Molecular Medicine最新文献

{"title":"Targeting GPR84 to alleviate acute immune-mediated liver injury.","authors":"Yanan Zheng, Yumeng Wang, Yujie Xu, Shanshan Shen, Haozhe Xu, Chao Hu, Yongzhen Chen, Fengmeng Teng, Jinshun Pan, Shuqian Zheng, Junqi Wang, Zhongping Su, Qiang You","doi":"10.1186/s10020-025-01248-9","DOIUrl":"https://doi.org/10.1186/s10020-025-01248-9","url":null,"abstract":"<p><strong>Background: </strong>GPR84 is a Gi-coupled G-protein-coupled receptor (GPCR) predominantly expressed in immune cells, with its expression upregulated during inflammatory conditions. However, its specific role in immune-mediated liver injury remains unclear.</p><p><strong>Methods: </strong>We utilized a concanavalin A (Con A)-induced mouse model to simulate immune-mediated liver injury. The expression of GPR84 was assessed by quantitative RT-PCR and western blotting. GPR84 gene knockout mice were employed to evaluate the receptor's functional role. Bone marrow chimeric mice were created to determine the involvement of hematopoietic cells. Infiltrating liver inflammatory cells were analyzed by flow cytometry. The activation of key signaling pathways in hepatic tissues was assessed by western blotting. The GPR84 antagonist GLPG1205 was tested in this model to evaluate its therapeutic potential.</p><p><strong>Results: </strong>GPR84 expression was significantly upregulated in the mouse liver following Con A injection. Mice lacking GPR84 exhibited reduced serum ALT and AST levels, diminished liver damage, and decreased apoptosis. Additionally, the expression levels of inflammatory cytokines MCP-1 and TNF-α were significantly lower in Gpr84^-/- mice compared to wild-type (WT) mice after Con A injection. Flow cytometry analysis revealed a notable reduction in the proportion of Kupffer cells and infiltrating monocytes (CD11b⁺Ly6C^lowLy6G⁻) in Gpr84^-/- mice. Using bone marrow chimeric mice, we demonstrated that GPR84-deficient bone marrow-derived cells mitigate Con A-induced liver injury. Furthermore, GPR84 deficiency was associated with reduced hepatic apoptosis and lower phosphorylation levels of STAT3, ERK, JNK, p38, and p65, effectively inhibiting key inflammatory signaling pathways. Importantly, treatment with the GPR84 antagonist GLPG1205 significantly lowered serum ALT and AST levels, reduced the expression of inflammatory cytokines, and alleviated liver damage.</p><p><strong>Conclusions: </strong>Our findings suggest that GPR84 plays a pivotal role in immune-mediated liver injury, primarily through its expression on hematopoietic cells. Targeting GPR84, particularly with the antagonist GLPG1205, offers a promising therapeutic strategy for treating immune-related liver diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"187"},"PeriodicalIF":6.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079026","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":"Arctiin, a lignan compound, enhances adipose tissue browning and energy expenditure by activating the adenosine A_2A receptor.","authors":"Yuanfeng Gu, Wenjun He, Wenxuan Li, Jingshu Cai, Zhuyun Wang, Kemeng Li, Guangcheng Qin, Xiaojie Gu, Xiaojing Lin, Li Ma, Xiaoqiu Xiao, Yi Hou, Ting Luo","doi":"10.1186/s10020-025-01249-8","DOIUrl":"https://doi.org/10.1186/s10020-025-01249-8","url":null,"abstract":"<p><strong>Background: </strong>The activation of brown adipose tissue (BAT) or the browning of white adipose tissue (WAT) represents a promising therapeutic strategy for obesity. Arctiin (ARC), a lignan compound known for its anti-inflammatory, anti-tumor, and hypoglycemic properties, has not been fully elucidated regarding its effects and mechanisms on obesity.</p><p><strong>Methods: </strong>In the present study, we established both high-fat diet-induced obese mouse models and mature adipocyte cultures to comprehensively investigate the therapeutic effects of ARC on obesity. Systemic energy metabolism and thermogenic capacity were assessed through metabolic cage monitoring and cold stimulation tests. Histopathological alterations in adipose tissues were examined using hematoxylin and eosin (H&E) staining, while key gene expression in adipocytes was determined by Western blotting (WB), immunohistochemistry, and immunofluorescence staining. To further elucidate the molecular mechanisms underlying ARC's anti-obesity effects, we employed an integrated approach combining network pharmacology analysis, molecular docking simulations, cellular thermal shift assay (CETSA), and WB to identify potential molecular targets and delineate the associated signaling pathways modulated by ARC treatment.