J Transl Med [JOURNAL]
Sun
200 papers
Microglial dysregulation and spatiotemporal dynamics of inflammation in multiple sclerosis white matter: an integrative transcriptomic analysis.
Ma K, Zhang Q, Du H … +7 more , Peng H, Kang J, Cai Y, Tan L, Chen X, Bian C, Qu X
J Transl Med · 2026 Jun · PMID 42304359 · Full text
OBJECTIVE: White matter damage in Multiple Sclerosis (MS) exhibits significant heterogeneity. The cellular and molecular underpinnings of this heterogeneity are not fully understood. This study investigated cell-specific...
OBJECTIVE: White matter damage in Multiple Sclerosis (MS) exhibits significant heterogeneity. The cellular and molecular underpinnings of this heterogeneity are not fully understood. This study investigated cell-specific changes and spatial heterogeneity in MS white matter by integrating single-cell and spatial transcriptomics (ST) to guide potential clinical interventions. METHODS: Single-nucleus RNA sequencing (snRNA-seq) identified key cell types, regulons, and cellular functional heterogeneity using Gene Regulatory Network (GRN) analysis, cell communication, subpopulation classification, functional enrichment, and pseudotime analysis. ST explored functional heterogeneity and cell type distribution in MS white matter niches via correlation, enrichment analysis, and deconvolution. RESULTS: snRNA-seq analysis identified module M3, showing transcription factor dysregulation in MS white matter compared to controls. These genes were predominantly expressed in microglia and enriched in inflammation related signaling pathways; IKAROS Family Zinc Finger 1 (IKZF1) was identified as a candidate transcriptional regulator connected to these changes. Microglia exhibited heterogeneity, existing in dynamic regulation from homeostatic to pro-inflammatory phenotypes, the latter showing Disease-associated Microglia (DAM) characteristics. Spatial transcriptomic analysis revealed strong heterogeneity within MS white matter with distinct niche functions. The Lesion Rim (LR), a transition zone, correlated strongly with microglia and was highly enriched with DAM characteristics. The LR was identified as an inflammatory hotspot enriched for DAM and altered IKZF1 regulon activity, supporting snRNA-seq findings. CONCLUSION: IKZF1 regulon inactivation in microglia coincides with altered white matter lesions in MS and dysregulated inflammatory pathways. Microglial heterogeneity in MS, including DAM phenotypes, extends beyond traditional polarization models. MS white matter displays significant spatial heterogeneity. Hindered remyelination in the LR may reflect inflammation from sustained microglial activation.
Long-term ovarian function risks associated with combined oral contraceptive administration in polycystic ovary syndrome: multisource data integration and protective mechanisms of metformin.
Li J, Wei J, Liu C … +4 more , He P, Zhou L, Chen S, Feng Z
J Transl Med · 2026 Jun · PMID 42298687 · Full text
BACKGROUND: Polycystic ovarian syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. Furthermore, the potential risks of long-term use of combined oral contraceptives (COCs) on ovarian reserve f...
BACKGROUND: Polycystic ovarian syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. Furthermore, the potential risks of long-term use of combined oral contraceptives (COCs) on ovarian reserve function remain unclear. We aimed to assess the association systematically between COC use and ovarian function decline in patients with PCOS and to explore potential mechanisms associated with metformin. METHODS: We analyzed 336 patients with PCOS and evaluated the association between COC use and ovarian function decline. A disproportionality analysis was performed to assess 3,424 COC-related ovarian-function adverse event reports in FAERS. Datasets of potential targets for ovarian function risk were constructed, and ovarian toxicity-related targets were screened. Intersection genes from the datasets were used to construct a protein-protein interaction (PPI) network. We identified core targets and pathways and predicted drug-target co-folded structures, while molecular dynamics simulations evaluated the binding stability and explored the potential regulatory effects of metformin. RESULTS: Prolonged COC use was significantly associated with an increased risk of premature ovarian insufficiency and premature ovarian failure. A history of metformin use was associated with lower odds of the broader ovarian function decline outcome. Computational analyses suggested that COCs may be linked to ovarian toxicity-related pathways, whereas metformin may modulate these predicted interactions through competitive binding and conformational alterations. CONCLUSIONS: This study represents the first integration of multisource data to systematically characterize potential ovarian-function risks associated with long-term COC therapy in patients with PCOS and to explore putative mechanisms that may underlie these associations. The findings suggest that a history of metformin use may be associated with attenuated risks, but future prospective or randomized investigations are warranted to validate these clinical associations and hypothesized mechanisms, thereby optimizing individualized management of PCOS.
First-in-human PET study of [F]FSW-100 for imaging histone deacetylase 6 in the brain: safety, biodistribution, radiation dosimetry, and brain kinetic analyses.
Tago T, Sakata M, Kamitaka Y … +3 more , Kameyama M, Ishii K, Toyohara J
J Transl Med · 2026 Jun · PMID 42298633 · Full text
BACKGROUND: Histone deacetylase 6 (HDAC6) is a lysine deacetylase that modulates protein function and turnover, and is critically implicated in the pathogenesis of neurodegenerative disorders. [F]FSW-100 is a promising r...
