J Transl Med [JOURNAL]
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200 papers
Letter to the Editor Regarding "The microbiome of host saliva, gastric fluid, and gastric mucosa as accurate diagnostic tools for gastric cancer detection".
Cui Y, Liu Y, Dou F … +1 more , Mao J
J Transl Med · 2026 Jun · PMID 42351162 · Full text
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Single-cell profiling reveals a novel CAF subpopulation linking stromal heterogeneity to immune suppression in breast cancer subtypes.
Vigiano Benedetti V, Conte F, Santoni D … +7 more , Pentimalli TM, Bei R, Cifaldi L, Barillari G, Spallotta F, Cencioni C, Melaiu O
J Transl Med · 2026 Jun · PMID 42351142 · Full text
BACKGROUND: The tumor microenvironment critically influences breast cancer (BC) progression, immune surveillance, and therapeutic response. Cancer-associated fibroblasts (CAFs), a heterogeneous stromal population, are ke...
BACKGROUND: The tumor microenvironment critically influences breast cancer (BC) progression, immune surveillance, and therapeutic response. Cancer-associated fibroblasts (CAFs), a heterogeneous stromal population, are key regulators of these processes, yet their subtype-specific contributions in BC remain insufficiently defined. METHODS: We integrated three single-cell RNA sequencing datasets from 29 BC patients to characterize stromal populations. Bulk RNA-seq data from The Cancer Genome Atlas (TCGA) were analyzed to assess correlations between CAF subsets and immune infiltration. Gene signatures were derived to identify subtype-specific CAF-immune interactions, prognostic markers, and potential predictors of chemotherapy response. RESULTS: Three conserved stromal populations (iCAFs, myCAFs, and pericytes) were identified, along with a previously unrecognized subset, the cluster 3 (CL3) CAF-like cells, referred as metabolic stressed CAF (msCAF). msCAF cells displayed transcriptional programs associated with antigen presentation, stress response, glycolysis, and extracellular matrix remodeling. Their abundance was inversely correlated with T-cell infiltration and function, in a subtype-specific manner: triple negative breast cancer (TNBC) was enriched for msCAFs in immune-infiltrated but functionally constrained microenvironments, whereas Luminal A tumors exhibited weaker immune infiltration with heterogeneous CAF-immune associations. msCAFs were characterized by a conserved gene signature (HLA-A, HLA-C, IL32, EMP3) and subtype-specific genes related to T-cell exhaustion. Several genes demonstrated prognostic relevance with distinct patterns in Luminal A (IER3, TIMP1, TBX3, SEC61G) and TNBC (ADM, C4orf3, LDHA) tumors, as well as shared biomarkers (FN1, LOXL2, P4HA1). Multiple msCAF genes also predicted chemotherapy response, suggesting utility as treatment stratification biomarkers. CONCLUSION: msCAFs represent a clinically relevant CAF subset that drives immune suppression, impacts subtype-specific prognosis, and influences therapy response in BC. These findings highlight msCAFs as promising targets for enhancing immunotherapy and personalizing treatment strategies.
Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.
Tan L, Hou T, Ying P … +3 more , Wang X, Jin H, Luo J
J Transl Med · 2026 Jun · PMID 42351126 · Full text
BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising th...
BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.
Regenerative Peripheral Nerve Interface (RPNI) and vascularized Denervated Muscle Targets (VDMT): a preclinical rabbit model as a translational feasibility and methodological platform.
González-Prieto J, Arenillas M, Sanz Barbero E … +7 more , Gutiérrez Pecharromán A, Muñoz JD, Alonso E, Morillo MDC, Cristóbal L, Giannetti R, Maldonado AA
J Transl Med · 2026 Jun · PMID 42343440 · Full text
BACKGROUND: Regenerative Peripheral Nerve Interfaces (RPNIs) and Vascularized Denervated Muscle Targets (VDMTs) are emerging strategies for nerve regeneration and myoelectric prosthesis control. Most preclinical studies...
BACKGROUND: Regenerative Peripheral Nerve Interfaces (RPNIs) and Vascularized Denervated Muscle Targets (VDMTs) are emerging strategies for nerve regeneration and myoelectric prosthesis control. Most preclinical studies have been conducted in rodents, limiting the evaluation of implantable electromyographic devices due to anatomical and scale-related constraints. This study aimed to develop and evaluate the first RPNI and VDMT models in rabbits as a translational platform for implantable neuromuscular interfaces. METHODS: A total of 8 rabbits (4 per group) were randomly assigned to RPNI (n = 4) and VDMT (n = 4) groups and evaluated at an 8-week follow-up. RPNIs were created using biceps femoris muscle grafts attached to the peroneal nerve. VDMTs were constructed using denervated, vascularized gastrocnemius muscle flaps sutured to a peroneal motor branch. The contralateral leg served as a denervated control. Electrophysiological and histological analyses were performed 8 weeks postoperatively. Between-group comparisons were conducted using exact Mann-Whitney U and Fisher's exact tests. RESULTS: VDMTs showed a trend toward better macroscopic vascularization and integration under the present experimental conditions. Electromyographic activity was detected in 3 of 4 VDMTs, whereas no signal was observed in RPNIs. Histological analysis demonstrated more favorable muscle tissue preservation in VDMTs, with no detectable necrosis (0% necrotic area in all specimens), while RPNIs exhibited substantial necrosis (20%-95% of the analyzed muscle area), which was significantly greater than in VDMTs (p = 0.0286). Neuroma formation occurred in all RPNIs and in 2 of 4 VDMTs. CONCLUSIONS: This study presents a feasible rabbit model for the preclinical evaluation of RPNI and VDMT constructs. Under the present experimental conditions, VDMTs were associated with more favorable tissue preservation and more frequent signal detection under the present experimental conditions. These findings support the feasibility and translational potential of the rabbit as a methodological platform for future neuromuscular interface research. Further studies with optimized surgical protocols and larger cohorts are required to confirm these findings.
