Clinical and Experimental Medicine最新文献

{"title":"PFAS is associated with perineural invasion in triple-negative breast cancer with a potential role for Cathepsin D dysregulation: a multi-omics and experimental study.","authors":"Shuran Chen, Rongsheng Su, Zhenglang Yin, Haohao Chen, Yanyan Liu, Angqing Li","doi":"10.1007/s10238-026-02164-w","DOIUrl":"10.1007/s10238-026-02164-w","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are persistent pollutants linked to breast cancer (BC), but their role in perineural invasion (PNI) of triple-negative breast cancer (TNBC) is unclear. Cathepsin D (CTSD), a lysosomal protease, is hypothesized to mediate PFAS-induced PNI, though systematic evidence is lacking. We integrated multi-omics data from TCGA-BRCA, METABRIC, and single-cell RNA-seq datasets. Analyses included differential gene expression, Mendelian randomization, consensus clustering, and machine learning for prognostic modeling. Single-cell analyses were performed using Seurat, Monocle2, and CellChat. GraphBan screened natural CTSD-binding compounds, with binding affinity evaluated by molecular docking and dynamics simulations. Experimental validation included immunohistochemistry, immunofluorescence, Transwell, and Western blot assays. We identified 5 PFAS-associated PNI-related genes (PPGs), with CTSD central to TNBC PNI. PPG-based molecular subtyping revealed a high-risk subgroup exhibiting enhanced epithelial-mesenchymal transition (EMT) activity, proliferation capacity, and significantly poorer overall survival. The PPG-based prognostic model effectively stratified patient outcomes and immunotherapy response. Mendelian randomization confirmed a causal link between genetically predicted CTSD levels and BC risk. Single-cell analysis showed CTSD specifically enriched in myeloid cells; CTSD⁺ myeloid cells displayed immunosuppressive signatures and therapy resistance. CTSD⁺ epithelial cells interacted with cancer-associated fibroblasts via FGF signaling and showed altered metabolism. GraphBan predicted and experiments confirmed Aurantio-obtusin as a high-affinity CTSD inhibitor. Molecular simulations demonstrated stable binding of both PFAS and Aurantio-obtusin to CTSD. Histologically, elevated CTSD expression co-localized with CD68⁺ macrophages in PNI-positive TNBC tissues, while Aurantio-obtusin suppressed CTSD expression and inhibited TNBC cell proliferation and migration. This study suggests that PFAS exposure is associated with PNI and malignant progression in TNBC, potentially involving dysregulation of CTSD. The robust PPG-based prognostic signature and the natural inhibitor Aurantio-obtusin offer novel biomarkers and a potential therapeutic strategy for mitigating PFAS-related cancer risks.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell atlas reveals the key role of pro-inflammatory IREB2⁺ microglia subsets in the microenvironment of Alzheimer's disease.","authors":"Wenzheng Rong, Jing Xu, Bo Li, Yapeng Li, Yuming Xu","doi":"10.1007/s10238-026-02188-2","DOIUrl":"10.1007/s10238-026-02188-2","url":null,"abstract":"<p><p>Chronic neuroinflammation driven by activated microglia is a critical hallmark of Alzheimer's disease (AD) progression. Metabolic dysregulation, particularly iron metabolism, has been implicated in neurodegeneration, yet the role of iron-responsive element-binding protein 2 (IREB2) in AD-associated neuroinflammation remains poorly understood. We performed integrative analysis of single-cell RNA sequencing (scRNA-seq) data from AD brain tissues, using non-negative matrix factorization (NMF) and intercellular communication algorithms to map cellular landscapes. We identified microglial subpopulations and their inflammatory signaling. To experimentally validate the functional role of IREB2 in inflammatory responses, we conducted siRNA-mediated knockdown in the human neuroblastoma cell line SH-SY5Y, which serves as a neuronal model for assessing IREB2's effect on cytokine expression. Single-cell analysis revealed a distinct microglial subpopulation (IREB2⁺ MC C1) that is significantly expanded in AD. This subpopulation exhibits a hyper-inflammatory state, with enrichment of Toll-like receptor and IL-17 signaling pathways, and functions as a primary source of outgoing inflammatory signals (CCL3, CCL4). Furthermore, IREB2 knockdown in SH-SY5Y cells significantly suppressed the expression of key pro-inflammatory cytokines (IL6, IL-1β, and TNF-α), confirming that IREB2 positively regulates inflammation in neurons as well. IREB2 drives both microglial activation and neuronal inflammatory responses in AD, potentially via the NF-κB pathway. The IREB2⁺ microglial subpopulation represents a specific pathogenic entity that orchestrates the inflammatory microenvironment. Targeting IREB2 may therefore offer a dual-pronged therapeutic strategy to mitigate neuroinflammation and slow AD progression.