Biomarker Research最新文献

{"title":"ZDHHC5-mediated S-palmitoylation of NOD2 drives neutrophil extracellular trap formation via mitophagy to exacerbate inflammation in COPD.","authors":"Ziyu Dai, Xi Chen, Yun Peng, Qiao Yu, Bin Xie, Ruixin Ma, Shaojin You, Chengping Hu, Qiong Chen","doi":"10.1186/s40364-026-01001-2","DOIUrl":"10.1186/s40364-026-01001-2","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is characterized by persistent neutrophilic inflammation, but its upstream molecular regulators remain incompletely defined. Here, NOD2 and the palmitoyl-acyltransferase ZDHHC5 were increased in COPD lung tissue and detected in pulmonary neutrophils. In CS-exposed mice, NOD2 deficiency attenuated lung inflammation, collagen deposition, EMT-associated changes, and neutrophil extracellular trap (NET) formation. Anti-Ly6G-mediated neutrophil depletion reproduced much of this protection and markedly reduced the differences between wild-type and NOD2-deficient mice, indicating that NOD2-associated pathology depends largely on neutrophils. In CSE-stimulated HL-60-derived neutrophil-like cells and primary mouse neutrophils, NOD2 loss reduced NET formation, intracellular reactive oxygen species accumulation, and mitophagy, whereas the autophagy inhibitor 3-MA attenuated NOD2-overexpression-induced NET formation. CSE also increased NOD2 S-palmitoylation. ZDHHC5 was associated with NOD2 and positively regulated its protein abundance, whereas mutation of C395 and C1033 reduced NOD2 palmitoylation, stability, membrane localization, and downstream signaling. ZDHHC5 overexpression partially counteracted the effects of NOD2 loss in vitro and in vivo, although residual effects in NOD2^-/- neutrophils indicated additional NOD2-independent mechanisms. Collectively, these findings identify ZDHHC5-NOD2 signaling as an important regulator of neutrophil-associated inflammation and NET formation in COPD.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149667","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":"Pannexin 1 expression in circulating progenitor marker-positive cells is associated with senescence and cardiovascular risk.","authors":"Ting-Yi Tien, Chiung-Yin Chang, Yih-Jer Wu, Chao-Feng Lin, Yi-Nan Lee, Hsin-I Lee, Yen-Hung Chou, Chung-Lieh Hung, Cheng-Huang Su, Hung-I Yeh","doi":"10.1186/s40364-026-01006-x","DOIUrl":"10.1186/s40364-026-01006-x","url":null,"abstract":"<p><strong>Background: </strong>Upregulation of Pannexin 1 (Panx1) has been reported in senescent human endothelial colony-forming cells. We examined whether Panx1 served as a potential biomarker of senescence in peripheral blood mononuclear cells (PBMCs) expressing progenitor markers and its association with inflammation, nitric oxide (NO), and cardiovascular risk.</p><p><strong>Methods: </strong>Panx1 transcripts were assessed in PBMCs from 60 non-diabetic donors (20 aged 20-30 years and 40 aged ≥ 65 years). ECFCs were examined for Panx1-NO interaction. A separate flow-cytometry cohort comprised 50 donors (25 young and 25 elderly) targeting CD34⁺CD45^- PBMCs and CD133⁺CD45^- PBMCs expressing kinase insert domain receptor (KDR), Panx1, senescence-associated beta-galactosidase (SA-β-gal), and NO. Plasma tumor necrosis factor-α and interleukin-6 were detected. Framingham Risk Score (FRS) analyses were confined to elderly participants. Correlation, partial-correlation, multivariable, ROC/AUC and incremental-value analyses were performed with false-discovery-rate and bootstrap procedures as appropriate.</p><p><strong>Results: </strong>Higher Panx1 transcript levels existed in PBMCs of the elderly versus young donors. Among the elderly, higher Panx1 transcript levels existed in those respectively with increased fasting glucose (> 100 versus 100 mg/dL) and moderate-to-high FRS (versus low FRS). Panx1 interacted with NO in ECFCs. The proportion of CD34⁺CD45^- cells in PBMCs was lower, whereas that of CD133⁺CD45^- cells was higher, in the elderly versus young donors. At individual cell level, the number of Panx1⁺ cells per 1 × 10⁴ cells increased, whereas the number of NO-related fluorescence-positive cells decreased, in the elderly versus young donors. Panx1 correlated with SA-β-gal in CD34⁺KDR⁺CD45^- progenitor populations after adjustment for age, sex, body mass index and fasting glucose, whereas associations in other populations were attenuated by age. No robust independent association existed between Panx1 and NO. Pooled Panx1-cytokine correlations were largely explained by age-group separation. In elderly participants, Panx1 in CD34⁺ CD45^- cells was associated with FRS (Spearman r_s=0.455, nominal p = 0.022; FDR p = 0.334) and discriminated FRS ≥ 10% (AUC 0.767, 95% CI 0.560-0.937), but incremental value over conventional clinical factors was inconsistently established.