Lower airway transcriptome signatures in asthma: a newly described cytokine C10orf99 identification.
Zhang D
J Transl Med · 2026 Jun · PMID 42343413 · Full text
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Identification of a 10-protein plasma signature for preclinical gout risk beyond serum urate: a robustness-first proteomic study in 33,147 normouricaemic individuals.
Yuan Y, Zhang H, Zhang K … +7 more , Wang M, Yan H, Zhang J, Wen C, Guo Z, Huang L, Wang Z
J Transl Med · 2026 Jun · PMID 42343390 · Full text
BACKGROUND: Gout risk assessment is currently reactive, relying on hyperuricaemia. However, a significant clinical gap exists for individuals who develop gout despite maintaining "normal" serum urate levels. We aimed to...
BACKGROUND: Gout risk assessment is currently reactive, relying on hyperuricaemia. However, a significant clinical gap exists for individuals who develop gout despite maintaining "normal" serum urate levels. We aimed to identify a plasma proteomic signature that defines a susceptibility state for gout years before clinical onset, specifically within individuals who are normouricaemic at baseline. METHODS: We analyzed large-scale plasma proteomic data (2,920 proteins) from 33,147 normouricaemic individuals (baseline serum urate < 360 μmol/L) in the UK Biobank. To ensure findings were not artifacts of specific algorithms, we employed a "robustness-first" machine-learning framework encompassing 756 model configurations. Longitudinal protein trajectories were traced up to 15 years prior to diagnosis. Incident osteoarthritis was used as a negative control to evaluate specificity. RESULTS: A 10-protein signature (including VSIG4, UBQLN3, and MB) predicted incident gout with high discrimination (ROC-AUC = 0.892). This signature identified a high-risk subgroup with a 4.46-fold increased hazard, independent of baseline serum urate and conventional risk factors. Notably, protein trajectories diverged between future cases and controls 10-15 years before clinical diagnosis, even while serum urate remained within the normal range. The signature showed minimal discrimination for osteoarthritis (AUC ≈ 0.60). CONCLUSIONS: In 33,147 normouricaemic individuals, plasma proteomics identifies a stable preclinical susceptibility state for gout that exists beyond the traditional serum urate paradigm. This 10-protein signature enables early risk stratification and offers a significant window for precision prevention a decade before clinical onset.
Development and evaluation of an explainable machine learning selection pipeline for predicting neoadjuvant chemoradiotherapy response in locally advanced rectal cancer.
Xu Y, Gong W, Ji L … +8 more , Xing Z, Zhu Z, Jin Z, Zhang J, Wang X, Qin S, Jiao Y, Wang L
J Transl Med · 2026 Jun · PMID 42343388 · Full text
BACKGROUND: The selection of appropriate machine learning (ML) methods for clinical research remains challenging, particularly when both predictive performance and model explainability are required in small-sample datase...
BACKGROUND: The selection of appropriate machine learning (ML) methods for clinical research remains challenging, particularly when both predictive performance and model explainability are required in small-sample datasets. Conventional approaches often rely on limited variables and expert-driven choices, whereas many ML models remain difficult to justify clinically. This study aimed to develop an explainable ML model selection pipeline and demonstrate its application in predicting neoadjuvant chemoradiotherapy (nCRT) response in locally advanced rectal cancer (LARC). METHODS: We proposed a six-stage explainable ML model selection pipeline comprising data selection and preprocessing, algorithm pool construction, model training, model evaluation, model explanation, and an internal clinical logic consistency check (non-deployable sanity check). The workflow was applied to a retrospective cohort of 128 patients with LARC treated with nCRT. Four ML algorithms, including support vector machine (SVM), decision tree (DT), random forest (RF), and logistic regression (LR), were evaluated. Model performance was assessed using accuracy, F1-score, AUROC, AUPRC, bootstrap confidence intervals, and five-fold cross-validation, followed by explainability screening using SHAP. RESULTS: Under predefined screening criteria, DT models achieved the most favorable balance between predictive performance and explainability. Using pretreatment tumor markers alone, the selected DT models achieved an accuracy of 0.82 and F1-score of 0.71 for pathological complete response (pCR) prediction, and an accuracy of 0.76 and F1-score of 0.72 for tumor regression grade (TRG) prediction. SHAP analysis consistently identified carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) as the most influential predictors, and lower baseline levels of these markers were associated with better pathological response. CONCLUSIONS: This study provides a practical and reproducible framework for selecting interpretable ML models in small clinical datasets. In the present LARC case study, DT-based models showed acceptable discrimination and transparent decision logic, while tumor markers emerged as clinically plausible predictors of nCRT response. The proposed workflow may support future multi-center validation and broader application in clinically interpretable predictive modeling.