BACKGROUND: Histone deacetylase 6 (HDAC6) is a lysine deacetylase that modulates protein function and turnover, and is critically implicated in the pathogenesis of neurodegenerative disorders. [F]FSW-100 is a promising radioligand designed to enable visualization of HDAC6 in the brain. In this first-in-human PET study, we evaluated the clinical applicability of [F]FSW-100 by comprehensively assessing its safety profile, biodistribution, radiation dosimetry, and brain kinetics. METHODS: In cohort A, whole-body PET was performed in three healthy men to evaluate radiation dosimetry, with serial imaging conducted from 1 min to 2 h after injection followed by additional scans at 4 h and 6 h. Absorbed doses in individual organs and the effective dose were estimated. In cohort B, five healthy men underwent 120-min dynamic brain PET with arterial blood sampling for radioactivity measurement and metabolite analysis. To determine optimal kinetic modeling, one- and two-tissue compartment models (1-TCM and 2-TCM), along with Logan graphical analysis (LGA), were applied to estimate distribution volume (V). Safety was monitored throughout both cohorts. RESULTS: The scan protocol was well tolerated by all subjects. In cohort A, effective dose was estimated at 18.9 ± 1.7 µSv/MBq, with the highest absorbed dose observed in the gallbladder wall (379 ± 136 µGy/MBq). Accordingly, as a precaution to minimize gallbladder dose, cohort B received a lower administered radioactivity. In brain PET analysis, 2-TCM better described radioligand kinetics than 1-TCM. V was highest in cerebellar gray matter (42.6 ± 9.7 mL/cm) and lowest in white matter (12.2 ± 3.6 mL/cm). V values from 2-TCM strongly correlated with those from LGA. The mean V coefficient of variation across regions was 26 ± 3%, decreasing to 19 ± 3% when the input function was derived from averaged unchanged fractions, and further to 9 ± 2% when V values were normalized to white matter. CONCLUSIONS: [F]FSW-100 PET demonstrated an acceptable safety profile. V estimation via 2-TCM appears suitable for quantitative assessment of HDAC6 in the brain. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT), jRCTs031240173. Registered 19 June 2024, https://jrct.mhlw.go.jp/latest-detail/jRCTs031240173.
Cross-kingdom microbial associations characterize responsiveness to fecal microbiota transplantation in patients with irritable bowel syndrome.
Yan Q, Li M, Wang G … +19 more , Zhang A, Li Y, Guo R, Zhang Y, Yang W, Zhang Y, Liu X, Li X, Zheng N, Wang L, Fan S, Ma R, Lu T, Zhou S, Guan T, Xing G, Li S, Wang L, Li Y
J Transl Med · 2026 Jun · PMID 42298631 · Full text
BACKGROUND: Precise outcome prediction for fecal microbiota transplantation (FMT) in irritable bowel syndrome (IBS) remains a clinical challenge. The roles of the gut virome and its interplay with bacteria in FMT efficac...
BACKGROUND: Precise outcome prediction for fecal microbiota transplantation (FMT) in irritable bowel syndrome (IBS) remains a clinical challenge. The roles of the gut virome and its interplay with bacteria in FMT efficacy are particularly underexplored. This secondary analysis aimed to conduct an exploratory, hypothesis-generating investigation into these cross-kingdom dynamics. METHODS: We conducted a secondary, integrative analysis of a published cohort, performing longitudinal, cross-kingdom metagenomic profiling on 83 samples from 22 IBS patients and healthy donors. We integrative approach combined microbial diversity, species-specific biomarker identification, bacterial-viral associated networks, and exploratory random forest modeling to identify microbial features associated with FMT outcomes. RESULTS: IBS patients showed higher bacterial and viral alpha diversity than donors. Cross-kingdom profiling identified 223 bacterial and 724 viral biomarkers. Donor-enriched biomarkers were predominantly health-associated Bacteroidetes (e.g., B. ovatus, B. faecis), whereas pre-FMT-enriched biomarkers were largely Firmicutes (e.g., B. obeum) with potential pathobiont roles. The Effect and No effect groups displayed different microbial trajectories. Although both groups shifted toward a donor-like composition initially, only responders maintained a stable donor-like ecology throughout the 12-month follow-up, supported by more resilient bacterial-viral association networks. Exploratory random forest modeling highlighted microbial features, such as R. pickettii, with high relative importance for outcome discrimination. However, permutation testing (p = 0.548-0.616) confirmed that model performance on this small cohort did not exceed chance level, underscoring the risk of overfitting and the exploratory nature of these computational findings. CONCLUSIONS: This integrative re-analysis provides preliminary evidence that cross-kingdom gut microbiome profiles are strongly associated with FMT outcomes in IBS. Successful outcomes appear linked to sustained donor-like remodeling and stable bacterial-viral networks. Our findings are primarily hypothesis-generating and offer a framework of candidate biomarkers for future validation in larger cohorts. This work underscores the necessity of external validation to develop robust, microbiome-based tools for personalized FMT therapy.