</p><p><strong>Conclusions: </strong>Panx1 in selected circulating progenitor-cell populations is associated with cellular senescence and cardiovascular risk in non-diabetic elderly individuals. Panx1 as a candidate cellular senescence-associated biomarker requires prospective validation.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148177","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":"Low-dose radiotherapy as an immunomodulator in cancer: dose-specific mechanisms and hybrid high-dose/low-dose strategies.","authors":"Jingjing Deng, Demiao Kong, Wentao Wang, Qikun Mao, Xun Zhao, Limin Ye, Dejun Cui, Qian Long, Chuan Xu, Liankui Han, Jianfeng Zhou, Lin Yang","doi":"10.1186/s40364-026-00999-9","DOIUrl":"10.1186/s40364-026-00999-9","url":null,"abstract":"<p><p>Low-dose radiotherapy (LDRT), conventionally defined as fractional doses of approximately 0.5-2 Gy, has attracted increasing interest as an immunomodulatory rather than a primarily cytoreductive use of ionizing radiation. Many of the immune mechanisms attributed to LDRT-immunogenic cell death (ICD), activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, antigen release, and remodeling of the tumor immune microenvironment (TIME)-occur across a wide range of radiation doses and are therefore not exclusive to the low-dose setting. This review is organized around that distinction: For each mechanism, we separate effects shared with radiotherapy in general from those for which dose-specific evidence supports a preferential or qualitatively different response at low doses, including the avoidance of TREX1-mediated degradation of cytosolic DNA that follows single fractions above approximately 12-18 Gy; the relative sparing of tumor-infiltrating lymphocytes; and the reprogramming of vascular, stromal, and myeloid compartments that remain viable after irradiation. We then examine immune cell reprogramming, the current clinical evidence for combining LDRT with immune checkpoint inhibitors (ICIs), and \"hybrid\" high-dose/low-dose (HDRT-LDRT) regimens, in which ablative doses to selected lesions prime antigen release while low doses to the remaining disease sustain immune cell infiltration. Because most mechanistic data are derived from individual preclinical models, whereas clinical data remain confined to early-phase, largely single-arm studies, we indicate throughout whether a conclusion is established, emerging, or model-specific, and we outline the trials required to define the LDRT dose window, its sequencing with ICIs, and appropriate patient selection.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148212","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":"Monocyte Galectin-9 is associated with CD8⁺ T-cell dysfunction and early relapse after haploidentical hematopoietic stem cell transplantation.","authors":"Weiqian Dai, Xueying Zhao, Linjie Wu, Aiming Pang, Lisha Wang, Shihui Ma, Chaofan Geng, Shiyang Wang, Xinhui Zheng, Fang Dong, Linping Hu, Erlie Jiang, Tao Cheng, Sha Hao","doi":"10.1186/s40364-026-01010-1","DOIUrl":"10.1186/s40364-026-01010-1","url":null,"abstract":"<p><strong>Background: </strong>Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) stands as a leading curative approach for AML in China. However, relapse remains a major challenge for patient survival, often occurring within six months post-transplant and associated with a five-year mortality rate of up to 80%. Here, we characterized early immune reconstitution after haplo-HSCT and investigated immune features associated with early relapse (ER) in AML.</p><p><strong>Methods: </strong>We analyzed two clinical cohorts: patients with AML (n = 44) and aplastic anemia (AA; n = 38), and AML patients with continuous complete remission (CCR, n = 55) versus ER (n = 38). Single-cell RNA sequencing was performed on longitudinal peripheral blood and bone marrow samples from AML and AA patients (n = 3 and 4), while single-cell RNA/TCR sequencing was performed on bone marrow samples from CCR and ER patients (n = 3 each). Flow cytometry assessed monocyte Galectin-9 surface expression and CD8⁺ T-cell phenotypes. Galectin-9-associated monocyte-T-cell interactions and the effects of the TIM-3 inhibitor MG-T-19 were evaluated in vitro and in a murine AML model.