USP22 suppresses trophoblast cell necroptosis in preeclampsia by stabilizing KAT2A-mediated histone acetylation at the SFRP1 promoter.
He L, Zhan F, Zheng S … +1 more , Lin N
J Transl Med · 2026 Jun · PMID 42343381 · Full text
BACKGROUND: Preeclampsia (PE) is a severe gestational disorder associated with impaired placental function. Necroptosis contributes substantially to trophoblast injury in PE, though the upstream epigenetic regulatory pat...
BACKGROUND: Preeclampsia (PE) is a severe gestational disorder associated with impaired placental function. Necroptosis contributes substantially to trophoblast injury in PE, though the upstream epigenetic regulatory pathways are not yet fully elucidated. This study investigated how the deubiquitinase USP22 suppresses trophoblast necroptosis via epigenetic modulation of the KAT2A-SFRP1 axis. METHODS: Preeclamptic and normal placental tissues were analyzed for USP22 and necroptosis pathway components by immunohistochemistry. Hypoxic conditions established in HTR-8/SVneo trophoblasts simulated the preeclamptic microenvironment. Cell death modality was characterized through complementary approaches including flow cytometry, cell viability assays, and transmission electron microscopy. Pathway selectivity was determined through systematic pharmacological inhibition of necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagy. RNA sequencing identified genome-wide transcriptional responses to USP22 perturbation. Direct protein-protein interactions and locus-specific histone modifications at the SFRP1 promoter were resolved by co-immunoprecipitation and chromatin immunoprecipitation followed by quantitative PCR. USP22-mediated deubiquitination of KAT2A and substrate ubiquitin chain linkage specificity were elucidated using protein stability assays, ubiquitination analysis, and catalytic activity-dependent rescue with a C185A point mutant. Findings were further validated in an in vivo L-NAME-induced rat model of PE. RESULTS: USP22 was significantly downregulated in PE placental tissues, concomitant with elevated expression of RIPK1, RIPK3, and MLKL. Necroptosis was confirmed as the dominant death modality in hypoxic trophoblasts. USP22 knockdown exacerbated necroptotic signaling, while USP22 overexpression restored H3K9ac and H3K27ac levels and suppressed necroptosis. RNA sequencing analysis identified 1,186 differentially expressed genes following USP22 knockdown, including notably repressed expression of the Wnt antagonist SFRP1. Mechanistically, USP22 directly interacted with KAT2A and stabilized it by selectively cleaving K48-linked polyubiquitin chains. This stabilization sustained KAT2A-dependent histone acetylation at the SFRP1 promoter, thereby maintaining SFRP1 transcription. Importantly, SFRP1 restoration in USP22-deficient trophoblasts substantially mitigated cell death and decreased the p-MLKL/MLKL ratio. The L-NAME rat PE model further confirmed coordinated downregulation of USP22, KAT2A, SFRP1, and histone acetylation marks in vivo. CONCLUSION: USP22 maintains trophoblast survival through selective K48-deubiquitination of KAT2A, which stabilizes KAT2A and sustains histone acetylation at the SFRP1 promoter, thereby promoting SFRP1 transcription and suppressing RIPK1-RIPK3-MLKL-mediated necroptosis. The USP22-KAT2A-SFRP1 axis represents a novel epigenetic checkpoint in PE pathogenesis and a potential therapeutic target for placental insufficiency.
ACOT9, a mitochondrial metabolism-related gene, promotes ROS-associated epithelial remodeling in laryngeal squamous cell carcinoma.
Wang W, Liu J, Yang H … +6 more , Wang Z, Xie M, Chen C, Zhou L, Li X, Zhao M
J Transl Med · 2026 Jun · PMID 42343374 · Full text
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is characterized by mitochondrial metabolic reprogramming, but its prognostic significance and underlying molecular mechanisms remain insufficiently understood. This s...
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is characterized by mitochondrial metabolic reprogramming, but its prognostic significance and underlying molecular mechanisms remain insufficiently understood. This study aimed to develop a prognostic mitochondrial metabolism-related genes signature (MMGS) for LSCC and to investigate the biological role of ACOT9 in tumor progression. METHODS: Differentially expressed mitochondrial metabolism-related genes (MMGs) were identified from TCGA-LSCC data. A MMGS was established through machine-learning evaluation of 178 model combinations and validated in the TCGA training cohort, TCGA test cohort, and the independent GSE65858 dataset. To explore its biological relevance, immune microenvironment analysis, single-cell RNA sequencing analysis of GSE290927, scTenifoldKnk-based virtual knockout analysis, and a series of experimental assays, including immunohistochemistry, immunofluorescence, qRT-PCR, Western blotting, ROS detection, CCK-8, wound-healing, and apoptosis assays, were performed to characterize immune features, cellular heterogeneity, and the functional role of ACOT9. RESULTS: The MMGS demonstrated excellent prognostic performance, with a C-index greater than 0.7388, and independently predicted overall survival in LSCC patients (multivariate Cox, p < 0.05). High-risk patients exhibited increased M0 macrophage infiltration, impaired T-cell co-stimulation, downregulated co-stimulatory molecules, and enrichment of drug metabolism-related pathways. Single-cell analysis revealed elevated MMGS scores in LSCC epithelial and myeloid cells, while ACOT9 was markedly upregulated in malignant epithelial subtypes and positively correlated with stemness (R = 0.18, p < 0.01). Virtual knockout of ACOT9 in epithelial cells identified LAMC2 and KRT17 as the two most significantly perturbed genes, and enrichment analyses indicated a downstream epithelial stress-remodeling network involving keratinization, extracellular matrix organization, inflammatory/immune signaling, and lipid inflammatory pathways. Experimental validation confirmed ACOT9 overexpression, mitochondrial colocalization with TOM20, and elevated mitochondrial ROS levels in LSCC tissues and cells. Furthermore, mitochondrial ROS scavenging or ACOT9 knockdown significantly reduced cell viability and migration while promoting apoptosis. CONCLUSIONS: MMGS is a robust and reliable prognostic tool for LSCC. ACOT9 functions as a mitochondrial-associated oncogenic factor that may promote LSCC aggressiveness through a mitochondrial ROS-dependent epithelial remodeling program, highlighting its potential as a therapeutic target for risk-stratified clinical management.