From metabolic dysregulation to clinical alert: a novel panel of biomarkers for staging alcohol-associated liver disease.
Gao H, Zhang X, Tian L … +24 more , Cheng Z, Gao W, Yang Y, Li Z, Che J, Zhu Y, Tan Y, Yang Y, Wang X, Wang S, Yuan Y, Cao Z, Zhao Y, Du X, Liu J, Liao N, Chen Y, Yan S, Yang L, Jiang L, Hou X, Xu K, Song Y, Chu H
J Transl Med · 2026 Jun · PMID 42298593 · Full text
BACKGROUND AND AIM: ALD is among the most prevalent chronic liver disorders with rising global incidence, the aim of our study is to evaluate the effect of metabolites in the progress of ALD, and build a prediction model...
BACKGROUND AND AIM: ALD is among the most prevalent chronic liver disorders with rising global incidence, the aim of our study is to evaluate the effect of metabolites in the progress of ALD, and build a prediction model for ALC. METHODS: A total of 161 subjects were prospectively enrolled and classified into HC, AUD, AH, ALC. Plasma samples underwent untargeted LC-MS/MS metabolomics analysis. Data were split into training, validation and test sets at a 6:2:2 ratio. Partial least squares discriminant analysis and random forest were employed for feature selection, followed by logistic regression to build metabolite-based and metabolite-plus-clinical composite models. Discrimination was evaluated by AUC, sensitivity, specificity and accuracy. RESULTS: Metabolomic profiles showed progressive separation among groups (Q² > 0.65 for all PLS-DA models). Five metabolites (Vecuronium, N-Docosahexaenoyl Cysteine, 7-Acetylintermedine, Hymenoxon, E-3174) were identified as the most influential features for distinguishing ALC from HC, yielding an AUC of 0.986 (95% CI: 0.969-0.999) in the validation set and 100% accuracy in the test set. Integration of these metabolites with AST further elevated the AUC to 0.998 with 96.70% sensitivity and 100% specificity. Similarly, a five-metabolite panel plus PT achieved perfect accuracy (AUC = 0.964) in discriminating ALC from AH. CONCLUSIONS: We delineate stage-specific metabolic fingerprints of ALD and present robust, non-invasive models for early identification of cirrhosis. Incorporating metabolomic biomarkers with routine clinical variables markedly improves diagnostic precision and offers a practical tool for risk stratification and personalized management of alcohol-related liver disease.
The oncogenic potential of SOX12: a comprehensive and perspective view.
Leng H, Liu Y, Wu L
J Transl Med · 2026 Jun · PMID 42298571 · Full text
BACKGROUND: Sex-determining region Y-box 12 (SOX12), a key member of the SOXC transcription factor subfamily, exerts oncogenic roles in multiple malignancies via its conserved HMG-box DNA-binding domain. Although existin...
BACKGROUND: Sex-determining region Y-box 12 (SOX12), a key member of the SOXC transcription factor subfamily, exerts oncogenic roles in multiple malignancies via its conserved HMG-box DNA-binding domain. Although existing studies have reported its abnormal expression and functional implications in various tumors, previous reviews lack a systematic summary of SOX12-mediated regulatory networks across cancers, failing to address research gaps and potential therapeutic targets. MAIN BODY: This review comprehensively summarizes SOX12's expression patterns and oncogenic functions in digestive, reproductive, hematologic, and other tumor types. We systematically dissect its core molecular mechanisms, including competing endogenous RNA (ceRNA) networks, activation of canonical signaling pathways (e.g. PI3K/AKT/mTOR, Wnt/β-catenin), metabolic reprogramming, and modulation of the tumor immune microenvironment. Additionally, we highlight SOX12's clinical potential as a prognostic biomarker and therapeutic target, discussing novel targeting strategies such as HMG-box domain inhibitors and ceRNA network intervention. CONCLUSIONS: SOX12 serves as a critical "metabolic-immune" cross-regulatory node in tumors, with conserved oncogenic mechanisms across cancer types. Its abnormal expression is closely associated with malignant phenotypes and poor prognosis, supporting its dual value as a prognostic indicator and therapeutic target. Future research should focus on exploring its post-translational modifications, synergistic mechanisms with other SOX family members, and conducting large-scale clinical trials to validate its translational potential.
PPARγ signalling pathway: molecular mechanisms and therapeutic potential in ligamentum flavum hypertrophy and lumbar spinal stenosis.
Chen X, Zhu C, Yang S … +6 more , Zeng Y, Zhang B, Liang C, Tian Y, Liu T, Wang S
J Transl Med · 2026 Jun · PMID 42298564 · Full text
BACKGROUND: Ligamentum flavum hypertrophy (LFH) is a multifactor-mediated degenerative change in the spine. Due to its complex aetiology and pathology, there is no targeted therapy for LFH in the clinic. Therefore, it is...
