Journal of Translational Medicine最新文献

{"title":"Chronic intermittent hypoxia impairs BM-MSC osteogenesis and long bone growth through regulating histone lactylation.","authors":"Fang Chen, Meizhen Gu, Hongming Xu, Shasha Zhou, Zilu Shen, Xiaoyan Li, Liangchao Dong, Pin Li","doi":"10.1186/s12967-025-06849-w","DOIUrl":"10.1186/s12967-025-06849-w","url":null,"abstract":"<p><strong>Background: </strong>Chronic intermittent hypoxia (CIH) caused by OSA often results in serious complications. However, the adverse effects of CIH on bone growth and development are often overlooked.</p><p><strong>Methods: </strong>CIH intervention was conducted using an OxyCycler model A84 system for 8 h per day (from 8:00 a.m. to 4:00 p.m.) over a period of 4 weeks. Body and femur lengths were measured, and micro-CT, histological analysis, and ELISA were performed to evaluate femoral development. Metabolomic, single-cell transcriptomic, Western blot, and ChIP‒qPCR analyses were conducted to explore the potential mechanisms underlying CIH-induced inhibition of long bone growth. T0070907 was administered intraperitoneally (0.5 mg/kg) every two days to investigate its effect on long bone growth under CIH conditions.</p><p><strong>Results: </strong>Here, we showed that CIH stimulation during long bone development significantly inhibited long bone growth. Multiomics analysis revealed that CIH induces anaerobic glycolysis in bone marrow mesenchymal stem cells (BM-MSCs), promotes adipogenic differentiation, and reduces their osteogenic differentiation capacity. Mechanistic studies demonstrated that CIH-induced lactate accumulation enhances lactylation at histone H3 lysine 18 (H3K18) on the PPARγ promoter in BM-MSCs, leading to the transcriptional activation of PPARγ and a consequent imbalance between the adipogenic and osteogenic differentiation of BM-MSCs. The PPARγ inhibitor T0070907 could partially rescue long bone developmental disorders induced by CIH.</p><p><strong>Conclusions: </strong>Our findings reveal an epigenetic mechanism underlying CIH-induced long bone dysplasia and highlight T0070907 as a promising targeted therapeutic agent.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"845"},"PeriodicalIF":7.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144731986","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":"Platelet membrane-coated nanoparticles inhibit platelet activation and neutrophil extracellular traps formation in acute lung injury.","authors":"Xingyu Li, Zhaoxia Tang, Liangjian Kuang, Yongjian Wu, Xi Huang","doi":"10.1186/s12967-025-06649-2","DOIUrl":"10.1186/s12967-025-06649-2","url":null,"abstract":"<p><strong>Background: </strong>Platelets play a critical role in the pathophysiology of acute lung injury (ALI) by activating neutrophils and promoting the formation of neutrophil extracellular traps (NETs). Excessive NETs formation exacerbates lung injury by triggering inflammation, impairing essential alveolar macrophage functions and activating the coagulation cascade. Consequently, inhibiting NETs formation represents a promising strategy for treating ALI.</p><p><strong>Methods: </strong>In this study, we developed platelet membrane-coated nanoparticles (PNPs) by encapsulating poly(lactic-co-glycolic acid, PLGA)‌ nanoparticles within platelet membranes, and we characterized their physicochemical and functional properties. We investigated the effects of PNPs on platelet activation, NETs formation, mitochondrial ROS (mtROS) production and Syk phosphorylation in vitro. Furthermore, we evaluated the therapeutic effects of PNPs on acute lung inflammatory responses in a murine model.</p><p><strong>Results: </strong>Compared with red blood cell membrane-coated nanoparticles (RBC-NPs), PNPs significantly inhibited both platelet activation and NETs formation. Mechanistic studies demonstrated that NETs generation was markedly attenuated via CD62P signaling inhibition in platelets and mitochondrial ROS scavenging in neutrophils (using mito-TEMPO), and these treatments exhibited a suppression efficiency that was comparable to that of PNPs treatment. In vivo experiments revealed that PNPs preferentially accumulated in the lungs of mice with ALI, reducing neutrophil infiltration and NETs formation. Furthermore, PNP treatment attenuated lung injury, as evidenced by reduced collagen deposition, decreased total protein levels and cell numbers in BALF, and decreased levels of proinflammatory cytokines in the lungs.