Molecular Medicine最新文献

{"title":"From clinical suspicion to molecular detection of low-level mosaicism in NF2-related schwannomatosis via ultra-sensitive duplex sequencing.","authors":"Monika Horbacz, Justyna Prokopiuk, Elisabeth Castellanos, Hilde Brems, Ignacio Blanco, Eric Legius, Seppe Van der Auweraer, Shehab Moukbel Ali Aldawla, Atena Yasari, Monika Heinzl, Piotr Madanecki, Natalia Filipowicz, Aleksandra Gintowt-Chakour, Beata S Lipska-Ziętkiewicz, Jan P Dumanski, Irene Tiemann-Boege, Arkadiusz Piotrowski, Magdalena Koczkowska","doi":"10.1186/s10020-026-01561-x","DOIUrl":"https://doi.org/10.1186/s10020-026-01561-x","url":null,"abstract":"<p><strong>Background: </strong>Schwannomatosis (SWN) is a rare tumor predisposition syndrome caused by pathogenic variants in NF2, SMARCB1, or LZTR1. Mosaicism contributes to up to 30% of de novo NF2-related cases, but its role in SMARCB1- and LZTR1-related SWN remains unclear. Accurate molecular classification is critical for clinical management, yet overlapping phenotypes complicate diagnosis. Because standard diagnostics have limited sensitivity and often require tumor tissue, we evaluated whether ultra-sensitive duplex sequencing of blood-derived DNA improves mosaic variant detection in SWN.</p><p><strong>Methods: </strong>We developed a duplex sequencing assay targeting NF2, SMARCB1, and LZTR1 and analyzed 102 individuals with suspected SWN previously negative for constitutional pathogenic variants, along with 35 controls.</p><p><strong>Results: </strong>Duplex sequencing identified low-level mosaic NF2 pathogenic variants in 11% of cases (11/102), with variant allele frequencies as low as 0.06%. In all patients with available tumor material (8/11), blood and tumor findings were concordant. No mosaic pathogenic variants were detected in SMARCB1 or LZTR1. Controls showed no deleterious variants except one LZTR1 splice-site variant.</p><p><strong>Conclusions: </strong>Duplex sequencing enables robust detection of ultra-low-frequency NF2 variants in SWN and complements existing diagnostic workflows. This approach may reduce dependence on tumor tissue in NF2-related SWN, improve differential diagnosis, and support patient management and genetic counseling.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial dysfunction in human diabetic vascular complications: translating single-cell transcriptomics into therapeutic opportunities.","authors":"Reem Alshehhi, Mira Mousa, Lena Lößlein, Thanumol Abdul Khader, Amaryllis H Van Craenenbroeck, Syed Salman Ashraf, Peter Carmeliet, Habiba Alsafar","doi":"10.1186/s10020-026-01562-w","DOIUrl":"10.1186/s10020-026-01562-w","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is increasingly recognized as a systemic vascular disease in which endothelial cell (EC) dysfunction is a central driver of diabetic vascular complications (DVCs), which account for most diabetes-related morbidity and mortality. Although conventional therapies improve glycemic control and reduce some cardiovascular risk, they do not fully prevent microvascular and macrovascular injury, highlighting the need for more precise vascular-targeted strategies. Recent advances in single-cell RNA sequencing have transformed our understanding of diabetic endothelial biology by resolving EC heterogeneity at unprecedented resolution across human tissues, yet insights from human diabetic tissues remain fragmented. Here, we provide a cross-tissue synthesis of currently available human single-cell studies profiling ECs across diabetic vasculature, focusing on diabetic arteries, diabetic retinopathy, diabetic nephropathy, and diabetic foot ulcers to define mechanisms underlying dysfunctional EC states in different DVCs. We propose a unifying framework in which DVCs are driven by tissue-specific endothelial-state transitions arising from combinations of epigenetic, transcriptional, post-translational, and intercellular signaling programs, rather than by isolated pathway abnormalities. These include a pro-inflammatory, pro-fibrotic, and anti-angiogenic state in diabetic arteries; a pathological angiogenic and barrier-disruptive inflammatory state in diabetic retinopathy; a pro-fibrotic and maladaptive angiogenic/proliferative state in diabetic nephropathy; and an inflammatory, anti-angiogenic state in diabetic foot ulcers. This framework also provides a mechanistic explanation for the limited efficacy of current single-pathway therapies, including VEGF-centered approaches, and uncovers VEGF-independent mechanisms that may be therapeutically actionable for these DVCs. Importantly, this review not only highlights the need for but also proposes combination therapeutic strategies that target multiple regulatory layers within tissue-specific endothelial states. Overall, this review supports a paradigm shift toward vascular bed-specific, combinatorial, and state-directed therapeutic strategies to reprogram endothelial dysfunction in DVCs.