BACKGROUND: Ligamentum flavum hypertrophy (LFH) is a multifactor-mediated degenerative change in the spine. Due to its complex aetiology and pathology, there is no targeted therapy for LFH in the clinic. Therefore, it is urgent to explore its potential mechanism and develop new therapeutic methods, which are conducive to the early recovery of patients. Peroxisome proliferator activated receptor γ (PPARγ), a nuclear receptor regulated by synthetic ligands and endogenous cellular lipids, is involved in a variety of biological processes. Currently, increasing evidence suggests that PPARγ may serve as a new pathway to guide the targeted treatment of LFH. Consequently, therapeutically harnessing the PPARγ signalling pathway to inhibit LFH could become a central focus of current research and clinical translation. MAIN BODY: LFH involves multiple pathological processes, including inflammation, fibrosis, angiogenesis, extracellular matrix (ECM) deposition, apoptosis and proliferation. PPARγ plays a key regulatory role in these biological processes. We further review strategies to modulate or target the PPARγ signalling pathway, highlight the related molecular mechanisms and recent clinical advances, and discuss potential possibilities for clinical translation and future perspectives. CONCLUSIONS: Although there is no direct evidence to support this, we found through a literature review that PPARγ may be involved in regulating various biological processes involved in the development of LFH. The PPARγ signalling pathway may be a potential therapeutic target for LFH, which provides new insights for future LFH research.
Single-cell and spatial transcriptomics identify SPP1 + trophoblast necroptosis as a potential contributor to late-onset preeclampsia via SPP1-CD44-mediated interaction with macrophages.
Li Q, Dong J, Wei X … +4 more , Qin C, Zhang Y, Zeng W, Lin Y
J Transl Med · 2026 Jun · PMID 42289736 · Full text
BACKGROUND: Late-onset preeclampsia (LOPE) is a complex placental disorder characterized by inflammation and placental dysfunction, yet the underlying molecular mechanisms remain incompletely understood. Necroptosis, a r...
BACKGROUND: Late-onset preeclampsia (LOPE) is a complex placental disorder characterized by inflammation and placental dysfunction, yet the underlying molecular mechanisms remain incompletely understood. Necroptosis, a regulated inflammatory form of cell death, has been implicated in various inflammation-associated diseases, but its role in LOPE has not been fully elucidated. METHODS: We performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) in placental tissues from LOPE and healthy pregnancies. Necroptosis activity was evaluated using gene-set scoring and validated by Western blotting and immunohistochemistry in human placentas. Pseudotime trajectory analysis, CellChat, and enrichment analysis were applied to characterize pathological cellular states and intercellular communication. Spatial deconvolution using RCTD was employed to map the localization and colocalization of specific cellular subtypes within placental niches. Functional validation was conducted in vivo using an L-NAME-induced preeclampsia-like mouse model in Mlkl knockout mice, together with multicolor immunofluorescence staining of human placental samples. RESULTS: Single-cell transcriptomic profiling revealed marked cellular heterogeneity between LOPE and healthy placentas and identified activation of necroptosis-related pathways in trophoblast populations in LOPE. A distinct SPP1 + extravillous trophoblast (EVT) subtype associated with necroptosis signatures was identified. Trajectory analysis indicated that this SPP1 + EVT subset represented a pathological state enriched for cell-death and inflammatory signatures. Spatial transcriptomics demonstrated specific localization of SPP1 + EVTs within the placental microenvironment and their spatial proximity to macrophages. Cell-cell communication analysis further highlighted a prominent SPP1-CD44 signaling axis mediating interactions between SPP1 + EVTs and macrophages. In vivo, Mlkl knockout attenuated L-NAME-induced preeclampsia-like phenotypes and reduced placental SPP1 expression. Consistently, multicolor immunofluorescence confirmed increased abundance of SPP1 + EVTs and spatially adjacent macrophages in LOPE placentas. CONCLUSIONS: Necroptosis is a predominant trophoblast cell death pathway in LOPE. The SPP1-CD44 axis may mediate EVT-macrophage crosstalk, contributing to placental inflammation and dysfunction. These findings provide mechanistic insight into LOPE pathogenesis, nominate necroptosis as a potential therapeutic target, and highlight SPP1 as a promising biomarker candidate.
Multicellular crosstalk in neutrophilic asthma: unraveling the pathogenic web of steroid resistance and emerging precision therapies.
Ye B, Yao J, Wang Y … +7 more , Liao X, Wu D, Wang M, Fang X, Gao J, Li Q, Gao W
J Transl Med · 2026 Jun · PMID 42288921 · Full text
BACKGROUND: Neutrophilic asthma (NA) is a severe, glucocorticoid-resistant phenotype. Although it represents a small proportion of asthma cases, it imposes a disproportionate burden due to its poor responsiveness to conv...