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13233937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics data integration using time-to event endpoint and supervised Cox penalized regression: a comprehensive review.","authors":"Antoine Dubray-Vautrin, Christophe Le Tourneau, Jimmy Mullaert","doi":"10.1007/s10238-026-02183-7","DOIUrl":"10.1007/s10238-026-02183-7","url":null,"abstract":"<p><p>The integration of multi-omics data, encompassing genomics, transcriptomics, epigenomics, and proteomics, has revolutionized medical research by enabling a more comprehensive understanding of complex diseases like cancer. Multi-omics prognostic models facilitate improved patient stratification through personalized prognostication. However, the high dimensionality, heterogeneity, and correlations between omics layers pose significant challenges for predictive modelling building, particularly in time-to-event analyses. This review synthesizes current methodologies for variable selection and regularization in high-dimensional settings, focusing on their application to survival outcomes. We explore global penalty approaches, such as LASSO, Ridge, and Elastic Net, which apply uniform penalties to control model complexity and improve generalizability. Parallel regression methods, which independently analyse different omics layers before integrating results, offering robustness but potentially missing critical correlation. Group regularization techniques, including Group LASSO and OSCAR regression, address multicollinearity by clustering correlated predictors, enhancing interpretability in high-dimensional datasets. Hierarchical regression models, such as Priority LASSO and IPF-LASSO, leverage prior knowledge of omics relationships to improve integration and interpretability but may overlook platform interactions. Kernel-based methods like KEN-COX are also examined for their ability to handle nonlinear relationships and reduce dimensionality. Each method presents unique trade-offs between interpretability, computational efficiency, and predictive performance. This review highlights the need for tailored approaches that balance these factors, emphasizing the importance of model transparency and clinical applicability. Future research should focus on refining these techniques to better capture the complex interplay of omics data in disease progression and survival outcomes.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-positive gastric cancer co-expressing AFP and CEA: an aggressive subtype defined by unique clinical and biological profiles.","authors":"Jiayu Jiang, Hongming Liu, Yong Liu, Lei Cao, Weihua Gong","doi":"10.1007/s10238-026-02175-7","DOIUrl":"10.1007/s10238-026-02175-7","url":null,"abstract":"<p><p>While alpha-fetoprotein-producing gastric cancer (AFPGC) is a highly aggressive variant, a distinct subpopulation exhibits concurrent elevation of both AFP and carcinoembryonic antigen (CEA). In this review, patients with gastric cancer presenting with concurrent elevation of serum AFP (> 7 ng/mL) and CEA (> 5 ng/mL) are classified as dual-positive gastric cancer (DPGC). Compared to AFPGC and common gastric cancer, this phenotype exhibits profoundly more aggressive clinicopathological characteristics. Nearly all cases present at advanced clinical stage III-IV (98.25%) and exhibit extensive lymph node involvement (98.25%), alongside a remarkably high incidence of hepatic metastasis affecting 82.86% of the patients. Beyond its aggressiveness, DPGC frequently presents with severe systemic manifestations, including prominent immune-inflammation, malnutrition and cancer-associated thrombosis. While patients exhibit a median overall survival of merely 6 months under standard chemotherapy, they paradoxically achieve an extended survival of 18 months with combined immunochemotherapy, even though immune infiltration profiling reveals a highly immunosuppressive baseline microenvironment. Since the initial description of concurrent CEA and AFP elevation in gastric cancer in 1977, standardized diagnostic criteria for this extreme phenotype have remained undefined. To address this diagnostic gap, concurrent AFP and CEA evaluation is imperative for prognostic stratification and timely immunotherapeutic interventions. The clinical cohort data were derived from our previously published retrospective study enrolling 127 patients in total, including 57 dual-positive (DPGC) and 70 AFP single-positive (SPGC) individuals. Bioinformatic analyses were based on the TCGA stomach adenocarcinoma cohort. Normal samples and tumor samples without clinical data were excluded, leaving 370 gastric adenocarcinoma