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422516","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":"Prognostic significance and tumor cell interactions of tumor-associated neutrophils in gastric cancer.","authors":"Soo Kyung Nam, Seo Hwan Yu, Sun-Young Ahn, Yujun Park, Hyeon Jeong Oh, Yoonjin Kwak, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Han-Kwang Yang, Hye Seung Lee","doi":"10.1186/s10020-026-01555-9","DOIUrl":"10.1186/s10020-026-01555-9","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to determine the clinicopathologic implications and tumor cell interaction of CD66b-positive (CD66b +) tumor-associated neutrophils (TANs) and CD66b and CD177 double positive (CD66b + /CD177 +) activated TANs in gastric cancer (GC).</p><p><strong>Methods: </strong>Single immunohistochemistry (sIHC) for CD66b, CD8, HER2, p53, and E-cadherin was performed in 1,060 patients with GC, together with microsatellite instability (MSI) testing and Epstein-Barr virus (EBV) in situ hybridization. Opal multiplex immunofluorescence (mIF) for cytokeratin (CK), CD66b, and CD177, and sIHC for ERα was performed on 59 microsatellite-stable (MSS) and 60 MSI-high (MSI-H) GCs. The immune cell densities were quantified using QuPath for sIHC and InForm for mIF.</p><p><strong>Results: </strong>On sIHC, a high density of CD66b + TANs was correlated with HER2 positivity, EBV positivity, and MSI-H phenotype (p < 0.001). Combined analysis of CD66b + TAN densities in the tumor center and invasive margin showed a significant association with better OS (p = 0.036), independent of major clinicopathologic factors. TAN densities were significantly associated with OS in female patients (p < 0.001), but not in male patients (p = 0.574). The density of ERα-positive immune cells was inversely correlated with TAN density (ρ = -0.41, p < 0.001). mIF analysis demonstrated that both CD66b + TANs and CD66b + /CD177 + activated TANs were significantly more abundant in MSI-H GC than in MSS GC. Moreover, the distance between TANs and CK + GC cells was significantly shorter in MSI-H GC than in MSS GC. A shorter distance between CD66b + /CD177 + activated TANs and GC cells was also associated with a better OS (p = 0.041).</p><p><strong>Conclusion: </strong>A high TAN density in GC is associated with a favorable prognosis, and the spatial proximity of TANs to GC cells, especially in MSI-H GC, provides additional prognostic value. These findings provide basic knowledge for the development of therapeutic targets related to TANs in GC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422608","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":"Lactate dynamics in Parkinson's disease: striatal circuit vulnerability, biomarker potential, and therapeutic windows.","authors":"Jianda Kong, Zizheng Yang, Yinhao Wang, Lingyun Liu, Yang Liu, Wei Chen","doi":"10.1186/s10020-026-01551-z","DOIUrl":"10.1186/s10020-026-01551-z","url":null,"abstract":"<p><p>Lactate is a mobile carbon substrate, extracellular signal, and candidate mediator of metabolism-to-gene coupling. These properties make lactate relevant to Parkinson's disease (PD), but current evidence does not support a simple protective or toxic interpretation. In this Review, we synthesize evidence that lactate dynamics may influence PD-relevant striatal biology through substrate provision, redox-sensitive NMDAR-ERK/MAPK-CREB signaling, HCAR1-mediated receptor signaling, and the emerging lactylation-linked modification of inflammatory or transcriptional states. We explicitly distinguish established non-PD mechanisms from direct PD-model evidence and from hypotheses that remain untested in D2 medium spiny neurons (D2-MSNs). We propose that the apparent lactate paradox in PD is best understood as a kinetic and compartmental problem: transient, well-cleared lactate pulses, such as those produced during exercise, may support metabolic