction is implicated in inflammatory bowel disease (IBD), the underlying mechanisms remain elusive. Tumor necrosis factor α stimulated gene 6 (TSG-6) is a secretory protein with anti-inflammatory properties. Our previous research demonstrated TSG-6 can relieve intestinal inflammation and mucosal damage. However, the underlying mechanism and targets remain unclear. This research sought to explore how TSG-6 regulates the intestinal epithelial barrier and its mechanistic role in experimental colitis.</p><p><strong>Methods: </strong>IBD mouse model was generated using dextran sodium sulfate (DSS), with or without intraperitoneal injection of TSG-6(100 µg/kg or 200 µg/kg). The effects of TSG-6 on colonic inflammation and intestinal barrier function were investigated. Label-free quantitative proteomic analysis was performed on intestinal samples to explore the mechanism and therapeutic target of TSG-6. Molecular interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence colocalization.</p><p><strong>Results: </strong>TSG-6 treatment significantly attenuated DSS-induced colitis symptoms and inflammatory cell infiltration. Microarray analysis revealed that TSG-6 decreased pro-inflammatory cytokine levels in colon tissue. TSG-6 restored the intestinal epithelial barrier through the promotion of intestinal epithelial cells (IECs) proliferation and mitigation of tight junctions (TJs) damage. Mechanistically, TSG-6 promoted tuft cells differentiation and increased interleukin-25 (IL-25) levels by directly binding to Pou class 2 homeobox 3(Pou2f3) and up-regulating its expression in the gut.</p><p><strong>Conclusions: </strong>This study demonstrated TSG-6 as a positive regulator of tuft cells differentiation by interacting with Pou2f3, and the effectiveness of exogenous TSG-6 treatment on maintaining intestinal barrier integrity showed a promising potential for its clinical application.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"157"},"PeriodicalIF":6.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}