Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"GraphCellNet: A deep learning method for integrated single-cell and spatial transcriptomic analysis with applications in development and disease.","authors":"Ruoyan Dai, Zhenghui Wang, Zhiwei Zhang, Lixin Lei, Mengqiu Wang, Kaitai Han, Zijun Wang, Zhenxing Li, Jirui Zhang, Qianjin Guo","doi":"10.1007/s00109-025-02575-4","DOIUrl":"https://doi.org/10.1007/s00109-025-02575-4","url":null,"abstract":"<p><p>Spatial transcriptomics (ST) integrates gene expression with spatial location, enabling precise mapping of cellular distributions and interactions within tissues, and is a key tool for understanding tissue structure and function. Single-cell RNA sequencing (scRNA-seq) data enhances spatial transcriptomics by providing accurate cell type deconvolution, yet existing methods still face accuracy challenges. We propose GraphCellNet, a model combining cell type deconvolution and spatial domain identification, featuring the Kolmogorov-Arnold Network layer (KAN) to enhance nonlinear feature representation and contextual integration. This design addresses ambiguous cell boundaries and high heterogeneity, improving analytical precision. Evaluated using metrics like Pearson correlation coefficient (PCC), structural similarity index (SSIM), root mean square error (RMSE), Jensen-Shannon divergence (JSD), and Adjusted Rand Index (ARI), GraphCellNet has been applied to various systems, yielding new insights. In myocardial infarction, it identified spatial regions with high Trem2 expression associated with metabolic gene signatures in the infarcted heart. In Drosophila development, it uncovered TWEEDLE dynamics. In human heart development, it identified cell compositions and spatial organization across stages, deepening understanding of cellular spatial dynamics and informing regenerative medicine. KEY MESSAGES: A novel deep learning architecture that effectively captures cellular composition and spatial organization in tissue samples. An innovative KAN layer design that improves the modeling of nonlinear gene expression relationships while maintaining computational efficiency. A graph-based spatial domain identification method that leverages the spatial relationships of cell type information to enhance domain recognition accuracy. Demonstration of the framework's applicability in various biological applications, providing new insights into tissue organization and development.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IQGAP1 participates in bone marrow-derived macrophage recruitment and involves in liver inflammation/fibrosis.","authors":"Na Chang, Yuehan Ma, Jing Liu, Weiyang Li, Jing Zhao, Yuran Liu, Fuquan Liu, Chengbin Dong, Chang Liu, Changbo Qi, Lin Yang, Liying Li","doi":"10.1007/s00109-025-02573-6","DOIUrl":"https://doi.org/10.1007/s00109-025-02573-6","url":null,"abstract":"<p><p>IQ motif containing GTPase activating protein 1 (IQGAP1), a scaffold protein, is implicated in cell migration. Our previous studies demonstrate that sphingosine 1-phosphate (S1P) induces bone marrow-derived macrophages (BMDMs) recruitment and promotes chronic liver inflammation/fibrosis. However, the role of IQGAP1 in S1P-induced BMDM migration and liver inflammation/fibrosis remains unclear. Mouse liver fibrosis was induced by carbon tetrachloride (CCl₄), bile duct ligation (BDL) or methionine-choline-deficient and high-fat (MCDHF) diet. Immunofluorescence and single-cell RNA sequencing were employed to study the expression of IQGAP1 in fibrotic liver. Selective knockdown of IQGAP1 expression in macrophages was performed using IQGAP1 siRNA-GeRPs. RT-qPCR and western blot were used to assess gene expression. The Boyden chamber assay was employed to analyze BMDM migration in vitro. IQGAP1, with significantly elevated expression, was highly expressed by hepatic macrophages and positively related with inflammatory marker expression in human or mouse fibrotic livers. In vivo, selective knockdown of IQGAP1 in macrophages effectively alleviated mouse liver inflammation/fibrosis. In vitro, IQGAP1, which was increased in S1P-treated BMDMs, participated in S1P-induced BMDM migration. S1P up-regulated IQGAP1 expression in a S1P receptor 2/3 (S1PR_2/3) dependent manner. S1P/S1PR_2/3 regulated IQGAP1 expression via up-regulating RNA binding protein Hu antigen R (HuR) expression. Further studies demonstrated that miR-455-5p, which was down-regulated by S1P, was also involved in IQGAP1 expression and BMDM migration. In conclusion, IQGAP1 plays a crucial role in S1P-induced BMDM migration and liver inflammation/fibrosis, providing new insight into the contribution of IQGAP1 to chronic liver inflammation/fibrosis.