Implementing informed consent in federated medical research: a blueprint designed to safeguard data subject rights in Germany.
Hampf C, Pley AW, Penndorf P … +8 more , Moser FM, Lang S, Werner P, Kästner A, Leddig T, Stahl D, Hoffmann W, Bialke M
J Transl Med · 2026 Jun · PMID 42337801 · Full text
BACKGROUND: The establishment of the complementary infrastructures Medical Informatics Initiative (MII) and the Network of University Medicine (NUM) has significantly advanced the medical research landscape in Germany. B...
BACKGROUND: The establishment of the complementary infrastructures Medical Informatics Initiative (MII) and the Network of University Medicine (NUM) has significantly advanced the medical research landscape in Germany. Both infrastructures focus on the cross-institutional integration of health data as the basis for strengthening medical research, with the MII focusing on the standardization and integration of routine university clinical data and the NUM representing a central infrastructure for clinical studies and data sharing. Within the project 'NUM Routine Data Platform' (NUM-RDP), a federated record linkage approach was implemented across 34 affiliated German university hospitals. Accordingly, a federated Trusted Third Party (fTTP) performed pseudonymization and privacy-preserving record linkage across all the participating sites. This work aims to extend the established fTTP approach to managing consent and withdrawal while considering the current legal frameworks and research initiatives for the use of health data. METHODS: A concept for an extended fTTP, termed 'fTTP Consent', is proposed to bridge communication gaps between different sites, facilities and components. This allows for central coordination for the implementation of patients' consent decisions regarding the storage, transfer and scientific use of their health data in a uniform manner. RESULTS: Two practical use cases for an 'fTTP Consent' have been identified and conceptualized. First, the cross-site improvement of workflows and automated processes should be performed to ensure that consent data are correct in formal, legal, semantic and syntactic terms. Second, the cross-site improvement of automated notification processes for new or updated consent data, including respective withdrawal- and objection-processes, should be performed. CONCLUSIONS: In this study, the 'fTTP Consent' has been proposed to reduce communicatory and personnel efforts. The correct and up-to-date realization of data subject rights should be ensured using the NUM-RDP as an example. The designed concept could help to overcome challenges in different consent scenarios (opt-in, opt-out). Furthermore, it could streamline communication and data linkage processes between institutions and countries in future research projects.
Tumor-derived progranulin promotes macrophage cholesterol efflux and associated immunosuppressive features in oral squamous cell carcinoma.
Luan Y, Xu Y, Zhao S … +4 more , Li H, Liu Z, Yang P, Yang C
J Transl Med · 2026 Jun · PMID 42337741 · Full text
BACKGROUND: Cholesterol efflux is increasingly recognized as an important regulator of macrophage polarization and immunosuppressive features; however, the tumor-derived signals that govern this process in oral squamous...
BACKGROUND: Cholesterol efflux is increasingly recognized as an important regulator of macrophage polarization and immunosuppressive features; however, the tumor-derived signals that govern this process in oral squamous cell carcinoma (OSCC) remain poorly defined. METHODS: We performed integrated single-cell RNA sequencing (scRNA-seq) on primary OSCC tumors (n = 3) and validated the findings in 77 head and neck squamous cell carcinoma (HNSCC)-related samples across five public datasets. The role of tumor-derived progranulin (PGRN) in macrophage cholesterol efflux and associated phenotypic changes was examined using genetic knockdown, pharmacologic inhibition of the PGRN-SORT1 interaction, and activation of downstream PPARγ signaling in vitro and in vivo. RESULTS: A malignant epithelial subpopulation with high PGRN expression was identified and associated with macrophage cholesterol efflux regulation through a prominent SORT1-associated signaling axis. Functional assays suggested that tumor-derived PGRN promoted a SORT1-linked PPARγ-LXRα-ABCA1/ABCG1 program, accompanied by enhanced cholesterol efflux and reduced intracellular cholesterol levels in macrophages. This metabolic rewiring was associated with immunosuppressive macrophage features, accompanied by increased secretion of IL-6, IL-10, and TGF-β. PGRN knockdown or SORT1 inhibition attenuated cholesterol efflux and increased intracellular cholesterol retention in vitro. In vivo, PGRN knockdown was associated with changes in macrophage polarization-related features, as reflected by an increased CD86/CD206 ratio. Notably, PPARγ agonism with rosiglitazone partially restored these phenotypic changes in PGRN-deficient tumors, supporting the involvement of this signaling axis. CONCLUSION: Tumor-derived PGRN is associated with immunosuppressive macrophage features in OSCC, at least in part through a SORT1-linked cholesterol efflux program involving downstream PPARγ-LXRα activation. These findings support a role for the PGRN-SORT1-associated axis as a potential immunometabolic pathway associated with macrophage cholesterol efflux and phenotypic features in OSCC.