</p><p><strong>Results: </strong>In diet-induced obese mice, ARC administration at doses of 20 and 60 mg/kg/day ameliorated metabolic dysfunction through enhanced WAT browning and increased energy expenditure. In C3H10T1/2-induced adipocytes, ARC upregulated the protein expression of uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and other brown-specific marker genes, promoting mitochondrial function and browning of adipocytes. Mechanistically, our findings suggest that ARC may promote adipocyte browning via the A_2AR-cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway.</p><p><strong>Conclusion: </strong>In summary, ARC exerts protective effects against obesity by promoting the browning of white adipocytes and holds promise as a potentially beneficial therapeutic agent for the treatment of obesity.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"188"},"PeriodicalIF":6.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078707","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":"JAK2/STAT3/HMGCS2 signaling aggravates mitochondrial dysfunction and oxidative stress in hyperuricemia-induced cardiac dysfunction.","authors":"Dewei Peng, Xiaoli He, Bowen Ren, Qian Wang, Lulu Peng, Yue Jiang, Shengqi Huo, Lintong Men, Wei Shi, Pengcheng Luo, Mengyin Zhu, Cuntai Zhang, Jiagao Lv, Li Lin, Sheng Li","doi":"10.1186/s10020-025-01246-x","DOIUrl":"10.1186/s10020-025-01246-x","url":null,"abstract":"<p><strong>Background: </strong>High uric acid levels play a critical role in cardiovascular disease pathophysiology, being closely linked to their occurrence, progression, and prognosis. To enhance prevention and treatment of hyperuricemia-related cardiovascular diseases, understanding underlying mechanisms and identifying novel therapeutic targets are essential.</p><p><strong>Methods: </strong>A hyperuricemic mouse model was established, and transcriptomic analysis of myocardial tissue was conducted using RNA sequencing. The role of HMGCS2 in hyperuricemia-induced cardiomyocytes was investigated through HMGCS2 knockout. The transcriptional regulation of HMGCS2 by STAT3 was explored via STAT3 knockdown, overexpression, and dual-luciferase reporter assays. To further elucidate the role of the JAK2/STAT3/hmgcs2 signaling pathway in hyperuricemia-induced cardiomyocytes, we overexpressed HMGCS2 while intervening in the JAK2/STAT3 pathway in vitro. The therapeutic potential of targeting the JAK2/STAT3/HMGCS2 pathway was evaluated in hyperuricemic mice using STAT3 and JAK inhibitors to assess effects on cardiac dysfunction.</p><p><strong>Results: </strong>RNA sequencing showed significant upregulation of HMGCS2 mRNA in hyperuricemic mouse cardiac tissue. Increased HMGCS2 protein levels were observed in cardiac tissue and AC16 cardiomyocytes. HMGCS2 knockdown alleviated uric acid-induced mitochondrial dysfunction, oxidative stress, and abnormal energy metabolism in AC16 cardiomyocytes. And high uric acid levels activate the IL-6/JAK2/STAT3 signaling pathway in AC16 cardiomyocytes, which regulates HMGCS2 expression. By modulating JAK2 and STAT3 expression and subsequently overexpressing HMGCS2, we identified the involvement of the JAK2/STAT3/HMGCS2 pathway in uric acid-induced mitochondrial dysfunction, oxidative stress, and energy metabolism abnormalities in AC16 cardiomyocytes. In vitro experiments demonstrated that intervention with the ruxolitinib and S3I-201 could ameliorate mitochondrial dysfunction, oxidative stress, and ATP levels in the heart tissue of hyperuricemic mice. Moreover, these treatments also reversed cardiac function abnormalities.</p><p><strong>Conclusions: </strong>The JAK2/STAT3/HMGCS2 pathway may contributes to uric acid-induced cardiac dysfunction by affecting mitochondrial function, oxidative stress, and ATP metabolism, offering a potential therapeutic strategy for mitigating high uric acid-induced cardiac damage.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"184"},"PeriodicalIF":6.