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD8 + T Cells in Gastrointestinal Cancer: a Perspective on Targeting MicroRNA.","authors":"Zihan Yuan, Wei He, Wenjia Luo, Chunxia Huang, Miao Li, Jie You, Jiaqiang Wu, Kangping Yang, Liang Yang","doi":"10.1007/s00109-025-02574-5","DOIUrl":"https://doi.org/10.1007/s00109-025-02574-5","url":null,"abstract":"<p><p>Gastrointestinal cancer, which is highly prevalent globally, constitutes a major threat to human health and life. The discovery of PD-L1/PD-1 has revolutionized immunotherapy, which has led to a shift in attention toward the antitumor functions of CD8 + T cells. CD8 + T cells are crucial effector cells in antitumor immunity, yet their functionality undergoes profound changes within the tumor microenvironment (TME). In the TME, gene mutations in cancer cells serve as initiating factors, remodeling the functions of various cells and the composition of noncellular substances. Cancer cells induce functional changes in other cells within the TME to favor their survival, notably impacting crucial antitumor effector cells such as CD8 + T cells, thereby furthering tumor progression. However, how tumor cells remodel CD8 + T cells remains inadequately understood, and targeted therapies against immune checkpoints face increasing challenges. An increasing number of findings suggest that miRNAs play a critical role in the process of remodeling CD8 + T cell function in tumors. Tumor cells regulate the expression of their own miRNAs to control the expression of surface molecules, modulate the release of secreted factors, or, through miRNA-containing exosomes, communicate with and remodel the function of CD8 + T cells. Elucidating the communication between CD8 + T cells and gastrointestinal cancer cells from a miRNA perspective to explain the shift of CD8 + T cells toward favorable types of tumors may inspire new therapeutic strategies. KEY MESSAGES: MicroRNAs regulate CD8+ T cells function in gastrointestinal cancers. MicroRNAs involve in crosstalk of gastrointestinal cancers with CD8+ T cells. MicroRNAs involve in crosstalk of the gastrointestinal immune microenvironment with CD8+ T cells. Focus on the application of targeted microRNA drugs and microRNA delivery strategies in gastrointestinal cancers.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex hormone-binding globulin restrains hepatic fibrosis via inhibition of Tgfβ expression.","authors":"Sang R Lee, Moeka Mukae, Eui-Ju Hong","doi":"10.1007/s00109-025-02569-2","DOIUrl":"https://doi.org/10.1007/s00109-025-02569-2","url":null,"abstract":"<p><p>Despite the advances in the development of therapeutic strategies for liver cirrhosis, finding novel molecular targets for drug discovery is still needed to broaden clinically available options. Sex hormone-binding globulin (SHBG) is an abundant circulating protein in the human bloodstream, which is reported to reduce pro-inflammatory cytokines and dampen liver cancer. However, its role in liver fibrosis has never been reported. In the human specimen and gene expression omnibus dataset, SHBG protein was accumulated around the fibrosis area, and SHBG expression was strongly inverse related to human liver fibrosis. By using SHBG-transgenic mice, we tried to elucidate the possible protective role of SHBG in liver fibrosis. Under chronic liver inflammatory conditions (DEN + NMOR, 32 weeks of age), SHBG-transgenic mice were resistant to liver fibrosis development. With scarce fibrotic areas in Masson-Goldner's trichrome staining and alpha-smooth muscle actin immunostaining, SHBG-transgenic mice significantly decreased transforming growth factor β (Tgfβ) expression and downstream signals. Under AXL inhibition, SHBG did not suppress Tgfβ suppression and downstream signals. SHBG transgenic mice reduced mesenchymal marker expression in fibrotic liver. When Lx-2 cells activated by damage-associated molecular patterns were treated with SHBG, the conditioned media suppressed mesenchymal marker expression and reduced the migration rate of SNU423 cells compared to the vehicle-treated group. Collectively, we suggest SHBG as a host protective factor and novel molecular target for liver fibrosis. KEY MESSAGES: The abundant human plasma protein, sex hormone binding globulin (SHBG), accumulates in fibrotic liver and associates with extended survival of cirrhotic patients. SHBG represses liver fibrosis development in chronic inflammatory mouse model. SHBG suppresses Tgfβ transcription level through AXL reduction.