Urinary ANGPTL3: a novel noninvasive biomarker for podocyte injury in pediatric glomerular diseases.
Wang H, Liu J, Dai R … +9 more , Wang C, Chen X, Wang X, Liu J, Tang X, Han X, Zhai Y, Shen Q, Xu H
J Transl Med · 2026 Jun · PMID 42337674 · Full text
BACKGROUND: Podocyte injury constitutes the pathological basis of various glomerular diseases; however noninvasive tools for assessing podocyte injury remain limited. Angiopoietin-like protein 3 (ANGPTL3) has been shown...
BACKGROUND: Podocyte injury constitutes the pathological basis of various glomerular diseases; however noninvasive tools for assessing podocyte injury remain limited. Angiopoietin-like protein 3 (ANGPTL3) has been shown to be pathologically elevated in glomerular diseases and is associated with podocyte injury. This study aimed to evaluate the clinical utility of the urinary ANGPTL3-to-creatinine ratio (ANGPTL3/Cre) as a noninvasive biomarker for assessing podocyte injury in children with glomerular diseases. METHODS: Renal ANGPTL3 expression was first examined in tissue samples from pediatric patients with podocyte injury (n = 25) and controls (n = 5), and its associations with established histological markers of podocyte injury and urinary ANGPTL3 levels were analyzed. Subsequently, pediatric patients aged 1-18 years with glomerular diseases complicated with podocyte injury and healthy controls were enrolled and divided into a test set (n = 346) and a validation set (n = 150). ANGPTL3 levels in serum and urine were measured. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curves. Associations with podocyte injury and improvements in risk stratification were assessed using logistic regression and reclassification improvement (NRI/IDI) analyses, respectively. RESULTS: Renal ANGPTL3 expression correlated negatively with the podocyte injury markers P57Kip2 (r = -0.55, P = 0.002) and Synaptopodin (r = -0.37, P = 0.04), while correlating positively with urinary ANGPTL3/Cre (r = 0.64, P < 0.001). Urinary ANGPTL3/Cre was significantly elevated in patients with podocyte injury and served as an independent risk factor for this condition (OR = 7.66, 95% CI: 2.27-25.84, P = 0.001). It demonstrated superior diagnostic performance (area under the curve, AUC = 0.90 in both sets) compared to serum ANGPTL3 or traditional biomarkers for podocyte injury. When combined with clinical variables, the AUC improved to 0.95 (95% CI: 0.93-0.97) with enhanced risk reclassification for podocyte injury. High diagnostic efficacy (AUC = 0.88/0.86) was maintained even in patients with normal protein excretion after clinical treatment. CONCLUSION: Urinary ANGPTL3/Cre is a reliable, noninvasive biomarker for podocyte injury in pediatric glomerular diseases. Notably, it may have potential value in identifying subclinical podocyte injury in patients with normal protein excretion, thereby supporting its robust potential for longitudinal monitoring and risk stratification in this patient population.
Exploring epigenome-proteome interactions underlying post-surgical progression of non-functioning pituitary adenomas using hypernetwork modelling.
Suman M, Hallén T, Garner T … +7 more , Thorsell A, Stevens A, Köster L, Carén H, Ragnarsson O, Skoglund T, Johannsson G
J Transl Med · 2026 Jun · PMID 42337646 · Full text
BACKGROUND: Non-functioning pituitary adenomas (NFPAs) present a complex clinical challenge due to their indolent and invasive growth patterns, and critical anatomical location. Post-surgical tumor progression is frequen...
BACKGROUND: Non-functioning pituitary adenomas (NFPAs) present a complex clinical challenge due to their indolent and invasive growth patterns, and critical anatomical location. Post-surgical tumor progression is frequent in patients with NFPAs, which often necessitates additional therapeutic interventions. The molecular mechanisms underlying post-surgical progression remain poorly understood and there are currently no reliable methods to stratify patients according to risk of tumor progression. The aim of this study was to comprehensively characterize the molecular alterations, together with an integrated understanding of their interactions, that could potentially uncover the biological processes driving post-surgical tumor progression of NFPAs. METHODS: We performed an integrated analysis of genome-wide DNA methylation and proteomics in 25 progressive and 15 indolent NFPAs using hypernetwork modelling linking CpG sites to the differentially expressed proteins to identify functional alterations associated with tumor progression. In addition, we investigated cis-regulatory relationships by examining CpG sites located within or in close proximity to the genes encoding the corresponding proteins, allowing assessment of the direct impact of DNA methylation changes on protein expression levels. RESULTS: Hypernetwork analysis uncovered extensive indirect and higher-order associations, capturing coordinated epigenetic influences on protein networks in indolent and progressive NFPAs. Progressive NFPAs were characterized by a compact and highly interconnected hub network with proteins primarily involved in DNA replication and transcription regulation (MCM6 and HDGFL2), chromatin organization (SAFB, HDGFL2, KDM3B, and TAF7), and cytoskeleton organization and cell structure maintenance (AJM1 and SYNE2). In contrast, indolent adenomas exhibited a broader and more diffuse network architecture with hub proteins linked to protein processing and transport (PSMD6, APMAP, B4GAT1, and COPE), extracellular matrix organization (LAMB2), and oxidative stress response (CISD2). Hub proteins in progressive NFPAs were enriched for metabolic pathways including glycolysis and tricarboxylic acid cycle, while enriched pathways for hub proteins in the indolent group were associated with genome maintenance and cellular stress responses. CONCLUSIONS: Hypernetwork analysis highlighted distinct epigenetic-proteomic regulatory mechanisms linked to tumor behavior that were not detected through cis-acting correlation analysis. Collectively, this integrative approach provides insight beyond direct regulation effects and offers a framework for identifying network-informed candidate markers with mechanistic relevance in tumor progression.