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972294","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":"QRICH1 regulates ATF6 transcription to affect pathological cardiac hypertrophy progression.","authors":"Lihui Zhang, Hongping Chen, Guangmei Zou, Wenjuan Jia, Haibin Dong, Chunxiao Wang, Hua Wang, Yugang Liu, Da Teng, Bowen Xu, Lin Zhong, Lei Gong, Jun Yang","doi":"10.1186/s10020-025-01241-2","DOIUrl":"10.1186/s10020-025-01241-2","url":null,"abstract":"<p><strong>Background: </strong>Many studies have shown that pathological cardiac hypertrophy is associated with active endoplasmic reticulum (ER) stress. Glutamine-rich protein 1 (QRICH1), as a transcriptional regulator, belongs to the caspase recruitment domain (CARD)-containing gene family. QRICH1 has been shown to influence the outcomes of endoplasmic reticulum stress by regulating the transcription of proteostasis-related genes. In this study, we explored the role of QRICH1 in pathological cardiac hypertrophy.</p><p><strong>Methods: </strong>We observed an increased expression of QRICH1 in the hearts of humans and mice with left ventricular hypertrophy (LVH). To assess the functional impact in this context, we employed gain- and loss-of-function approaches, using AAV9 injections to establish cardiac-specific QRICH1 knockdown or overexpression models in transverse aortic constriction (TAC) or isoproterenol (ISO)-induced cardiac hypertrophy.</p><p><strong>Results: </strong>Our data indicated that cardiomyocyte-specific knockdown of QRICH1 alleviated the hypertrophic phenotype in response to TAC or ISO injection. However, overexpression of QRICH1 exacerbated cardiac hypertrophy, remodeling, dysfunction, cell apoptosis, and inflammatory responses. Mechanistically, we demonstrated that ATF6 was significantly enriched by QRICH1 in cardiomyocytes treated with ISO using RNA-seq combined with CUT&TAG analysis. ChIP-qPCR and luciferase assays further confirmed that ATF6 is a target gene of QRICH1 in cardiomyocytes under growth stimulation. Knockdown of QRICH1 in cardiomyocytes blocked ISO-mediated induction of ATF6, activation of mTORC1, and cellular growth. And all of the above was restored by the overexpression of ATF6.</p><p><strong>Conclusions: </strong>QRICH1 plays a pivotal role in cardiac hypertrophy by regulating ATF6, and QRICH1 may be a potential new therapeutic target for pathological cardiac hypertrophy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"183"},"PeriodicalIF":6.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972305","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":"Transcriptomic analysis of non-leukemic cell subsets in azacytidine-responsive AML highlights pathways associated with adhesion, platelet aggregation, and angiogenesis in mice and humans.","authors":"Nancy D Ebelt, Suvithanandhini Loganathan, Lara C Avsharian, Edwin R Manuel","doi":"10.1186/s10020-025-01233-2","DOIUrl":"10.1186/s10020-025-01233-2","url":null,"abstract":"<p><strong>Background: </strong>Hypomethylating agents (HMAs), such as 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia (AML). Despite providing significant extensions in survival when used alone or in combination with BCL-2 inhibitors, resistance and eventual relapse is observed. Reported mechanisms of these outcomes are inconsistent when focusing on leukemic populations within bone marrow, indicating a need for studies on the impact of HMAs on non-leukemic cells in the blood and other tissue compartments.</p><p><strong>Methods: </strong>Whole blood and spleens from vehicle- or AZA-treated mice implanted with the syngeneic AML line C1498 were transcriptionally profiled using a comprehensive panel of immune-related gene probes. Publicly available RNAseq data from blood of AZA-responsive, human AML patients were analyzed compared to matched, pre-treatment samples. Genes differentially expressed between vehicle- and AZA-treated (mouse) or pre- and post-AZA treatment (human) samples were analyzed for statistical overrepresentation in gene ontologies using Fisher's one-tailed t-test. Pathological analyses of various tissues in AML relapsed, AZA-responsive mice were compared to the corresponding tissues in vehicle-treated mice.</p><p><strong>Results: </strong>We observed hematologic recovery in the peripheral blood of AZA-treated groups, versus vehicle control, that was associated with significant extensions in survival. Transcriptional analysis of AZA-treated samples revealed decreased cell type scores for suppressive subsets and increased pathway scores for T and B cell functions. Comparisons of gene ontology annotations enriched from genes differentially regulated by AZA in human and mouse blood samples revealed overlap in numerous biological pathways including adhesion, thrombosis, and angiogenesis. Consistently, C1498 permeated the liver at end-stage disease in vehicle-treated mice, while AZA treatment limited their spread to just outside the bone after relapse.