</p><p><strong>Conclusions: </strong>Our findings demonstrate that PNPs have potential for use in treating ALI by simultaneously attenuating platelet activation and NETs formation.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"841"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718063","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":"Spatial features of tumor-infiltrating lymphocytes in primary lesions of lung adenocarcinoma predict lymph node metastasis.","authors":"Huibo Zhang, Ming Luo, Junwei Feng, Juan Tan, Yan Jiang, Dmitrij Frishman, Yang Liu","doi":"10.1186/s12967-025-06860-1","DOIUrl":"10.1186/s12967-025-06860-1","url":null,"abstract":"<p><strong>Background: </strong>Lymph node metastasis (LNM) is critical for staging, prognosis, and treatment decisions in lung adenocarcinoma (LUAD). While tumor-infiltrating lymphocytes (TILs) have demonstrated prognostic value, their role in LNM risk remains uninvestigated. This study evaluates the relationship between TIL features from primary tumor whole slide images (WSIs) and LNM in LUAD.</p><p><strong>Methods: </strong>TILScout was utilized to derive patch-level TIL scores and generate global TIL maps from primary tumor WSIs. Hot spot analysis and deep learning-based feature extraction followed by K-means clustering were applied to identify and characterize spatial TIL clusters (sTILCs) from the global TIL maps. Random forest models incorporating clinical/pathological data with (M1) and without (M2) TIL features (TIL scores and sTILCs) were developed on a training cohort (N = 312) to predict LNM, and performance was compared across validation (N = 78) and independent test cohorts (N = 148).</p><p><strong>Results: </strong>Two sTILC types (\"TIL-cold\" cluster [sTILC1] and \"TIL-hot\" cluster [sTILC2]) were identified. Model M1 significantly improved LNM prediction over M2, with AUCs increasing from 0.63 to 0.78 (Z = 5.366, P < 0.001) and from 0.61 to 0.72 (Z = 1.999, P = 0.046) in the training and validation cohorts, and from 0.69 to 0.80 (Z = 3.030, P = 0.002) in the test cohort. Decision curve analysis indicated that M1 provided greater net benefit across a broad spectrum of threshold probabilities. Importantly, patients with lower TIL scores and/or classified as sTILC1 consistently had an increased risk of LNM.</p><p><strong>Conclusions: </strong>Spatial TIL features in primary tumors are linked to LNM in LUAD, thereby enabling the identification of high-risk patients and guiding personalized treatment strategies.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"842"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718067","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":"KAT2B regulates estradiol synthesis via H3K27ac/PPARα in granulosa cells of PCOS patients.","authors":"Ao Wang, Xiao-Fei Zhang, Cong-Jian Luo, Yu-Dong Liu, Pei-Ru Chen, An-Lan Wang, Jun Zhang, Song-Yu Huang, Xin-Yi Huang, Shi-Ling Chen, Xing-Yu Zhou","doi":"10.1186/s12967-025-06848-x","DOIUrl":"10.1186/s12967-025-06848-x","url":null,"abstract":"<p><strong>Background: </strong>Polycystic ovary syndrome (PCOS) is one of the main cause of female infertility worldwide, however the aetiology of PCOS remains elusive. In our previous microarray analysis of granulosa cells (GCs), Lysine Acetyltransferase 2B (KAT2B) was significantly highly expressed in GCs of PCOS patients. While KAT2B has been documented to participate in various biological processes, its specific role and mechanism in the pathogenesis of PCOS remain largely unknown.</p><p><strong>Methods: </strong>We collected GCs from PCOS patients to quantify the expression levels of KAT2B and analyzed the correlation between KAT2B expression and clinical characteristics. In vitro, we used KAT2B-specific siRNA to suppress KAT2B expression in GCs and employed lentivirus to achieve KAT2B overexpression. In vivo, we established a rat model with ovary-specific overexpression of KAT2B through ovarian in situ injection of lentivirus. Furthermore, transcriptomic sequencing was conducted to elucidate the underlying molecular mechanisms. Untargeted metabolomics analysis provided additional insights into systemic circulatory changes in the two rat models.