flexibility, neurovascular adaptation, and selected forms of plasticity, whereas sustained lactate accumulation in mitochondrially constrained or inflammatory environments may promote acid-ion stress, oxidative injury, neuroimmune activation, and impaired dopaminergic signaling. The D2-MSN axis is therefore presented not as a proven site of lactate-mediated rescue, but as a high-priority experimental test bed for linking lactate dynamics to hypokinetic network states. Translationally, lactate is unlikely to serve as a stand-alone diagnostic biomarker. Its more realistic near-term uses are as a pharmacodynamic readout, a challenge-response variable for exercise dosing, and a target-engagement marker for interventions that modify lactate transport, signaling, or inflammatory metabolic state. This framework defines lactate kinetics, compartment, and disease context as the critical variables for biomarker-guided rehabilitation and future PD trials.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397409","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":"MIR133B-SEPT9 axis suppresses colorectal cancer progression by inhibiting β-catenin-mediated EMT signaling and is associated with poor prognosis.","authors":"Ji-Su Mo, Sang Jae Noh, Kyoung Min Kim, Jun Sang Bae","doi":"10.1186/s10020-026-01540-2","DOIUrl":"10.1186/s10020-026-01540-2","url":null,"abstract":"<p><strong>Background: </strong>MIR133B is a colorectal cancer (CRC)-associated gene, and its mature product, miR-133b, is significantly downregulated in CRC tissues.</p><p><strong>Methods: </strong>We aimed to elucidate the tumor-suppressive role of miR-133b in CRC. To identify its downstream target genes, we compared the transcriptome of miR-133b-overexpressing cells with bioinformatic predictions and identified 23 potential target genes. We focused on SEPT9, a gene involved in tumor progression. We confirmed that SEPT9 is a direct target of miR-133b and investigated its role in cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). In addition, we evaluated the expression and prognostic relevance of SEPT9 and active β-catenin in 219 patients with CRC.</p><p><strong>Results: </strong>We confirmed the direct interaction between miR-133b and SEPT9 using luciferase reporter assay, qRT-PCR, and western blot. SEPT9 expression was significantly upregulated in CRC tissues compared with that in adjacent normal controls. In HCT116 and SW48 CRC cell lines, overexpression of miR-133b or knockdown of SEPT9 significantly reduced SEPT9 protein levels; suppressed proliferation, colony formation, and invasiveness; inhibited KRAS, BRAF, PI3K, pAKT, and pERK expression; and regulated EMT by downregulating N-cadherin, Vimentin, Snail, Twist, and active β-catenin while upregulating E-cadherin. Nuclear SEPT9 expression positively correlated with active β-catenin in human CRC tissues. In multivariate analysis, SEPT9 positivity independently predicted poor OS and RFS, and the combined SEPT9/active β-catenin expression pattern was an independent predictor of OS for both subgroups and of RFS specifically for the co-positive (SEPT9+/active β-catenin+) subgroup.</p><p><strong>Conclusion: </strong>This study suggests that miR-133b suppresses CRC progression by directly targeting SEPT9 and inhibiting β-catenin-mediated EMT, as well as identifies the miR-133b-SEPT9-β-catenin axis as a potential prognostic indicator in patients with CRC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397385","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":"Integrative statistical genetics prioritizes candidate ASCVD susceptibility genes across tissues.","authors":"Qin Liu, Xiaodi Han, Yue-Qing Hu, Liwan Fu","doi":"10.1186/s10020-026-01554-w","DOIUrl":"10.1186/s10020-026-01554-w","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of mortality worldwide, yet its genetic architecture and underlying mechanistic hypotheses have not been fully elucidated.</p><p><strong>Methods: </strong>We applied genomic structural equation modeling (SEM) to five ASCVD-related phenotypes with a total combined sample size of approximately 3.8 million individuals across the five component GWAS. Leveraging these genetic insights, we performed a cross-tissue transcriptome-wide association study (TWAS) using the UTMOST framework by integrating ASCVD genetic data with gene expression from 49 tissues (GTEx v8). Complementary analyses included single-tissue TWAS (FUSION) and gene-level analysis (MAGMA). By triangulating evidence from these multiple convergent statistical approaches, we identified robust candidate genes, which were further prioritized using Mendelian randomization, Bayesian colocalization, phenome-wide association studies (PheWAS), tissue/cell-type enrichment analyses, and AlphaFold-based structural predictions integrated with chemical interaction profiling.