BACKGROUND: Neutrophilic asthma (NA) is a severe, glucocorticoid-resistant phenotype. Although it represents a small proportion of asthma cases, it imposes a disproportionate burden due to its poor responsiveness to conventional therapies. Challenging the traditional view of isolated molecular defects, emerging evidence positions steroid resistance in NA as a product of dynamic, self-perpetuating pathogenic networks involving neutrophils, airway epithelial cells, T helper cells, macrophages, and B cells. MAIN BODY: This review synthesizes the cellular crosstalk underlying NA, emphasizing how convergent interactions impair glucocorticoid receptor function, a final common pathway to steroid resistance. We critically examine emerging therapeutic strategies that disrupt key network nodes, highlighting a shift from single‑target to rational combination regimens. In parallel, we propose a biomarker‑anchored endotyping framework for precision patient stratification, an essential step toward translating network‑targeted interventions into clinical practice. Finally, we identify major knowledge gaps in NA pathogenesis and steroid resistance, and outline priority directions for future research. CONCLUSIONS: This review provides an integrated perspective on the pathogenesis of steroid-refractory NA and offers actionable insights for precision management, aiming to improve clinical care for this severe asthma subtype.
The role of macrophage autophagy and mitochondrial metabolic reprogramming in the treatment of myocardial infarction.
Zhang G, Hu F, Deng Y … +7 more , Li D, Huang T, Zhou L, Zhang Y, Deng X, Fu C, Dong B
J Transl Med · 2026 Jun · PMID 42288911 · Full text
BACKGROUND: Myocardial infarction (MI) is a life-threatening cardiovascular event, and preventing subsequent heart failure remains a major clinical challenge despite available treatments. The repair outcome critically de...
BACKGROUND: Myocardial infarction (MI) is a life-threatening cardiovascular event, and preventing subsequent heart failure remains a major clinical challenge despite available treatments. The repair outcome critically depends on the cardiac immune microenvironment, where macrophages play a pivotal role. Their functional switch from pro-inflammatory to reparative phenotypes is driven by mitochondrial metabolic reprogramming, a process regulated by autophagy, particularly mitophagy. However, the integrated role of the macrophage autophagy-metabolism axis in post-MI repair is not fully systematized. MAIN BODY: This review comprehensively examines the interplay between macrophage autophagy and mitochondrial metabolic reprogramming. It details how mitophagy maintains mitochondrial fitness to suppress inflammation and fuel the oxidative metabolism essential for reparative macrophage function. The discussion extends to advanced regulatory mechanisms, including inter-organelle communication, mechanosensing, and intercellular mitochondrial transfer. Furthermore, the review evaluates emerging therapeutic strategies, such as precision nanomedicine and multi-target interventions, within complex clinical contexts like diabetic MI. Key challenges, including the spatiotemporal complexity of macrophage dynamics and translational bottlenecks, are also addressed. CONCLUSIONS: By synthesizing current insights, this review establishes a novel immunometabolic framework centered on the macrophage autophagy-metabolism axis. It highlights that targeting this axis holds significant therapeutic potential for optimizing cardiac repair. The review provides forward-looking perspectives, emphasizing the need for intelligent, spatiotemporally precise therapeutic platforms to advance the development of targeted therapies for MI.
ARF-like GTPase 8B orchestrates lipophagy and exocytosis to drive single-stranded RNA virus replication.
Lv B, Wang X, Zhou Y … +7 more , Su Z, Sun Y, Zhou L, Lu Y, Pan Z, Tang XF, Shen C
J Transl Med · 2026 Jun · PMID 42288899 · Full text
BACKGROUND: Single-stranded RNA (ssRNA) viruses, including foot‑and‑mouth disease virus (FMDV), enterovirus 71 (EV71), and vesicular stomatitis virus (VSV), reprogram host lipid metabolism to facilitate replication. Howe...
BACKGROUND: Single-stranded RNA (ssRNA) viruses, including foot‑and‑mouth disease virus (FMDV), enterovirus 71 (EV71), and vesicular stomatitis virus (VSV), reprogram host lipid metabolism to facilitate replication. However, the mechanisms governing virus‑induced lipid droplet (LD) degradation remain poorly defined, which limits the development of host‑directed antiviral strategies. METHODS: We employed virological, biochemical, and imaging approaches to investigate the role of the lysosomal GTPase ARL8B in ssRNA virus infection. Lipid droplet dynamics, lipophagy, and lysosomal exocytosis were assessed using confocal microscopy and biochemical assays. Small‑molecule inhibitors targeting ARL8B were identified through virtual screening and validated in vitro for antiviral activity. The in vivo efficacy of selected inhibitors was evaluated in a murine EV71 infection model, with disease severity and survival as endpoints. RESULTS: ARL8B was identified as a central host factor that promotes replication of multiple ssRNA viruses by coordinating LD degradation with viral egress. Mechanistically, ARL8B drove lysosome‑dependent LD breakdown via selective lipophagy, releasing free fatty acids that fuel membrane remodeling within viral replication complexes. Concurrently, ARL8B facilitated viral exit through a noncanonical lysosomal-exosome pathway, enhancing progeny virus dissemination. Virtual screening yielded small‑molecule ARL8B inhibitors that potently suppressed ssRNA virus replication in vitro. In a murine EV71 infection model, these inhibitors provided robust protection and substantially reduced disease severity. CONCLUSIONS: Our findings establish ARL8B as a key host factor coupling lipid catabolism with viral export, and unveil a class of broad‑spectrum antiviral candidates targeting a lipid reprogramming node essential for multiple pathogenic RNA viruses. This study provides a mechanistic framework for developing host‑directed antiviral therapies against ssRNA viruses.