</p><p><strong>Results: </strong>KAT2B is abnormally overexpressed in GCs of PCOS patients, and its expression level is positively correlated with serum luteinizing hormone (LH), testosterone levels, antral follicle count (AFC), and LH/follicle-stimulating hormone (FSH) ratio, while negatively correlated with serum progesterone levels and age. In vivo experiments demonstrated that rats with ovary-specific overexpression of KAT2B exhibited PCOS-like features. Transcriptomic sequencing of cell and rat ovarian samples indicated that the PPAR signaling pathway might be a key downstream pathway of KAT2B. Further in vitro experiments demonstrated that KAT2B regulates the transcription of PPARα by modulating H3K27ac, thereby impacting aromatase expression and estradiol synthesis. Metabolomic analysis indicated altered systemic pyruvate metabolism in rats with ovary-specific overexpression of KAT2B.</p><p><strong>Conclusions: </strong>Our study revealed that the high expression of KAT2B in GCs might play a critical role in the development of PCOS by regulating estradiol synthesis, thereby offering a novel perspective for future investigations into the endocrine mechanisms underlying PCOS.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"833"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718150","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":"Letter to editor: development and validation of a multienzyme isothermal rapid amplification and lateral flow dipstick combination assay for HTLV-1 proviral DNA detection.","authors":"Dequan Liu, Lei Liu, Xiangyu Che, Guangzhen Wu","doi":"10.1186/s12967-025-06823-6","DOIUrl":"10.1186/s12967-025-06823-6","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"838"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718151","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":"Platelet-derived microparticles increase the interaction of colorectal cancer cells with the endothelium to promote metastatic events.","authors":"Izabela Papiewska-Pająk, Hassan Kassassir, Wiktoria Moczkowska, Marcin Braun, Anna Rybicka, Joanna Boncela, M Anna Kowalska","doi":"10.1186/s12967-025-06858-9","DOIUrl":"10.1186/s12967-025-06858-9","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"843"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718064","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":"FCGBP promotes ovarian cancer progression via activation of IL-6/JAK-STAT signaling pathway.","authors":"Zhiqin Fu, Kelie Chen, Fang Zheng, Wangang Gong, Ding Chao, Chao Lu","doi":"10.1186/s12967-025-06854-z","DOIUrl":"10.1186/s12967-025-06854-z","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer is among the deadliest gynecological malignancies, primarily due to late-stage diagnosis and poor prognosis. Novel biomarkers and therapeutic targets are urgently needed to enhance early detection and treatment efficacy. Fc fragment of IgG-binding protein (FCGBP), a mucin-like glycoprotein, has been associated with various cancers, but its specific role in ovarian cancer progression has not been well-defined. This study aimed to investigate the clinical relevance, functional role, and underlying mechanisms of FCGBP in ovarian cancer progression.</p><p><strong>Methods: </strong>Gene expression profiles from multiple public datasets were analyzed to identify differentially expressed genes. Weighted gene co-expression network analysis was performed to correlate FCGBP expression with clinical traits. Single-cell RNA sequencing and pseudotime trajectory analyses were used to examine FCGBP expression dynamics. FCGBP expression was validated in ovarian cancer tissues using quantitative PCR, western blotting, and immunohistochemistry. Functional assays, including proliferation, migration, invasion, and colony formation, were conducted in SKOV3 and ES-2 ovarian cancer cell lines with FCGBP knockdown. The molecular mechanism was explored using dual-luciferase reporter assays and co-immunoprecipitation. Enzyme-linked immunosorbent assays and western blotting assessed cytokine levels and pathway activation. An in vivo xenograft mouse model was used to evaluate tumorigenic effects.</p><p><strong>Results: </strong>FCGBP expression was significantly elevated in ovarian cancer tissues and correlated with advanced tumor stage and poor prognosis. Single-cell analysis showed FCGBP expression peaked in terminally differentiated epithelial cancer cells. Silencing FCGBP significantly reduced proliferation, migration, invasion, and colony formation in vitro, and suppressed tumor growth and improved survival in vivo. Mechanistically, FCGBP enhanced interleukin-6 expression by interacting with NF-kappaB subunit p65, leading to activation of the JAK-STAT signaling pathway. Rescue experiments confirmed that exogenous interleukin-6 could restore the tumor-promoting effects lost upon FCGBP knockdown.