</p><p><strong>Results: </strong>We identified 14 genes robustly associated with ASCVD susceptibility, including four genes-ARVCF, GFPT1, NFU1, and USP39-some of which have been previously implicated in coronary artery disease genetics (ARVCF) or are newly prioritized in the composite ASCVD phenotype (USP39), exhibiting broad tissue expression patterns. Mendelian randomization and colocalization provided supportive evidence consistent with potential causal relationships, with pronounced tissue specificity (e.g., ARVCF in artery aorta, GFPT1 in heart atrial appendage, NFU1 in adipose subcutaneous). Cell-type enrichment highlighted erythroid progenitor cells and immune populations. PheWAS revealed potential horizontal pleiotropy, while network and pathway analyses implicated these genes in cell adhesion, amino sugar metabolism, iron-sulfur cluster assembly, and RNA splicing. Structural predictions confirmed protein model reliability, and chemical interaction profiling linked these genes to cardiovascular and metabolic disease pathways.</p><p><strong>Conclusions: </strong>Our integrative statistical genetics approach advances the functional understanding of ASCVD genetics, implicates four genes in disease pathogenesis with tissue-specific mechanisms, and highlights promising candidate genes for future investigation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391446","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":"An AI-augmented review of childhood atopic dermatitis biomarkers across genetic, immune, microbial, and metabolic domains.","authors":"Jia Wei Lee, Evelyn X L Loo, Samuel S Chong, Kenneth H K Ban, Caroline G Lee","doi":"10.1186/s10020-026-01533-1","DOIUrl":"10.1186/s10020-026-01533-1","url":null,"abstract":"<p><strong>Background: </strong>Atopic dermatitis (AD) is a prevalent inflammatory skin disease and a major source of disease burden in children. Biomarker studies in childhood AD span genetic, immune, microbial and metabolic domains, but prior reviews have often focused on single molecular layers, specific sample sites or clinical classification. As a result, the field lacks an integrated, systems-level synthesis that compares and contextualizes biomarkers across domains while clearly distinguishing evidence strength. The rapid growth of literature in this field also poses practical challenges for traditional manual review workflows.</p><p><strong>Main body: </strong>To address these gaps, we conducted an AI-augmented, multi-domain review of childhood AD biomarkers. ASReview supported title and abstract screening, while ChatGPT assisted structured data extraction with human validation. Across 526 studies, we identified 141 genome, 95 immunome, 57 microbiome and 75 metabolome childhood AD biomarkers. The most frequently reported biomarkers included Filaggrin, IgE, CCL17, Staphylococcus, Bifidobacterium and vitamin D. Using a structured evidence-grading framework, eight biomarkers were categorized as having strong evidence: IgE, CCL17, CCL27, eosinophil cationic protein, eosinophil, IL-18, IL-31 and Escherichia. By synthesizing evidence across biomarker domains, we developed a systems-level, conceptual AD model in which barrier defects, Th2 inflammation, microbial dysbiosis and metabolic imbalance drive a self-perpetuating cycle of inflammation and barrier dysfunction. We also developed a web app for exploration of the biomarker findings: https://leejw.shinyapps.io/eczema_review_526/ .</p><p><strong>Conclusion: </strong>This review provides a broad synthesis of childhood AD biomarkers and frames the evidence within an integrated, multi-domain conceptual model. The findings support the rationale for approaches that consider multiple biological nodes, including barrier repair, immune modulation, microbiome-directed strategies and metabolic factors, while underscoring the need for further validation before clinical implementation. Methodologically, the study illustrates how a hybrid human-AI review workflow can support scalable biomedical evidence synthesis without replacing human oversight.