</p><p><strong>Conclusions: </strong>AZA-induced differences in C1498 spread could be a result of gene expression changes in adhesion, platelet aggregation and/or angiogenesis in non-leukemic compartments; however, further mechanistic studies must be done to confirm a direct link between modulated genes and disease manifestation. Overall, these studies provide rationale for expanding the exploration of biomarkers and therapeutic targets to include normal immune cells in blood, spleen, or other microenvironments of AML patients treated with HMA, rather than limiting studies to the bone marrow and leukemic blasts.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"185"},"PeriodicalIF":6.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011683","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":"Correction: NEK8 promotes the progression of gastric cancer by reprogramming asparagine metabolism.","authors":"Mingliang Wang, Kexun Yu, Futao Meng, Huizhen Wang, Yongxiang Li","doi":"10.1186/s10020-025-01234-1","DOIUrl":"https://doi.org/10.1186/s10020-025-01234-1","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"182"},"PeriodicalIF":6.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005746","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":"Unraveling the complex genetic landscape of OTOF-related hearing loss: a deep dive into cryptic variants and haplotype phasing.","authors":"Pei-Hsuan Lin, Cheng-Yu Tsai, Yu-Ting Chiang, Chang-Han Ho, Yue-Sheng Lu, Jacob Shu-Jui Hsu, Yen-Fu Cheng, Shih-Feng Tsai, Chuan-Jen Hsu, Pei-Lung Chen, Chen-Chi Wu","doi":"10.1186/s10020-025-01225-2","DOIUrl":"https://doi.org/10.1186/s10020-025-01225-2","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in OTOF are a major cause of auditory synaptopathy. However, challenges remain in interpreting OTOF variants, including difficulties in confirming haplotype phasing using traditional short-read sequencing (SRS) due to the large gene size, the potential incomplete penetrance of certain variants, and difficulties in assessing variants at non-canonical splice sites. This study aims to revisit the genetic landscape of OTOF variants in a Taiwanese non-syndromic auditory neuropathy spectrum disorder (ANSD) cohort using a combination of sequencing technologies, predictive tools, and experimental validations.</p><p><strong>Methods: </strong>We performed SRS to analyze OTOF variants in 65 unrelated Taiwanese patients diagnosed with non-syndromic ANSD, complemented by long-read sequencing (LRS) for haplotype phasing. A prediction-to-validation pipeline was implemented to assess the pathogenicity of cryptic variants using SpliceAI software and minigene assays.</p><p><strong>Results: </strong>Biallelic pathogenic OTOF variants were identified in 33 patients (50.8%), while monoallelic variants were found in five patients. Three novel variants, c.3864G > A (p.Ala1288 =), c.4501G > A (p.Ala1501Thr), and c.5813 + 2T > C, were detected. The pathogenicity of two non-canonical mis-splicing variants, c.3894 + 5G > C and c.3864G > A (p.Ala1288 =), was confirmed by minigene assays. LRS-based haplotype phasing revealed that the common missense variant c.5098G > C (p.Glu1700Gln) and the novel variant c.5975A > G (p.Lys1992Arg) are in cis and form a founder pathogenic allele in the Taiwanese population.</p><p><strong>Conclusions: </strong>Our study highlights the genetic heterogeneity of DFNB9 and emphasizes the importance of population-specific variant interpretation. The integration of advanced sequencing technologies, predictive algorithms, and functional validation assays will improve the accuracy of molecular diagnosis and inform personalized treatment strategies for individuals with DFNB9.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"181"},"PeriodicalIF":6.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019358","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":"The MYC/TXNIP axis mediates NCL-Suppressed CD8⁺T cell immune response in lung adenocarcinoma.","authors":"Dan Xiao, Tanxiu Chen, Xinlin Yu, Ying Song, Yigang Liu, Wei Yan","doi":"10.1186/s10020-025-01224-3","DOIUrl":"https://doi.org/10.1186/s10020-025-01224-3","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma is a deadly malignancy with immune evasion playing a key role in tumor progression. Glucose metabolism is crucial for T cell function, and the nucleolar protein NCL may influence T cell glucose metabolism. This study aims to investigate NCL's role in T cell glucose metabolism and immune evasion by lung adenocarcinoma cells.