</p><p><strong>Conclusions: </strong>Our findings establish FCGBP as a crucial oncogenic regulator in ovarian cancer, acting through the IL-6-mediated activation of the JAK-STAT signaling pathway. FCGBP holds promise as a novel diagnostic biomarker and therapeutic target, potentially improving early diagnosis, prognosis, and management of ovarian cancer.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"827"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718147","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":"ImmuProgML: machine learning-based dissection of cancer-immune dynamics during tumor progression to improve immunotherapy.","authors":"Hanxiao Zhou, Lan Mei, Qianyi Lu, Yakun Zhang, Yue Sun, Caiyu Zhang, Han Jiang, Jiajun Zhou, Xia Li, Yunpeng Zhang, Shangwei Ning","doi":"10.1186/s12967-025-06872-x","DOIUrl":"10.1186/s12967-025-06872-x","url":null,"abstract":"<p><strong>Background: </strong>Cancer progression involves distinct stages, with a critical tipping point marking the transition from early to advanced phases, driven by complex tumor-immune dynamics. While immunotherapy has significantly improved outcomes, current biomarker models lack integration of cancer-immune interactions and progression dynamics. Leveraging advances in machine learning, there is an urgent need for a comprehensive framework to systematically analyze these dynamics, predict immunotherapy responses, and improve patient outcomes.</p><p><strong>Methods: </strong>We developed ImmuProgML framework by integrating multi-omics data and dynamic network biomarker (DNB) analysis to identify key pathways and critical stages in cancer progression, tested in melanoma and non-small cell lung cancer (NSCLC). We introduced the DNEX score, which combines expression changes with immunotherapy-driven network topologies, and employed machine learning algorithms for prognostic and immunotherapy response predictions. We utilized molecular docking to identify potential therapeutic targets and drug candidates.</p><p><strong>Results: </strong>ImmuProgML pinpointed tipping points at stage III for melanoma and stage II for NSCLC, characterized by accelerated disease progression, significant survival differences, heightened DNA damage repair mechanisms, and enhanced immune responses, with lymph nodes as pivotal hubs. By introducing the DNEX score, an integrative metric combining differential expression and network analysis, ImmuProgML evaluated gene immunomodulation activity during tumor progression and identified immunotherapy targets. High DNEX score correlated with immune-related pathways, including T cell activation and PD1 signaling, in melanoma and NSCLC. Using DNEX score, 62 machine learning models were integrated to create DNEX-SM, which predicted immunotherapy prognosis in melanoma with a C-index of 0.69, a perfect 3-year survival AUC of 1.0 in the GSE78220 dataset, and an AUC of 0.94 in the VanAllen_Science_2015 dataset, outperforming 35 published signatures. DNEX-RM, another immunotherapy response classifier within ImmuProgML, achieved an F1 score of 81.91% and AUCs of 0.912 in training, 0.877 in cross-validation, and 0.749 in testing, with an average AUC improvement of 0.053 across three datasets compared to other methods. Furthermore, DNEX ranking and molecular docking analysis identified four potent protein-drug pairs with strong binding affinities and unique binding pockets: CXCR4 with PIK-93, LCK with PAC-1, PRKCB with SNX-2112, and PRKCB with PIK-93.</p><p><strong>Conclusions: </strong>ImmuProgML offers a promising avenue for understanding the intricate relationship between tumors and the immune system, providing a machine learning framework for personalized cancer immunotherapy selections.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"826"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718149","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":"Reversing the \"cold\" tumor microenvironment: the role of neoantigen vaccines in prostate cancer.","authors":"Jiani Wang, Rui Guo, Luyao Zhang, Wen Zuo, Xuan Li, Sha Zhang, Qin Tan, Jie Ma","doi":"10.1186/s12967-025-06867-8","DOIUrl":"10.1186/s12967-025-06867-8","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PCa) is a common malignancy with a \"cold\" tumor microenvironment (TME) that limits immunotherapy efficacy. Neoantigens from non-synonymous mutations are potential immunotherapeutic targets.</p><p><strong>Methods: </strong>We identified the neoantigens map in the RM-1 murine prostate cancer model by the whole exome sequencing. The immunogenicity of the identified neoantigens was subsequently assessed using enzyme-linked immunospot assays. In vivo neoantigen vaccination experiments were finally conducted in mice to assess the antitumoral effect on PCa, and comprehensively understand the intrinsic dynamic mechanisms for reversing \"cold\" TME.