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387763","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":"PD-L1 and PD-L2 regulate in cell-autonomous and N-glycosylation-dependent manners the pro-tumorigenic characteristics and functions of human cancer-associated fibroblasts.","authors":"Alaa Abu Raiya, Tsipi Meshel, Iris Kamer, Christina Lipin, Raneen Tarabe, Amit Kessel, Tamar Horvitz, Linor Rubinstein-Achiasaf, Dina Morein, Jair Bar, Adit Ben-Baruch","doi":"10.1186/s10020-026-01531-3","DOIUrl":"10.1186/s10020-026-01531-3","url":null,"abstract":"<p><strong>Background: </strong>Tumor progression is regulated by cancer-associated fibroblasts (CAFs), pro-inflammatory cytokines (e.g., TNFα, IL-1β, IFNγ) and acquired immunity (such as inhibitory immune checkpoints: PD-L1, PD-L2). Here, we determined the interactions between these elements by analyzing the impact of pro-inflammatory cytokines on the proportions of PD-L1 + PD-L2-expressing CAFs; the cell-autonomous regulation of pro-tumorigenic characteristics and functions of CAFs by PD-L1/PD-L2; and the control of PD-L1/PD-L2 activities in CAFs by their N-glycosylation.</p><p><strong>Methods: </strong>CAFs were obtained from breast and lung cancer patients (BC-CAFs, Lung-CAFs). PD-L1/PD-L2 surface and whole-cell expression were determined by flow cytometry and Western blot, respectively. CAFs were transduced to express WT-PD-L1, WT-PD-L2, WT-PD-L1 + WT-PD-L2, PD-L1/PD-L2 N-glycosylation mutants or vector controls, followed by determination of the pro-tumorigenic factors osteopontin (qRT-PCR) and CXCL8 (IL-8)/CCL2 (MCP-1)(ELISA). The effects of factors produced by CAFs expressing WT-PD-L1/WT-PD-L2/their N-glycosylation mutants on tumor cell migration were analyzed by wound-healing assays.</p><p><strong>Results: </strong>TNFα + IL-1β potently increased the expression of CXCL8, whereas IFNγ stimulation up-regulated the proportions of BC-CAFs and Lung-CAFs expressing PD-L1 + PD-L2 at cell surface. Combined TNFα + IL-1β + IFNγ stimulation has prominently increased intracellular pools of N-glycosylated PD-L1 and PD-L2, in BC-CAFs and Lung-CAFs. WT-PD-L1 induced in cell-autonomous manners pro-tumorigenic characteristics and functions in BC-CAFs: elevated the expression of osteopontin, CXCL8 and CCL2 and induced the production of factors that promoted tumor cell migration. WT-PD-L2 also acted in a cell-autonomous manner in BC-CAFs, generally down-regulating these phenotypes and activities. When co-expressed in BC-CAFs, the cancer-supporting effects of WT-PD-L1 dominated the anti-tumorigenic impacts of WT-PD-L2. The cell-autonomous functions of PD-L1 and PD-L2 were regulated, in context- and function-dependent manners, by their N-glycosylation sites, primarily N35/N192 in PD-L1 and N37/N163 in PD-L2.</p><p><strong>Conclusions: </strong>Chronic inflammation can up-regulate the proportions of PD-L1 + PD-L2 expressing CAFs. PD-L1 and PD-L2 act in cell-autonomous manners to control the pro-tumorigenic characteristics and functions of CAFs, with dominance of the tumor-promoting effects of PD-L1 over the tumor-inhibiting roles of PD-L2. The cell-intrinsic functions of PD-L1 and PD-L2 in CAFs depended on their N-glycosylation. These observations emphasize the need to consider the expression of PD-L1 and PD-L2 in stromal cells when designing treatments with immune checkpoint blockades in patients.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387791","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":"Dopamine signaling reprograms macrophage FAO to alleviate acute lung injury by inhibiting NETosis via the CXCL10-CXCR3 axis.","authors":"Ximing Liao, Changwen Deng, Jing Gao, Ziqi Yang, Tian Li, Jialin Yao, Muyun Wang, Fengyang Xie, Zhaoqi Li, Kun Wang, Qiang Li, Di Wu, Wujian Xu, Wei Gao","doi":"10.1186/s10020-026-01549-7","DOIUrl":"10.1186/s10020-026-01549-7","url":null,"abstract":"<p><strong>Background: </strong>Dysregulated innate immunity and oxidative stress drive the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), yet master endogenous regulators that orchestrate inflammation resolution remain elusive.