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of SUMOylation in epithelial-mesenchymal transition.","authors":"Shujing Li, Xiaomin Yu, Lei Liang, Yang Zheng","doi":"10.1007/s00109-025-02568-3","DOIUrl":"https://doi.org/10.1007/s00109-025-02568-3","url":null,"abstract":"<p><p>Tumor metastasis remains a leading cause of mortality in cancer patients. The epithelial-mesenchymal transition (EMT) is pivotal for the invasion and metastasis of cancer cells, facilitating the transformation from epithelial to mesenchymal phenotypes and thereby altering cellular morphology and function. SUMOylation, a critical post-translational modification, orchestrates a myriad of cellular physiological responses by binding to lysine residues on target substrates. This review delineates the signaling pathways of EMT, the mechanism of SUMOylation, and its consequential impact on the EMT process. Insight into the intricate regulation of SUMOylation within the EMT pathway could unlock novel avenues for the development and optimization of targeted EMT inhibitors that are dependent on SUMOylation modulation. This could potentially offer significant advances in the therapeutic strategies against cancer metastasis.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the roles of CTRP family in cardiac remodeling.","authors":"Shuhong Zhao, Dan Huang, Rong Huang, Zhuoyu Shen, Pan Wu, Zhenguo Ma","doi":"10.1007/s00109-025-02565-6","DOIUrl":"https://doi.org/10.1007/s00109-025-02565-6","url":null,"abstract":"<p><p>The C1q/TNF-related protein family (CTRPs), a group of adipokines sharing structural homology with adiponectin (APN), have emerged as crucial regulators of metabolic and cardiovascular homeostasis. As secreted proteins with pleiotropic functions, CTRPs are involved in various physiological and pathological processes through autocrine, paracrine, and endocrine mechanisms. Cardiac remodeling, a central pathological process in cardiovascular diseases (CVDs) triggered by various cardiac injuries, involves structural and functional alterations in the myocardium. Emerging evidence has demonstrated that CTRPs play dual roles in cardiac remodeling, either ameliorating or exacerbating this process. Mechanistically, CTRPs modulate oxidative stress, inflammation, and metabolic reprogramming, all of which regulate cardiac hypertrophy and fibrosis. This review provides a systematic overview of the functional roles of CTRPs in cardiac remodeling, with a focus on their structural features, tissue distribution, and receptor-mediated signaling pathways. Furthermore, we discuss the therapeutic potential of CTRPs as biomarkers and molecular targets in CVDs, emphasizing the necessity of mechanistic and translational studies to advance clinical applications. The elucidation of CTRP-mediated pathways may offer novel insights into the pathogenesis of cardiac remodeling and facilitate the development of therapeutic strategies for treating CVDs.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular landscape of glioblastoma-associated epilepsy.","authors":"Thamiris Becker Scheffel, Fernando Mendonça Diz, Andréa Wieck, Karine Rech Begnini, Jaderson Costa da Costa","doi":"10.1007/s00109-025-02567-4","DOIUrl":"https://doi.org/10.1007/s00109-025-02567-4","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor. Tumor-associated epilepsy is a clinical challenge in GBM patients, with seizures being a common symptom and reflecting complex interactions within the tumor microenvironment. This review highlights key molecular mechanisms behind GBM-associated epilepsy, including genetic alterations, increased glutamate release, ion channel dysfunction, and inflammation. These factors disrupt the surrounding neurons, promoting seizures. Shared pathways between epilepsy and GBM, such as those involved in synaptic signaling and immune responses, present potential therapeutic targets. Antiseizure drugs remain the primary treatment, with newer options like perampanel showing promise in reducing seizures and possibly influencing tumor growth. Understanding the interplay between epilepsy and GBM at the molecular level is crucial for advancing personalized treatment strategies and improving outcomes for patients.