Cervical cancer screening policy inequality worldwide: a systematic review of disparities in access and implementation.
Xin R, Gong M, Guo J … +3 more , Tian J, Wu X, Zhu B
J Transl Med · 2026 Jun · PMID 42288897 · Full text
BACKGROUND: The rising global burden of cervical cancer and persistent inequalities in screening access underscore the need to strengthen implementation. Therefore, we compiled the cervical cancer screening guidelines fr...
BACKGROUND: The rising global burden of cervical cancer and persistent inequalities in screening access underscore the need to strengthen implementation. Therefore, we compiled the cervical cancer screening guidelines from different countries/regions and evaluated their implementation status and coverage situation. METHODS: In this study, we conducted comprehensive search of the PubMed, Embase and Web of Science databases (from their establishment to February 1, 2025), websites and the World Health Organization (WHO) database. Studies included in our analysis provide detailed information on the official cervical cancer screening recommendations for each country. All indicators were stratified based on factors such as human development index (HDI), income level, geographical location, WHO regions, disease risk, and age. The systematic review was prospectively registered at PROSPERO (registration number: CRD420251087263). RESULTS: Our study incorporated data from 77 countries/regions, only 62.3% (48/77) of them provided the year of published/updated protocol. Cytology was the primary screening test in 62 (80.5%) of 77 countries. Visual inspection with acetic acid (VIA) was the most recommended test in low HDI countries. Relatively few countries had adopted Human papillomavirus (HPV) testing as a primary screening method. Screening coverage was associated with HDI/income (low HDI: 12.43% vs. very high HDI: 49.74%; high-income: 51.68% vs. low income and middle-income countries [LMICs]:34.45%), with high-risk regions (29.88%) significantly lower than other areas (46.76%). Age-stratified analysis showed minimal coverage in the 20-29 and 70-79 groups, while coverage peaked in the 30-39 group. Our results also showed substantial heterogeneity in screening quality indicators (positive rate, further assessment rate, detection rate, and positive predictive value [PPV]) due to factors such as differences in the HDI. CONCLUSIONS: This study highlights global inequities in cervical cancer screening guidelines, particularly in the transition of screening methods among different countries/regions. Global cervical cancer coverage remains significantly below the target of 70%. Accelerate screening strategies, improve screening-diagnosis-treatment accessibility, establish monitoring systems, and strengthen global cooperation.
A decoy virus strategy using plant-produced SARS-CoV-2 virus-like-particles to inhibit infection and lung injury.
Liang J, Onodera Y, Li Y … +10 more , Wu J, McColman S, Cramb DT, Khang J, Khine AA, Chen YW, Rotstein OD, Mubareka S, Slutsky AS, Zhang H
J Transl Med · 2026 Jun · PMID 42288894 · Full text
BACKGROUND: The rapid emergence of highly transmissible and immune-evasive SARS-CoV-2 variants, including Omicron lineage strains, has reduced the effectiveness of existing vaccines and antiviral therapies. Safe and rapi...
BACKGROUND: The rapid emergence of highly transmissible and immune-evasive SARS-CoV-2 variants, including Omicron lineage strains, has reduced the effectiveness of existing vaccines and antiviral therapies. Safe and rapidly deployable biologics capable of limiting viral entry and attenuating early inflammatory responses remains needed, particularly for high-risk exposure settings. METHODS: We evaluated engineered non-replicating SARS-CoV-2 virus-like particles (VLPs), which structurally mimic the native virus, for antiviral and immunomodulatory effects in human induced pluripotent stem cell (iPSC)-derived lung organoids and K18-hACE2 transgenic mice. Cytopathic effects, viral RNA levels, cytokine expression, and lung pathology were quantified, while biodistribution and acute safety were assessed by fluorescence imaging and inflammatory profiling. RESULTS: Pre-exposure of lung organoids to VLPs attenuated SARS-CoV-2-induced cytopathic injury, reduced viral replication and IL-6 expression, and preserved epithelial integrity. Intranasal administration in K18-human angiotensin-converting enzyme 2 (ACE2) mice achieved uniform pulmonary distribution without acute inflammatory responses. A single pre-exposure prophylaxis dose of high-titer VLPs reduced viral burden and IL-6 levels, attenuated lung injury, and improved clinical parameters. Fluorescent VLPs co-localized with ACE2 and underwent cellular uptake in Calu-3 cells, supporting a competitive decoy mechanism, while preservation of ACE2 expression in vivo suggested reduced virus-induced ACE2 downregulation. CONCLUSIONS: SARS-CoV-2 VLPs function as safe, non-replicating biologics that limit viral entry and attenuate downstream inflammation under pre-exposure conditions. Their stability, scalability, and intranasal support further development as a pre-exposure prophylactic strategy, while additional studies are required to determine efficacy against contemporary variants and under post-exposure conditions.