cases for analysis. AFP and CEACAM5 were used as transcriptomic surrogates for AFP and CEA, respectively. An AFP-CEA based risk score was calculated using Cox regression coefficients and corresponding gene expression values. Patients were divided into high- and low-risk groups according to the median score. All statistical analyses were performed using R software (version 4.5.1). Kaplan-Meier curves were used to estimate survival outcomes, and group differences were compared using the log-rank test. Cox proportional hazards regression was used for univariate and multivariate survival analyses. Immune infiltration analysis and gene expression comparisons were performed according to the risk groups. Between-group comparisons were performed using the Wilcoxon rank-sum test. All statistical tests were two-sided, and P < 0.05 was considered statistically significant.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13357629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictors of pathologic complete response in triple‑negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and meta-analysis.","authors":"Xingyu Li, Ke Peng, Qiuxia Li","doi":"10.1007/s10238-026-02162-y","DOIUrl":"10.1007/s10238-026-02162-y","url":null,"abstract":"<p><p>Preoperative neoadjuvant chemotherapy (NAC) is a commonly employed treatment strategy for triple-negative breast cancer (TNBC). Various clinical factors may influence the likelihood of achieving a pathological complete response (pCR) following NAC. This study conducted a meta-analysis to identify factors associated with pCR to inform clinical decision-making. EMBASE, PubMed, WOS, Scopus databases were selected as the information sources to identify studies published before July 1, 2025. Predefined inclusion and exclusion criteria were applied, and the quality of included studies was assessed. Commonly reported factors were subjected to meta-analysis. Thirteen studies published between 2011 and 2025 were included, with eight published before 2020 and five thereafter. Seven potential influencing factors were analyzed, including individual characteristics, pathological features, and serum biomarkers. The pooled results indicated that clinical tumor stage (OR (odds ratio) = 0.35, 95% CI: 0.21-0.59, p = 0.032), Ki-67 expression (OR = 2.91, 95% CI: 1.64-5.16, p < 0.001), BRCA1/2 mutation status (OR = 1.95, 95% CI: 1.04-3.66, p = 0.037), and neutrophil-to-lymphocyte ratio (NLR) (OR = 5.61, 95% CI: 2.05-15.34, p < 0.001) were significantly associated with pCR. In contrast, age at diagnosis, histological grade, and nodal status were not statistically significant predictors. The likelihood of achieving pCR in TNBC patients undergoing NAC is significantly associated with clinical stage, Ki-67 expression, BRCA1/2 mutation status, and NLR. These factors should be evaluated prior to chemotherapy to help tailor treatment strategies and optimize therapeutic outcomes.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation biomarkers associated with early gastric cardia carcinogenesis.","authors":"Xiaoqi Liao, Zhihua Zhang, Guohua Xu, Danwei Zheng, Zhijin Lei, Songqin Chen, Shukun Zhao, Runhua Lin","doi":"10.1007/s10238-026-02173-9","DOIUrl":"10.1007/s10238-026-02173-9","url":null,"abstract":"<p><p>Gastric cardia cancer (GCC) is an aggressive malignancy with poor prognosis, underscoring the need for better characterization of molecular alterations during early gastric cardia carcinogenesis. This study aimed to identify and validate tissue-based DNA methylation markers associated with early precancerous and neoplastic lesions of the gastric cardia. We integrated genome-wide DNA methylation data (850 K array) from 69 gastric cardia samples, including normal mucosa (n = 22), intestinal metaplasia (IM, n = 32), intraepithelial neoplasia (IEN, n = 7), and GCC (n = 8). Differential methylation analysis revealed stage-specific methylation patterns. Machine learning algorithms, including Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest, were used to refine candidate diagnostic biomarkers, followed by immunohistochemical validation of candidate gene expression in an independent cohort (n = 212). GCC progression showed increasing epigenetic dysregulation, with hyper-differentially methylated probes (DMPs) predominating in precancerous lesions (79.3-86.3%) and hypo-DMPs in GCC (87.7%). Hyper-DMPs were enriched in promoter-associated cytosine-phosphate-guanosine (CpG) islands (P < 0.001). Two DMPs, EDNRB_cg04390523 and SALL1_cg09016242, were consistently identified by both algorithms and showed good diagnostic accuracy (AUC = 0.947, 95% CI: 0.897-0.997) for distinguishing precancerous gastric cardia lesions and GCC from normal tissue in the integrated dataset. Consistent with methylation findings, EDNRB protein expression progressively decreased from normal to IM/IEN tissues (P < 0.001). This study identifies EDNRB and SALL1 promoter hypermethylation as promising tissue-based candidate biomarkers associated with early neoplastic transformation and provides a basis for further longitudinal and translational studies in gastric cardia precancerous lesions and cancer.