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF4 in proximal tubules modulates kidney function and modifies the metabolome.","authors":"Yuling Chi, Eduardo Mere Del Aguila, Tuo Zhang, Charles D Warren, Helen R Hoxie, Qiuying Chen, Steven S Gross, Jacob B Geri, David M Nanus, Lorraine J Gudas","doi":"10.1007/s00109-025-02559-4","DOIUrl":"10.1007/s00109-025-02559-4","url":null,"abstract":"<p><p>Activating transcription factor 4 (ATF4) is a transcription factor that mediates the response to stress at the cellular, tissue, and organism level. We deleted the gene encoding ATF4 in the proximal tubules of the mouse kidney by using a temporal and cell type-specific approach. We show that ATF4 plays a major role in regulating the transcriptome and proteome, which, in turn, influences the metabolome and kidney functions. Genome-wide transcriptomics and single-plot, solid-phase-enhanced sample preparation (SP3)-proteomics studies reveal that ATF4 deletion changes more than 30% of transcripts and, similarly, corresponding proteins in the proximal tubules. Gene Set Enrichment Analysis indicates major changes in transporters, including amino acid transporters. Metabolomic analyses show that these changes in transporters are associated with altered profiles of amino acids in the blood, kidney, and urine. Stable isotope glutamine tracing in primary tubule cells isolated from kidney cortices confirms that ATF4 regulates glutamine transport and metabolism. We suggest that even in the absence of additional stresses, such as kidney injury, ATF4 in the proximal tubules modulates both retention of specific nutrients and excretion of catabolic products like creatinine to maintain normal kidney function. KEY MESSAGES: Activating transcription factor 4 (ATF4) deletion changed more than 30% of genome-wide transcripts and corresponding proteins in the proximal tubules. One set of the profound changes occurred in amino acid transporters and Slc22 family transporters. Changes in transporters were accompanied by altered profiles of amino acids and wastes in the blood, kidney, and urine. ATF4 in the kidney proximal tubules plays a key role in regulating both the reabsorption of nutrients and the excretion of wastes.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIPE2: a novel regulatory factor for cardiovascular-related diseases.","authors":"Ruomei Li, Zhikun Guo","doi":"10.1007/s00109-025-02564-7","DOIUrl":"https://doi.org/10.1007/s00109-025-02564-7","url":null,"abstract":"<p><p>Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is a novel regulatory factor involved in innate and adaptive immunity that negatively regulates the functions of toll-like receptors and T-cell receptors. Its selective expression within the immune system serves to inhibit inflammatory responses and maintain immune homeostasis. Inflammation and immune cell signaling initiate the innate immune response in the cardiovascular system through intricate acute and chronic adaptation processes, resulting in tissue damage and significantly contributing to the onset and progression of cardiovascular diseases. Consequently, TIPE2 presents a potential target for the diagnosis and treatment of various cardiovascular diseases. This paper reviews the structural characteristics and biological functions of TIPE2, as well as its role in the onset and progression of cardiovascular diseases, providing new strategies for prevention and treatment.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selenium and selenoproteins: key regulators of ferroptosis and therapeutic targets in cancer.","authors":"Jaewang Lee, Jong-Lyel Roh","doi":"10.1007/s00109-025-02563-8","DOIUrl":"https://doi.org/10.1007/s00109-025-02563-8","url":null,"abstract":"<p><p>The interplay between selenium (Se) metabolism and ferroptosis presents a compelling area of study in cancer biology. This review synthesizes the current understanding of key pathways implicated in ferroptosis susceptibility, with a focus on the role of selenoproteins, particularly glutathione peroxidase 4 (GPX4), which mitigates lipid peroxidation and prevents ferroptotic cell death through the system Xc^-/GSH axis. Additionally, selenoprotein P contributes to Se transport, playing a crucial role in ferroptosis resistance observed in certain cancers. Targeting Se pathways, especially disrupting GPX4 and selenoprotein P functions, offers promising avenues for cancer therapy. The differential dependence of cancer cells on Se and selenoproteins highlights the potential for selective induction of ferroptosis in malignant cells. Future research should focus on unraveling the mechanistic underpinnings of Se-mediated ferroptosis and exploring combinatorial therapeutic strategies. This review sets the stage for innovative approaches that leverage Se metabolism to enhance cancer treatment efficacy through ferroptosis modulation. KEY MESSAGES: Selenium (Se) and selenoproteins regulate ferroptosis, a lipid peroxidation-driven form of cell death. GPX4, a Se-dependent enzyme, defends cells by neutralizing lipid hydroperoxides. Xc^-/GSH/GPX4 and FSP1-CoQ₁₀ pathways are critical in modulating ferroptosis susceptibility. Selenoprotein P, SEPHS2, and SQOR highlight vulnerabilities in Se-dependent cancer cell survival. Se's role in balancing antioxidant defense and ferroptosis offers therapeutic insights.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}