</p><p><strong>Results: </strong>AML and AA patients showed different patterns of early immune reconstitution after haplo-HSCT, including differences in monocyte and T-cell recovery. Within AML, ER patients exhibited increased T-cell representation but reduced basal TNF-α expression and altered exhaustion-associated CD8⁺ T-cell phenotypes before relapse. Monocytes represented a prominent Galectin-9-expressing compartment, and surface Galectin-9 on monocytes was elevated in ER compared with CCR patients as early as day 30 post-transplantation. Exogenous Galectin-9 induced dose-dependent functional and exhaustion-associated changes in CD8⁺ T cells, while Galectin-9-high IFN-conditioned monocytes impaired CD8⁺ T-cell responses in vitro. MG-T-19 partially reversed these alterations, increased CD8⁺ T-cell TNF-α production, and enhanced leukemia-cell apoptosis. In the MLL-AF9 murine AML model, MG-T-19 reduced leukemia burden and prolonged survival.</p><p><strong>Conclusions: </strong>Increased monocyte Galectin-9 during early immune reconstitution is associated with subsequent early relapse and CD8⁺ T-cell dysfunction after haplo-HSCT. Further Galectin-9-specific mechanistic studies and prospective clinical validation are warranted to establish its causal relevance and potential utility as an early relapse biomarker.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149129148","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":"Cell death in ischemia-reperfusion injury: beyond a single-cell-death perspective.","authors":"Chuang Yao, Qi Wu, Zhi Wang, Changli Wang, Wangzheqi Zhang, Lulong Bo","doi":"10.1186/s40364-026-01009-8","DOIUrl":"https://doi.org/10.1186/s40364-026-01009-8","url":null,"abstract":"<p><p>Ischemia-reperfusion injury (IRI) contributes to the pathogenesis of major diseases, including acute kidney injury, stroke, and myocardial infarction. Multiple forms of cell death, including apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis, are key contributors to IRI. The interplay among these cell-death programs adds to the complexity of the IRI landscape. Cell-death patterns differ markedly between the ischemic and reperfusion phases and across organs, reflecting the spatiotemporal and organ-specific features of IRI. Given the complex molecular mechanisms underlying IRI, multi-target small-molecule drugs, combination regimens, and nanodelivery systems have been explored, although most remain at the preclinical stage. In this review, we summarize the major cell-death modalities involved in IRI, their interconnected molecular targets and signaling pathways, and their phase-specific and organ-specific regulation. We further discuss the coordinated roles of non-coding RNAs, metabolic reprogramming, and epigenetic alterations in regulating cell death, as well as their therapeutic potential. Finally, we propose therapeutic strategies aimed at modulating crosstalk among cell-death modalities, with potential implications for individualized IRI therapy.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149118599","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":"ZNF292 mutations impair RNA and protein biosynthesis defining an adverse prognostic subset in early-stage chronic lymphocytic leukemia.","authors":"Alberto Rodríguez-Sánchez, María Alonso-Gago, Claudia Pérez-Carretero, Luis A Corchete-Sánchez, Cristina Miguel-García, Sandra Santos-Minguez, Ángela Villaverde-Ramiro, José Antonio Queizán-Hernandez, Araceli Rubio, Rocío Benito-Sánchez, Federico Lo Schiavo, Martina Ghetti, Giorgia Simonetti, Ana E Rodríguez-Vicente, Jesús M Hernández-Rivas, Miguel Quijada-Álamo","doi":"10.1186/s40364-026-01005-y","DOIUrl":"https://doi.org/10.1186/s40364-026-01005-y","url":null,"abstract":"<p><strong>Background: </strong>ZNF292 alterations are recurrently detected in patients with chronic lymphocytic leukemia (CLL), occurring in 3%-6% of patients as mutations and in 2% as 6q deletions. Although preliminary evidence suggested an independent prognostic role for ZNF292 mutations, their specific clinical relevance in early-stage CLL and the underlying biological mechanisms remain poorly defined.</p><p><strong>Methods: </strong>488 CLL patients were analyzed using targeted Next-Generation Sequencing (NGS) to characterize the landscape and clinical significance of ZNF292 mutations. CRISPR/Cas9-genome editing was employed to introduce the most prevalent ZNF292 variants into CLL cellular models. Their biological and functional implications were evaluated by integrating RNA-sequencing data from these isogenic cellular models with transcriptomic data from primary patient samples, complemented by functional validation and drug response assays.