</p><p><strong>Methods: </strong>Utilizing single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we analyzed cell clustering, annotation, and prognosis. In vitro experiments involved manipulating NCL expression in CD8⁺ T cells to study immune function and glucose metabolism. In vivo studies using an orthotopic transplant mouse model monitored NCL's impact on CD8⁺ T cell glucose metabolism and anti-tumor immune function.</p><p><strong>Results: </strong>NCL was associated with T cell dysfunction and glucose metabolism. NCL silencing enhanced CD8⁺ T cell glucose metabolism, cytotoxicity, and infiltration, while NCL overexpression had the opposite effect. NCL overexpression relieved MYC-mediated transcriptional repression of TXNIP, reducing CD8⁺ T cell glucose metabolism. In vivo, NCL inhibited CD8⁺ T cell glucose metabolism through the MYC/TXNIP axis, hindering anti-tumor immune function.</p><p><strong>Conclusions: </strong>NCL overexpression suppresses CD8⁺ T cell glucose metabolism and anti-tumor immune function, promoting lung adenocarcinoma progression via the MYC/TXNIP axis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"180"},"PeriodicalIF":6.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008790","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":"Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer.","authors":"Hongwei Wang, Yu-Nan Zhu, Sifan Zhang, Kexin Liu, Rong Huang, Zhigao Li, Lan Mei, Yingpu Li","doi":"10.1186/s10020-025-01237-y","DOIUrl":"https://doi.org/10.1186/s10020-025-01237-y","url":null,"abstract":"<p><strong>Background: </strong>The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive.</p><p><strong>Methods: </strong>Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters.</p><p><strong>Results: </strong>Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)⁺ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)⁺ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4⁺ and CFD⁺ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy.</p><p><strong>Conclusion: </strong>We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4⁺ and CFD⁺ fibroblasts as potential biomarkers for immunotherapy in breast cancer.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"179"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027534","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":"Surgery/anesthesia may cause monocytes to promote tumor development.","authors":"Yang-Yang Wang, Rui-Lou Zhu, En-Qiang Chang, Xiao-Zhuan Liu, Guang-Zhi Wang, Ning-Tao Li, Wei Zhang, Jun Zhou, Ming-Yang Sun, Xin Zou, Jie Hao, Jia-Qiang Zhang","doi":"10.1186/s10020-025-01213-6","DOIUrl":"https://doi.org/10.1186/s10020-025-01213-6","url":null,"abstract":"<p><strong>Background: </strong>The immune system of patients undergoing major surgery usually has obvious immune responses during the perioperative period, and the patient's immune status would affect the patient's prognosis. In this study single-cell sequencing technology was used to investigate the effect of surgery/anesthesia on peripheral blood mononuclear cells (PBMCs) in depth during the perioperative period.</p><p><strong>Methods: </strong>We performed an in-depth analysis of our previously published data, which included a total of 4 patients were recruited in this study. Their peripheral blood samples were collected pre operation, 0, 24, and 48 h post operation, and then PBMCs were extracted, followed by single cell sequencing. The results of sequencing were analyzed with R packages seurat and scSTAR. Finally, RT-PCR technology was used to verify the expression of key genes in monocyte.</p><p><strong>Results: </strong>The ratio of CD4⁺ and CD8⁺ T cells and Tregs showed little change, and the function of CD4⁺ and CD8⁺ T cells recovered soon. The function of Treg had not been restored 48 h post operation. Non-classical monocyte was impressed after surgery and showed no recovery trend within 48 h. Similar to scRNA-seq, the expression levels of MDM2 and SESN1 in patients with tumor increased significantly after surgery.</p><p><strong>Conclusions: </strong>Surgery/anesthesia had little effect on CD4⁺ and CD8⁺ T cells, and continued to affect the functional changes of Treg. It had more impact on monocytes, which may cause them to promote tumor development to a certain extent.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"178"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028437","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}