SFRP2 drives aerobic glycolysis and tumor progression in ovarian cancer by transcriptional upregulation of PTK2B.
Sheng J, Xing Y, Luan J … +9 more , Liu X, Song H, Sun L, Yu M, Fu X, Wu H, Chen Y, Liu W, Wang K
J Transl Med · 2026 Jun · PMID 42337619 · Full text
BACKGROUND: Ovarian cancer is a highly lethal gynecologic malignancy, with metabolic reprogramming being a key contributor to its progression and therapeutic resistance. Although Secreted Frizzled-Related Protein 2 (SFRP...
BACKGROUND: Ovarian cancer is a highly lethal gynecologic malignancy, with metabolic reprogramming being a key contributor to its progression and therapeutic resistance. Although Secreted Frizzled-Related Protein 2 (SFRP2) has been implicated in various cancers, its functional role and molecular mechanisms in ovarian cancer, particularly in regulating metabolic pathways, remain poorly defined. METHODS: Bioinformatic analyses of GEO (GSE66957) and TCGA-OV datasets were performed to assess SFRP2 expression and its prognostic correlation. Immunohistochemistry (IHC) on a human ovarian cancer tissue microarray was used for clinical validation. SFRP2 was knocked down or overexpressed in ovarian cancer cell lines (HEY and SK-OV-3) using lentiviral shRNA vectors. Functional assays (CCK-8, colony formation, apoptosis, migration) and metabolic assays (glucose consumption, lactate/ATP production, ECAR/OCR) were conducted. The mechanistic link between SFRP2, transcription factor CEBPA, and downstream target PTK2B was investigated using co-immunoprecipitation (Co-IP), nuclear-cytoplasmic fractionation, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. Rescue experiments were performed both in vitro and in vivo (xenograft mouse models). RESULTS: SFRP2 was significantly overexpressed in ovarian cancer tissues and cell lines, and high SFRP2 expression correlated with advanced disease and poor patient survival. SFRP2 knockdown suppressed cell proliferation, colony formation, and migration, while promoting apoptosis. Mechanistically, SFRP2 interacted with the transcription factor CEBPA, promoted its nuclear translocation, and enhanced its occupancy at the PTK2B promoter, thereby driving PTK2B transcriptional activation. This SFRP2/CEBPA/PTK2B axis further activates the AKT/mTOR signaling pathway, upregulating key glycolytic enzymes. Importantly, inhibiting glycolysis with 2-DG or knocking down PTK2B effectively reversed the oncogenic effects of SFRP2 both in vitro and in vivo. CONCLUSION: Our findings identify a novel SFRP2/CEBPA/PTK2B signaling axis that drives aerobic glycolysis and malignant progression in ovarian cancer, highlighting SFRP2 and PTK2B as potential prognostic markers and therapeutic targets.
Letter to the Editor: Single-cell multi-omics reveals DUSP9 as a key regulator of cancer stemness and a potential therapeutic target in hepatocellular carcinoma.
Zhang J, Zheng Q, Liu M
J Transl Med · 2026 Jun · PMID 42337610 · Full text
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Spatial architecture of the melanoma immune niche reveals CORO1A as a functional hub for T cell cytotoxicity and immunotherapy synergy.
Zhang S, Wang H, Wu J … +4 more , Fan P, Liu Y, Ma T, Li L
J Transl Med · 2026 Jun · PMID 42337596 · Full text
BACKGROUND: Immune checkpoint blockade (ICB) often fails in cutaneous melanoma due to an incomplete understanding of the spatially organized tumor microenvironment (TME). This study aims to define the spatial architectur...
BACKGROUND: Immune checkpoint blockade (ICB) often fails in cutaneous melanoma due to an incomplete understanding of the spatially organized tumor microenvironment (TME). This study aims to define the spatial architecture of the melanoma TME and identify key molecular regulators that determine anti-tumor immunity and ICB response. METHODS: We employed an integrative analysis of single-cell and spatial transcriptomics to map the TME. We defined spatial domains and deconvoluted their cellular composition. Cell-cell communication and risk modeling were performed. Functional roles of candidate genes were assessed using in vitro co-culture with anti-PD-1 and in vivo knockdown in a humanized mouse model. RESULTS: We delineated two prognostically significant spatial domains: an Immune region and a Melanocyte region. Multi-omics convergence nominated CORO1A as a key regulator within the immune niche. Its knockdown synergized with anti-PD-1 to suppress tumor growth in vivo, and anti-PD-1 downregulated its expression in vitro. We further identified APP-CD74 and FN1-CD44 as key inter-domain communication axes. CONCLUSION: Our study provides a spatially resolved blueprint of the melanoma TME and identifies CORO1A as a functional regulator within the immune niche, where its modulation enhances T-cell activity and synergizes with ICB. These findings reveal spatial organization as a critical determinant of immunotherapy efficacy and nominate CORO1A as a promising target for combination therapy.