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative bioinformatics and experimental validation identify IL1A as a novel therapeutic target for diabetic wound healing.","authors":"Guowang Zhang, Tao An, Shuai Dai, Jinliang Huang, Pei Chen","doi":"10.1007/s10238-026-02121-7","DOIUrl":"10.1007/s10238-026-02121-7","url":null,"abstract":"<p><p>Diabetic foot ulcers (DFUs) represent a severe complication of diabetes mellitus, characterized by impaired wound healing and persistent inflammation. Despite advances in understanding the molecular mechanisms underlying DFU pathogenesis, effective therapeutic targets remain limited. This study aimed to identify novel biomarkers and therapeutic targets for diabetic wound healing through integrative bioinformatics analysis and experimental validation. We performed comprehensive transcriptomic analysis of DFU samples (n = 6) compared to normal skin controls (n = 6) from the GEO database (GSE80178). Differential expression analysis, functional enrichment, gene set enrichment analysis (GSEA), and protein-protein interaction network analysis were conducted to identify hub genes. Key findings were validated through in vitro experiments using keratinocyte cell lines cultured under normal glucose (NG), low glucose (LG), and high glucose (HG) conditions, with functional assays including colony formation and scratch wound healing assays. We identified 8,269 differentially expressed genes (DEGs), including 1,852 upregulated and 6,417 downregulated genes in DFU samples. Functional enrichment analysis revealed significant alterations in skin development, keratinocyte differentiation, inflammatory responses, and IL-17 signaling pathways. Hub gene analysis identified interleukin-1 alpha (IL1A) as a central hub gene and a key inflammatory mediator (log2FC = 5.18, adjusted p < 0.001), participating in seven distinct biological pathways. Experimental validation demonstrated that high glucose conditions impaired keratinocyte colony formation and wound closure capacity, accompanied by dysregulated inflammatory responses, consistent with the bioinformatics predictions. Through integrative computational and experimental approaches, we identified IL1A as a critical therapeutic target in diabetic wound healing. Our findings provide mechanistic insights into DFU pathogenesis and establish IL1A as a promising biomarker for developing targeted interventions to improve diabetic wound healing outcomes.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of an explainable machine learning model using routine laboratory biomarkers for identifying prevalent MASLD: Evidence from two observational studies.","authors":"Jialin Wu, Wenting Wei, Terry Cheuk-Fung Yip, Xinyi Deng, Bonan Chen, Yang Lyu, Peiyao Yu, Tiejun Feng, Fuda Xie, Ge Zhang, Kangmin Zhuang, Aimin Li, Wei Kang","doi":"10.1007/s10238-026-02163-x","DOIUrl":"10.1007/s10238-026-02163-x","url":null,"abstract":"<p><p>Although many predictive models for metabolic dysfunction-associated steatotic liver disease (MASLD) have been developed, their performance remains suboptimal. We aimed to develop an interpretable machine learning (ML)-based plasma biomarker model for identifying prevalent MASLD. Data from the National Health and Nutrition Examination Survey (NHANES 2017-2020) were randomly divided into a training cohort (N = 2760) and an internal cohort (N = 1184). Eleven ML algorithms were employed to construct classification models. Model interpretability was visualized via the SHapley Additive exPlanations (SHAP) method. External validation of these models was further conducted using data from the Korea NHANES (KNHANES) 2019-2021. The association between the selected features and prevalent MASLD was evaluated using restricted cubic spline regression analysis. Feature selection was performed using LASSO regression and the Boruta algorithm. Key predictors included diabetes mellitus (DM), waist circumference (WC), age, hypertension, and atherogenic index of plasma (AIP). All evaluated ML algorithms demonstrated robust predictive capabilities, with areas under the curve (AUC) exceeding 0.70. Among these, the Extra Trees (ET) performed the best, achieving an AUC of 0.879 (95% CI 0.856-0.897) in the internal testing group and maintaining good performance in the external KNHANES cohort with an AUC of 0.822 (95% CI 0.815-0.829). The DeLong test revealed significant differences in AUC between ET and other algorithms. These findings suggest that age, WC, DM, hypertension, and AIP are informative features associated with prevalent MASLD. The ET model showed strong discriminative performance and may serve as a practical tool for MASLD screening.