</p><p><strong>Results: </strong>ZNF292 mutations were associated with shorter time to first treatment (TTFT; median 25 vs. 52 months, P = 0.009) and inferior overall survival (OS, median 93 vs. 148 months, P = 0.004). Importantly, when restricting the analyses to early-stage cases, ZNF292 alterations were independently associated with shorter TTFT and OS, identifying a high-risk subgroup. Mechanistically, transcriptomic analyses revealed that ZNF292 mutations suppress global protein biosynthesis and modulate cell cycle progression in both primary CLL samples and CRISPR/Cas9-edited cells. Furthermore, ZNF292 deficiency impaired replication stress responses via defective CHK1 activation, resulting in DNA damage accumulation. Evaluating potential therapeutic vulnerabilities, ZNF292-mutated cells exhibited enhanced in vitro sensitivity to ibrutinib and venetoclax.</p><p><strong>Conclusions: </strong>Our findings propose ZNF292 alterations as an independent prognostic factor in early-stage CLL and unveil their role in disease progression.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149118611","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":"Advances in molecular pathobiology of PCNSL - towards clinical implementation of novel diagnostics and therapeutics.","authors":"Yi Chye Law, Jason Yongsheng Chan","doi":"10.1186/s40364-026-01008-9","DOIUrl":"https://doi.org/10.1186/s40364-026-01008-9","url":null,"abstract":"<p><p>Primary central nervous system lymphoma (PCNSL) is a rare aggressive extranodal non-Hodgkin's lymphoma which outcomes remain poor despite therapeutic advances. Recent improvements in our understanding of the molecular diversity of aggressive diffuse large B cell lymphomas suggest that the biological refinement of PCNSL diagnostics may be enabled by an integrated multi-modal approach, augmenting clinical data with modern minimally-invasive liquid biopsy-based assays and multi-omic molecular profiling. Single cell sequencing and spatial imaging technologies dissecting the immune microenvironmental architecture of PCNSL are anticipated to further refine future diagnostics. Concurrently, several innovative strategies featuring immunomodulatory agents, oncogenic kinase inhibitors and immunotherapies including chimeric antigen receptor (CAR) T-cell therapy have emerged. In this review, we provide an update of recent advances in the understanding of the pathobiology of PCNSL focusing on clinically relevant molecular subclassifications, highlight emerging therapeutics, and discuss the translational roadmap to clinical implementation of next-generation diagnostic platforms based on novel technologies.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149118481","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":"A biomarker-driven approach to targeting polyamine depletion in triple negative breast cancer.","authors":"Chloe A K White, Janice C Wu, Thomas J Velenosi","doi":"10.1186/s40364-026-01007-w","DOIUrl":"10.1186/s40364-026-01007-w","url":null,"abstract":"<p><strong>Background: </strong>Triple negative breast cancer (TNBC) is the most aggressive and heterogenous breast cancer subtype. Polyamines are essential for TNBC growth and proliferation; however, therapeutic strategies targeting polyamine metabolism have shown limited efficacy in TNBC. In this study, we demonstrate a biomarker-driven approach to treating TNBC through polyamine depletion. As the rate limiting catabolic enzyme in the polyamine pathway, spermidine/spermine N¹-acetlytransferase (SAT1) reduces polyamines and generates the metabolite, diacetylspermine.</p><p><strong>Methods: </strong>TNBC cell lines, ex vivo tumor slices, and in vivo patient-derived xenograft (PDX) models with low, moderate and high baseline levels of SAT1 were used to determine whether the efficacy of polyamine depletion therapy depends on their SAT1 metabolic phenotype.</p><p><strong>Results: </strong>TNBC with high baseline SAT1 expression was sensitive to the SAT1 agonist N¹, N¹¹-diethylnorspermine (DENSpm) resulting in reduced cell viability, polyamine depletion and elevated diacetylspermine production. Cell viability in moderate baseline SAT1 expressing TNBC was further reduced by combining DENSpm with both therapeutic and subtherapeutic doxorubicin treatment. In vivo, the addition of DENSpm to doxorubicin treatment further attenuated tumor growth in moderate SAT1 expressing TNBC-PDX, which corresponded to a sustained increase in urine diacetylspermine as a biomarker of treatment effectiveness. Mechanism delineating experiments demonstrated that doxorubicin induces SAT1 expression while DENSpm promotes productive splicing, effectively increasing and sustaining SAT1 function, depleting polyamines and increasing diacetylspermine production.</p><p><strong>Conclusions: </strong>In conclusion, these findings suggest that an SAT1-defined metabolic phenotype may enable a precision-guided strategy to effectively target polyamine depletion as a TNBC treatment and that treatment effectiveness may be monitored through evaluation of urine diacetylspermine as a non-invasive biomarker of treatment response.