Late-stage dedifferentiation and epigenetic memory of cancer stem cells in hepatocellular carcinoma.
Hu YK, Tan KJ, Feng N … +5 more , Li J, Chen L, Lin YX, Wang HY, He YF
J Transl Med · 2026 Jun · PMID 42337581 · Full text
BACKGROUND: Cancer stem cells (CSCs) drive recurrence and drug resistance in hepatocellular carcinoma (HCC), but their origin remains controversial: are they tumour-initiating cells or late-stage dedifferentiation produc...
BACKGROUND: Cancer stem cells (CSCs) drive recurrence and drug resistance in hepatocellular carcinoma (HCC), but their origin remains controversial: are they tumour-initiating cells or late-stage dedifferentiation products? Direct human single-cell evidence linking bipotent progenitors (BPs) and CSCs has been lacking. METHODS: We integrated single-cell RNA sequencing (scRNA-seq) data from 109 samples (44 patients; 410,608 cells) across five public cohorts and generated EpCAM-enriched scRNA-seq from two additional HCC patients. Single-cell somatic mutations were inferred from the transcriptomic data, yielding 384,867 high-confidence variants across 31,908 cells from 20 patients. Clonal evolution was reconstructed through copy number variation (CNV) phylogenies and transcription-coupled-repair-based cell-of-origin inference. CSC and non-CSC subpopulations from Huh7 cells were flow-sorted before and after two weeks of culture and profiled by targeted bisulfite sequencing. A core-imprint risk score was evaluated in multiple cohorts and validated on a 97-case tissue microarray by multiplex immunofluorescence. RESULTS: Unexpectedly, BPs harboured higher mutation burdens than other non-malignant parenchymal cells, and CSCs harboured higher mutation burdens than most other tumour cells, challenging their role as genomically quiescent ancestors. CNV phylogenies and evolutionary distances placed CSCs at the most distal branches of the tumour tree, while cell-of-origin analysis identified BPs as a pre-malignant precursor arising from hepatocyte dedifferentiation. RNA velocity, pseudotime and SNP-integrated lineage reconstruction converged on this directionality, with CSCs arising at the terminus of tumour evolution, reproduced at single-patient resolution in the EpCAM-enriched samples. Mechanistically, CSCs upregulated DNA methyltransferases (DNMTs), and ~78% of CSC-specific methylation changes were stably retained after CSC differentiation but not reproduced during de novo stemness acquisition, indicating locked-in epigenetic memory. A 16-gene core-imprint risk score specifically predicted early recurrence (≤2 years), and CD13 CD133 CSCs showed elevated 5-hydroxymethylcytosine correlating with poor prognosis. CONCLUSIONS: We propose a framework in which hepatocytes dedifferentiate into BPs as a pre-malignant state, undergo malignant transformation, and a subset acquires stemness through DNMT-mediated reprogramming stabilized by epigenetic memory. These findings challenge the classical stem cell origin hypothesis, showing that CSCs in established HCC are late-stage dedifferentiation products, provide a rationale for targeting CSC epigenetic stability, and offer a biomarker for early recurrence.
Application of cerium dioxide nanoparticles in the treatment of intervertebral disc degeneration induced by oxidative stress.
Cao R, Wang P, Guo S … +7 more , Yang Z, Li D, Pan X, Mou H, Liu Z, Wu L, Hao J
J Transl Med · 2026 Jun · PMID 42337560 · Full text
BACKGROUND: Oxidative stress (OS) induced by local reactive oxygen species (ROS) accumulation plays a vital role in initiating and accelerating intervertebral disc degeneration (IDD). Cerium oxide nanoparticles (CeNPs) h...
BACKGROUND: Oxidative stress (OS) induced by local reactive oxygen species (ROS) accumulation plays a vital role in initiating and accelerating intervertebral disc degeneration (IDD). Cerium oxide nanoparticles (CeNPs) have specific and efficient superoxide dismutase (SOD)-mimicking activity for ROS degradation. Their nanoscale particle size and nonstringent catalytic reaction conditions can potentially address challenges faced by traditional antioxidants in terms of remaining stable when used in degenerative avascular intervertebral disc (IVD). METHODS: We cocultured three kinds of IVD cells (cells of annulus fibrosus (AF), cartilage endplate (CEP) and nucleus pulposus (NP)) with CeNPs to determine the safe range of CeNPs concentrations. Additionally, Cell Counting Kit-8 (CCK-8) assay, ROS level assay and calcein/PI staining were performed to detect the protective effect of CeNPs on IVD cells against OS in vitro. Transmission electron microscopy (TEM), inductively coupled plasma mass spectrometry (ICP-MS) and blood analysis were used to describe its distribution pattern and the possible effects CeNPs may have on the body. Histological and immunohistochemical studies were implemented to analyse the capacity of CeNPs to prevent IDD induced by OS. Then western blotting was used to explore the corresponding mechanisms. RESULTS: The results showed that ≤ 40 µM CeNPs was safe for the three kinds of IVD cells. CeNPs alleviated the inhibition of cell proliferation and reduced the degree of cell death caused by OS to different degrees. Additionally, the OS-induced degeneration of each part of the IVD was partially relieved after pretreatment with CeNPs. These improvements might be achieved through reducing OS-mediated cellular inflammatory response, extracellular matrix (ECM) catabolism and apoptosis. CONCLUSION: This study proposes that the local application of CeNPs to the IVD could mitigate OS-induced IDD. Our findings indicate that experimental designs incorporating multiple IVD structures, IVD cells, and surrounding tissues are essential for evaluating drug effect and safety in IDD therapeutic development.