In-situ self-gelling adhesive hydrogel powder for immediate sutureless closure of open ocular injuries.
Wang Y, Wang J, Chen Z … +4 more , Wang H, Zhao P, Han Y, Lin Q
J Transl Med · 2026 Jun · PMID 42288837 · Full text
BACKGROUND: Open globe injuries (OGIs) are a major cause of blindness and visual impairment, posing a significant public health challenge worldwide. Timely intervention is essential for the treatment of open eye trauma....
BACKGROUND: Open globe injuries (OGIs) are a major cause of blindness and visual impairment, posing a significant public health challenge worldwide. Timely intervention is essential for the treatment of open eye trauma. Suturing remains the primary method for managing ocular trauma. However, suturing is time-consuming, require highly skilled physicians, and carry multiple potential risks. Therefore, there is an urgent clinical need to explore a more convenient and effective approach for ophthalmic trauma management. METHODS: This study aims to develop a rapid self- gelling adhesive hydrogel powder for sutureless wound closure in OGI. We create a water-triggered in situ self-gelling adhesive hydrogel powder based on the composite aggregation of two oppositely charged polymers (polyethyleneimine and polyacrylic acid) for rapid, sutureless closure of OGIs. RESULTS: This powder can rapidly absorb interfacial water and forms in situ bonded hydrogels through strong physical interactions between polymers and between the polymer and tissue interface. The hydrogel was demonstrated to have strong tissue adhesion and excellent mechanical properties. In vitro cellular experiments and in vivo animal studies confirm its favorable biocompatibility. Animal studies demonstrated that this powder can effectively seal irregularly damaged tissue on the corneal and scleral surfaces. In conclusion, PEI/PAA powder exhibits good wet-interface adhesion and biocompatibility. CONCLUSIONS: Overall, our study demonstrate that PEI/PAA powder can rapidly absorb interfacial water to form an in-situ hydrogel. Experimental results confirm that this hydrogel exhibits strong tissue adhesion and excellent biocompatibility. These findings support the use of PEI/PAA powder as a rapid, effective, and safe therapeutic approach for OGI treatment.
AI in respiratory care: findings from the GOLD report.
Al-Waqeerah A, Bashah A, Ghaleb E … +2 more , He H, Gao L
J Transl Med · 2026 Jun · PMID 42288832 · Full text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) requires personalised, guideline-based management according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report. As large language models (...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) requires personalised, guideline-based management according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report. As large language models (LLMs) are increasingly used for medical guidance, their adherence to updated clinical recommendations requires systematic evaluation. This study assessed and compared ChatGPT-5, DeepSeek-V3.2, Gemini 3, Grok, Manus, and Kimi K1.5 in delivering 2025 GOLD-consistent responses, focusing on accuracy, consistency, and clinical reasoning. METHODS: A standardised dataset of 90 questions derived from the 2025 GOLD Report was categorised into YES/NO, multiple-choice, and open-ended formats. During a 7-day longitudinal study in December 2025, all questions were administered daily across the six platforms, generating 3,780 responses. Performance was evaluated against the 2025 GOLD Report, and open-ended responses were assessed for quality and clinical comprehensiveness. RESULTS: Performance was assessed across two separate primary outcomes. For binary accuracy (YES/NO and MCQ questions), Kimi K1.5 achieved the highest rate (97.1%; 408/420; 95% CI, 95.1-98.4%), and Gemini 3 the lowest (89.5%; 376/420; 95% CI, 86.2-92.1%). For open-ended clinical reasoning quality, Gemini 3 achieved the highest weighted score (96.5%; 95% CI, 93.3-98.4%) and DeepSeek-V3.2 the lowest (91.8%; 95% CI, 87.4-94.9%), reflecting a performance inversion between the two outcome domains. All platforms exhibited statistical stability across the seven-day study period (p > 0.05 for all models). CONCLUSION: Large language models showed high but format-dependent adherence to the 2025 GOLD COPD guidelines, with clear divergence between binary accuracy and open-ended reasoning. While they may serve as supplementary tools under expert supervision, generalization to other settings requires further validation. Residual performance gaps persisted across both domains, with binary error rates ranging from 2.9% (Kimi K1.5) to 10.5% (Gemini 3), and open-ended weighted-score deficits ranging from 3.5% (Gemini 3) to 8.2% (DeepSeek-V3.2).
Cross-trait mapping of shared susceptibility across inflammatory bowel disease and spondyloarthropathies.