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082702","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":"Genetic orchestration of the primary central nervous system lymphoma microenvironment.","authors":"Xiyue Xu, Xinyi Huang, Cong Li, Jialiang Lu, Xi Chen, Haifeng Yu, Zucheng Xie, Tao Lei, Xiaowu Dong, Haiyan Yang","doi":"10.1186/s40364-026-01004-z","DOIUrl":"10.1186/s40364-026-01004-z","url":null,"abstract":"<p><p>Primary central nervous system lymphoma (PCNSL) of the CNS is a distinct entity of diffuse large B-cell lymphoma (DLBCL). CNS lymphomas primarily occur in immune-privileged sites and tend to be confined to extranodal locations such as the brain, spinal cord, meninges, and/or eyes. Due to the presence of the blood-brain barrier and the inherent \"immune privilege\" characteristics of brain tissue, the tumor microenvironment (TME) of PCNSL exhibits unique features. Additionally, genetic factors originating from the lymphoma cells themselves significantly influence the TME. Substantial evidence has demonstrated that PCNSL exhibits highly characteristic molecular genetic alterations, with a mutational profile distinctly different from that of systemic DLBCL. These unique genetic variations collectively shape the malignant biological behavior of PCNSL, including activation of signal transduction, evasion of immune surveillance, and promotion of malignant progression. Here, we synthesize current evidence to conceptualize the genetic-TME axis as a unifying framework for PCNSL biology, wherein tumor-intrinsic genetic alterations and the specialized CNS microenvironment interact bidirectionally to shape immune evasion, tumor evolution, and therapeutic response. We review the distinctive genetic landscape of PCNSL, the cellular and molecular architecture of its TME, and the reciprocal mechanisms linking these compartments during disease progression. Integrating these dimensions may refine molecular stratification, facilitate biomarker-guided therapeutic selection, and inform more rational treatment strategies for PCNSL.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082712","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":"Megakaryocytes in myelofibrosis: mechanisms of fibrotic niche remodeling and therapeutic implications.","authors":"Jiansong Huang, Xiaoyue Yin, Xiaofeng Shi, Xiudi Yang, Rumeng Li, Xiang Zhang, Yi Zhang, Hongyan Tong, Jie Jin, Jian Huang","doi":"10.1186/s40364-026-01003-0","DOIUrl":"10.1186/s40364-026-01003-0","url":null,"abstract":"<p><p>Myelofibrosis is a clonal myeloproliferative neoplasm characterized by progressive remodeling of the bone marrow microenvironment. Megakaryocyte (MK) abnormalities are defining histological features of prefibrotic and overt primary myelofibrosis and contribute to disease pathogenesis. Dysplastic MKs can directly modify the pericellular extracellular matrix (ECM), but their main fibrogenic influence comes from coordinating stromal, immune, and endothelial responses. This Review synthesizes evidence linking abnormal MK biology to fibrotic progression and examines its implications for biomarkers and therapy. In normal bone marrow, MKs regulate hematopoietic stem cell quiescence, organize the ECM and vascular niches, and participate in immune regulation. Hematopoiesis driven by mutations in JAK2, CALR, or MPL, together with chronic inflammation, disrupts these functions. Dysplastic MKs release or activate transforming growth factor-β1 (TGF-β1), platelet factor 4 (PF4/CXCL4), and other profibrotic mediators and interact with neutrophils, monocytes, mesenchymal stromal cells, and endothelial cells. These interactions promote stromal activation, monocyte-to-fibrocyte differentiation, vascular and osteogenic remodeling, and ECM accumulation. As disease progresses, collagen cross-linking and altered bone marrow mechanics help stabilize the remodeled niche. Janus kinase inhibitors reduce splenomegaly and symptoms, but pharmacological therapies have not been shown to consistently reverse established bone marrow fibrosis. Durable disease modification will likely require sustained suppression of mutant progenitors and dysplastic MK production together with inhibition of stromal activation, inflammatory signaling, and matrix deposition or cross-linking. Clinical improvement, suppression of abnormal megakaryopoiesis, reduction in profibrotic signaling, and regression of bone marrow fibrosis should therefore be assessed separately using measures matched to each therapeutic mechanism.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082731","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}