Self-supervised graph contrastive learning for scRNA-seq clustering.
Wu T
J Transl Med · 2026 Jun · PMID 42337558 · Full text
BACKGROUND: Single-cell RNA sequencing (scRNA-seq) enables characterization of cellular heterogeneity, but accurate and stable clustering remains challenging due to high dimensionality, sparsity, and technical noise. Man...
BACKGROUND: Single-cell RNA sequencing (scRNA-seq) enables characterization of cellular heterogeneity, but accurate and stable clustering remains challenging due to high dimensionality, sparsity, and technical noise. Many existing methods insufficiently exploit intrinsic cell-cell relationships and latent cell-type signals, leading to suboptimal representations and unstable assignments. The objective of this study is to develop a self-supervised graph contrastive framework for scRNA-seq clustering that jointly leverages augmented views, intrinsic cell-cell relationships, and pseudo-label-guided graph refinement to improve clustering robustness and biological interpretability. METHODS: We propose Self-Supervised Contrastive Graph Learning (SSGL), which refers specifically to the proposed scRNA-seq clustering framework and not to a generic or pre-existing method. SSGL generates two augmented views of each cell via dual random gene masking, then learns representations with a momentum-encoder architecture. A refined cell-cell graph is constructed by intersecting a k-nearest-neighbor similarity graph with pseudo-label consistency, and a graph-aware contrastive objective enforces agreement between augmented views while preserving local neighborhood structure. RESULTS: We evaluated SSGL on eight public scRNA-seq benchmarks spanning different tissues and sequencing platforms, and compared it with representative clustering baselines using NMI and ARI. Across all datasets, SSGL achieved the best overall clustering performance, with average NMI = 0.876 and average ARI = 0.926, outperforming competing approaches and showing more consistent results across heterogeneous datasets. Relative to AttentionAE-SC, the strongest overall baseline based on the averaged results, SSGL improved the average NMI and ARI by approximately 4.4% and 6.7%, respectively. Ablation analyses demonstrated that incorporating the self-supervised refined graph improves clustering beyond conventional contrastive objectives. Visualization and marker-gene analyses further supported that SSGL yields compact, well-separated clusters and recovers biologically coherent cell groups, including rare populations. CONCLUSIONS: SSGL improves scRNA-seq clustering accuracy and stability by jointly leveraging augmented views, intrinsic cell-cell relationships, and pseudo-label-guided graph refinement within a graph contrastive learning framework. This provides robust representations that support reliable cell-type discovery and downstream biological interpretation.
A novel EGR1-driven GLUL/mTOR axis regulates macropinocytosis-mediated crosstalk in pancreatic stellate cell-cancer metastasis.
Xue R, Zhou J, Liu Y … +3 more , Liu Y, Wu J, Song X
J Transl Med · 2026 Jun · PMID 42337536 · Full text
BACKGROUND: Pancreatic cancer liver metastasis relies on crosstalk between pancreatic stellate cells (PSCs) and cancer cells, yet the role of transcriptional regulation in this interplay, particularly via macropinocytosi...
BACKGROUND: Pancreatic cancer liver metastasis relies on crosstalk between pancreatic stellate cells (PSCs) and cancer cells, yet the role of transcriptional regulation in this interplay, particularly via macropinocytosis, remains unclear. Here, we aimed to explore a novel EGR1-driven pathway linking PSC function to cancer cell nutrient acquisition and liver metastasis. METHODS: Single-cell RNA sequencing (scRNA-seq) was performed on human pancreatic cancer tissues to identify key regulators of PSC-cancer cell crosstalk. ChIP, EMSA, luciferase reporter assays, and western blotting were used to validate transcriptional regulation of GLUL by EGR1. Functional assays included cell proliferation, migration, invasion, and macropinocytosis analyses in co-culture systems. In vivo studies utilized a murine model of pancreatic cancer liver metastasis to assess the impact of the EGR1-GLUL/mTOR axis on metastasis. RESULTS: scRNA-seq identified EGR1 as a transcription factor enriched in PSCs, with strong co-expression of GLUL and mTOR pathway genes. EGR1 directly bound the GLUL promoter, promoting its transcription and activating mTOR signaling. This axis suppressed PSC activation (reduced α-SMA expression). EGR1 over-expressed PSCs inhibited pancreatic cancer cell macropinocytosis, leading to impaired nutrient uptake, reduced ATP production, and suppressed malignant behaviors (proliferation, migration, invasion). Additionally, the EGR1-GLUL/mTOR axis reduced liver metastasis in vivo. CONCLUSION: The EGR1-driven GLUL/mTOR axis in PSCs suppresses pancreatic cancer progression by inhibiting PSC activation, reducing cancer cell macropinocytosis, and restraining metastasis. This axis represents a promising therapeutic target for disrupting PSC-cancer cell crosstalk in pancreatic cancer.
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