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Network Pharmacology and Experimental Validation to Elucidate the Role of Huaier in Attenuating Liver Fibrosis via the AKT Signalling Pathway.","authors":"Jiachun Ding, Jiaqiang Ren, Fan Chen, Ye Lu, Yifei Ma, Ting Zhang, Zehua Shao, Huijing Tian, Siyu Wang, Zhenchao Gao, Yiqun Song, Jiahui Zeng, Jiaoxing Wu, Zhengyuan Feng, Cancan Zhou, Zheng Wang, Weikun Qian","doi":"10.1007/s10238-026-02168-6","DOIUrl":"10.1007/s10238-026-02168-6","url":null,"abstract":"<p><p>Liver fibrosis, a critical pathological precursor of cirrhosis and hepatocellular carcinoma, represents a significant unmet global health challenge because of the lack of effective targeted therapies that can reverse established fibrotic scarring. An integrated strategy was employed. Network pharmacology was used to identify potential targets, followed by molecular docking and dynamics simulations. In vivo validation utilized two established murine models: carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced fibrosis. In vitro studies employed human LX-2 hepatic stellate cells to assess the antifibrotic effects on myofibroblasts. Huaier administration significantly attenuated liver fibrosis, improved liver function and reduced collagen deposition in both animal models. Histopathological analysis confirmed diminished inflammatory infiltration and fibrotic scarring. In vitro, Huaier suppressed LX-2 cell proliferation and migration. Bioinformatics and simulation analyses suggested AKT1 as a central target, with high-affinity binding with the bioactive steroidal components of Huaier. Mechanistically, Huaier specifically inhibited the phosphorylation and activation of the AKT signalling pathway in hepatic myofibroblasts. This study provides the first compelling evidence that Huaier granules alleviate liver fibrosis by targeting the AKT pathway to inhibit myofibroblast activation. These findings illuminate its mechanistic basis and suggest that Huaier is a promising, multitarget therapeutic candidate for combating fibrotic liver disease.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-transplant JAK-inhibition improves post-transplant outcome in myelofibrosis.","authors":"Patrycja Zielińska, Agata Wieczorkiewicz-Kabut, Adrianna Spałek, Anna Kopińska, Anna Koclęga, Krzysztof Woźniczka, Kinga Boral, Aleksandra Butrym, Grzegorz Helbig","doi":"10.1007/s10238-026-02153-z","DOIUrl":"10.1007/s10238-026-02153-z","url":null,"abstract":"<p><p>Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative approach in myelofibrosis (MF). Janus-Associated Kinase inhibitors (JAKi) have changed the treatment paradigm of MF patients, becoming a therapeutic mainstay in those with splenomegaly and/or constitutional symptoms. The impact of JAKi prior to allogeneic transplant is still under investigation. The aim of the current study was to analyze the outcome and prognostic factors, especially JAKi impact on transplantation outcome in MF patients. The study comprised 96 patients (64 - MF, 21 - post-polycythemia vera (PV), 11 - post-essential thrombocythemia (ET) at a median age of 54 years at transplant (44 females, 52 males) who underwent alloHSCT in years 2008-2025. Forty-seven patients (49%) had previously received JAKi with a median treatment duration of 11 months. Median follow-up after alloHSCT was 11 months. A 2-year probability of overall survival (OS) was 78.5% for JAKi exposed patients and 48.2% for JAKi naïve ones (p = 0.005), event free survival (EFS) was 70.0% and 46.2%, respectively (p = 0.02). A 2-year relapse incidence (RI) was 13.7% and 22.6% (p = 0.298) and non-relapse mortality (NRM) was 18.9% and 40.3% (p = 0.033) in JAKi and no-JAKi exposed group, respectively. Prior JAKi use was the only factor favorably impacting post-transplant overall survival both in uni- and multivariable analysis (p = 0.02 and p = 0.03, respectively). Low ECOG score and low HCT-CI positively affected survival. Transfusion dependency prior to alloHSCT was identified as an unfavorable factor. It was demonstrated that pre-transplant JAK inhibition significantly improved post-transplant overall survival. Patient's performance status and comorbidities are variables significantly affecting survival. Transfusion burden not only adversely impacts quality of life but was also found as an adverse factor in terms of EFS, NRM and RI.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13342027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}