</p><p><strong>Results: </strong>We identified 252 nonsynonymous somatic mutations in RM-1 murine PCa, and the allele frequency of 62 mutations were above 60%. The immunogenicity and specificity of 10 candidate mutations were estimated by immunizing RM-1 mice with neoantigen peptides. Among them, four of these epitopes exhibited the immunogenicity, and three of them (Med12^D182fs, Stxbp4^A535T and Hp1bp3^L16F) were proved to have therapeutic efficacy in the PCa murine model. Functional immunological experiments and bulk RNA sequencing indicated a significantly enhanced infiltration and activation of T cells, as well as upregulation of activated immune-related genes, and finally reversed the \"cold\" TME into \"hot\".</p><p><strong>Conclusions: </strong>This study contributed to an unmet therapeutic need for PCa, particularly its potential mechanisms for reversing \"cold\" TME, which lays the foundation for future application of neoantigen vaccine immunotherapy in prostate cancer.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"835"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718066","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":"Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry.","authors":"Natalie Thomas, S J Kumari A Ubhayasekera, Christopher W Armstrong, Katherine Huang, Jonas Bergquist","doi":"10.1186/s12967-025-06841-4","DOIUrl":"10.1186/s12967-025-06841-4","url":null,"abstract":"<p><strong>Background: </strong>Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterised by unrelenting fatigue, post-exertional malaise, and dysfunction across immune, nervous, metabolism, and endocrine systems. Given the broad role of steroid hormones in regulating these systems, this study investigated differences in the steroid metabolome and network dynamics between ME/CFS patients and matched controls.</p><p><strong>Methods: </strong>Blood plasma steroid levels were quantified using Ultra-Performance Supercritical Fluid Chromatography- Tandem Mass Spectrometry (UPSFC-MS/MS) in ME/CFS patients (n = 24) and age and gender matched controls (n = 24). Group comparisons of absolute steroid concentrations were performed using Mann-Whitney U tests. Partial Spearman correlation networks were evaluated to examine direct associations between steroids within each group, and centrality metrics were used to evaluate structural differences. Steroid-steroid ratios were analysed to reflect biochemical relationships. Multivariate analysis with Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) was also conducted.</p><p><strong>Results: </strong>No significant group differences in absolute steroid concentrations were observed following FDR correction. However, network analysis revealed a marked reduction in direct steroid-steroid relationships in ME/CFS, with controls exhibiting 52 significant partial correlations, while the ME/CFS group retained only one (cortisol - corticosterone). Centrality analysis further revealed a shift in network structure, with cortisone emerging as highly central in ME/CFS (degree = 7, betweenness = 16.7), despite being peripheral in controls, and progesterone showing reduced integration in ME/CFS (degree = 3 vs. 12, eigenvector = 0.40 vs. 0.93). Steroid-steroid ratio analysis revealed a higher cortisol-to-pregnanolone ratio and a lower pregnanolone-to-progesterone ratio in ME/CFS, although these findings did not remain significant after FDR correction. OPLS-DA indicated a modest relationship between steroid levels and group classification (R²Y = 22.8%), but negative Q² values suggested poor predictive power.</p><p><strong>Conclusions: </strong>Despite no significant differences in absolute steroid levels, network analysis revealed profound disruptions in steroid-steroid relationships in ME/CFS compared to controls, suggesting disrupted steroid homeostasis. Collectively the results suggest dysregulation of HPA axis function and progestogen pathways, as demonstrated by altered partial correlations, centrality profiles, and steroid ratios. These findings illustrate the importance of hormone network dynamics in ME/CFS pathophysiology and underscores the need for more research into steroid metabolism.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"829"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718068","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}