</p><p><strong>Methods: </strong>This study employed public database mining, clinical data investigation, murine disease models, mouse bone marrow-derived macrophages and neutrophils, and human macrophages from healthy donors and ARDS patients, to investigate the dynamic changes of the dopaminergic signaling system in the acute pulmonary inflammatory environment and its role in regulating macrophage metabolism and neutrophil extracellular trap formation (NETosis).</p><p><strong>Results: </strong>Public database mining and experimental data reveal accelerated dopamine (DA) turnover during ALI. DA, signaling via D1-like receptors, reprograms macrophage metabolism by enhancing carnitine palmitoyltransferase 1 A (CPT1A)-dependent fatty acid oxidation (FAO) and mitochondrial fitness, which is coupled with the suppression of MAPK/NF-κB and NLRP3 inflammasome activation. These modulated macrophages restrain neutrophilic inflammation by secreting IL-10 to inhibit the CXCL10-CXCR3 axis, thereby curtailing neutrophil hyperactivation and pathogenic NETosis. Crucially, this protective mechanism is conserved in human macrophages from both healthy donors and ARDS patients.</p><p><strong>Conclusion: </strong>Our findings establish DA as a therapeutic target for recalibrating innate immunity in ALI, providing a mechanistically grounded framework for targeting dopaminergic signaling to resolve dysregulated inflammation, with exploratory preclinical translational implications for ALI/ARDS therapy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387846","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-PSMA hormone-sensitive prostate cancer: a distinct clinical and molecular state.","authors":"Haotian Wu, Ang Li, Zhou Jiang, Weiwei Zhang, Kai Shen, Bo Liu, Ruopeng Su, Xinyu Liu, Xinyu Chai, Tianxiang Wang, Junyi Wang, Jiayan Yi, Xiang Zhou, Yinjie Zhu, Dengfeng Cao, Qi Wang, Jiahua Pan, Wei Xue","doi":"10.1186/s10020-026-01546-w","DOIUrl":"10.1186/s10020-026-01546-w","url":null,"abstract":"<p><strong>Background: </strong>A subset of hormone-sensitive prostate cancer (HSPC) exhibits low prostate-specific membrane antigen (PSMA) uptake on PET imaging, which may limit the performance of PSMA-based detection and PSMA-directed therapeutic strategies. However, the clinical features and molecular basis of HSPC with low PSMA expression remain incompletely defined.</p><p><strong>Methods: </strong>We first analyzed a retrospective dual-tracer PET cohort to estimate the frequency and clinical characteristics of tumors with low PSMA uptake at initial diagnosis. We then collected radical prostatectomy specimens for proteomics profiling, classifying tumors as low-PSMA (N = 16) or high-PSMA (N = 19) based on concordant [⁶⁸Ga]Ga-PSMA-11 PET and PSMA immunohistochemistry, with adjacent benign tissues included as controls. Label-free quantitative proteomics and integrative bioinformatic analyses were used to characterize low-PSMA-associated protein features and nominate candidate cell-surface membrane targets, followed by validation using RT-qPCR and immunohistochemistry.</p><p><strong>Results: </strong>Low-PSMA HSPC was identified in 7.23% (122/1,688) of patients in the retrospective dual-tracer PET cohort, indicating that reduced PSMA uptake is already observable at initial diagnosis. Although these tumors showed reduced PSMA expression, they were not uniformly low-risk, with 42.62% of cases exhibiting Gleason score ≥ 8. In the proteomic cohort, low-PSMA tumors showed concordant reductions in PSMA uptake and protein expression, supporting imaging-pathology alignment. Proteomic analysis revealed a distinct molecular state characterized by enrichment of tissue remodeling, repair, epithelial organization, and microenvironment-related programs, together with attenuation of androgen-response, E2F, and MYC-associated proliferative signaling. Cell-surface membrane surface target prioritization identified ALCAM and TACSTD2 as candidates, among which ALCAM was consistently upregulated in low-PSMA tumors at both mRNA and protein levels.</p><p><strong>Conclusions: </strong>HSPC with low PSMA expression represents a distinct clinical and molecular state rather than a simple low-risk subgroup. Its proteomic features suggest altered epithelial differentiation, tissue remodeling, and reduced canonical prostate cancer signaling. ALCAM may serve as a complementary membrane biomarker for improving the molecular recognition of low-PSMA HSPC and supporting future alternative imaging or targeting strategies.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376532","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}