Wang L, Li F, Wang J … +3 more , Wang H, Gong L, Wang Y
J Transl Med · 2026 Jun · PMID 42286689 · Full text
BACKGROUND: Inflammatory bowel diseases (IBDs) and spondyloarthropathies (SpAs) frequently co-occur, yet the subtype-specific genetic architecture and effector tissues that implement this gut-joint coupling remain poorly...
BACKGROUND: Inflammatory bowel diseases (IBDs) and spondyloarthropathies (SpAs) frequently co-occur, yet the subtype-specific genetic architecture and effector tissues that implement this gut-joint coupling remain poorly defined. METHODS: We integrated European-ancestry GWAS summary statistics for IBD, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, reactive arthritis and enteropathic arthritis, covering 22.21 million variants across 1,263,767 individuals. We quantified genome-wide and local sharing (S-LDSC/LDSC, ρ-HESS), identified pleiotropic loci (MTAG, CPASSOC) in trait pairs with significant genome-wide genetic correlation, and prioritized shared loci by integrating local-correlation evidence with GWAS-PW and GCTA-COJO, mapped signals to tissues/cell types (LDSC-SEG, gsMap), prioritized effector genes (UTMOST, FUSION, SMR, immune-cell scPrediXcan), and assessed directionality using bidirectional Mendelian randomization. RESULTS: IBD showed 16.4% liability-scale SNP heritability (CD 21.5%; UC 15.2%), whereas SpA subtype heritability ranged from 2.4% (ReA) to 62.9% (AS). Genetic correlations were positive but heterogeneous, with the strongest sharing observed for EnA-related pairs. Local genetic analyses indicated structured but uneven regional sharing across subtype pairs, with the most robust local support concentrated in PsA- and EnA-related comparisons. Tissue and cell-type analyses converged mainly on immune- and barrier-related contexts, including blood, synovial fluid, spleen, lung, and lymphoid tissues, as well as T-lineage and myeloid immune compartments. Complementary gsMap projection suggested a developmentally informed gut-immune spatial scaffold rather than a uniform anatomical pattern. Pair-specific transcriptomic integration further prioritized recurrent candidate effectors across the IBD-SpA axis, while bidirectional Mendelian randomization supported a predominantly forward component from intestinal inflammatory liability to selected SpA phenotypes. CONCLUSION: These results provide a multi-layer genetic and biological framework for gut-joint comorbidity, implicating shared immune and barrier niches and supporting a gut-first component in the IBD-SpA axis.
Two-timepoint multidomain follow-up of post-COVID condition and ME/CFS: overlapping autonomic, small-fiber, and cognitive changes.
Azcue N, Barranco C, Tijero-Merino B … +7 more , Acera M, Fernández-Valle T, Lafuente JV, Gabilondo I, Ruiz-Lopez M, Del Pino R, Gómez-Esteban JC
J Transl Med · 2026 Jun · PMID 42286686 · Full text
BACKGROUND: Post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show marked clinical overlap, suggesting a shared post-infectious pathophysiology. This study aims to characterize th...
BACKGROUND: Post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show marked clinical overlap, suggesting a shared post-infectious pathophysiology. This study aims to characterize the longitudinal change of autonomic function, small-fiber integrity, cognitive performance, and clinical symptoms in PCC and ME/CFS, and to determine whether trajectories differ between diagnostic groups. METHODS: Thirty-eight participants (21 PCC, 17 ME/CFS) underwent two standardized evaluations separated by a median of 31 months. Assessments included comprehensive autonomic testing, small-fiber evaluation, and an extensive neuropsychological battery. RESULTS: ME/CFS showed longer disease duration than PCC at baseline (median 42 vs. 12 months), while the interval between evaluations was comparable (31 vs. 30 months). Baseline profiles were largely overlapping, although ME/CFS showed nominally higher QST warm detection thresholds (p = 0.034), greater autonomic symptom burden (p = 0.038), and lower hemodynamic scores (p = 0.019), none surviving FDR correction. Cross-domain analyses linked small-fiber symptoms with autonomic symptom burden (Rho = 0.65, pFDR = 0.002) and fatigue (Rho = 0.55, pFDR = 0.018), while fatigue was negatively associated with processing speed (Rho = - 0.57, pFDR = 0.004), attention (Rho = - 0.49, pFDR = 0.018), and executive function (Rho = - 0.44, pFDR = 0.047). Rank-transformed mixed-effects models identified FDR-corrected Time effects, with increases in CHEPs (pFDR < 0.001) and verbal memory (pFDR = 0.010), and decreases in processing speed (pFDR = 0.006) and QST cold thresholds (pFDR = 0.038). CONCLUSIONS: PCC and ME/CFS showed broadly overlapping multidomain profiles, with particularly similar profiles at follow-up. This suggests that, among individuals with persistent symptoms, PCC may increasingly resemble longer-standing ME/CFS across autonomic, small-fiber/sensory, and cognitive domains. These findings are consistent with overlapping post-infectious mechanisms, but do not establish identical disease trajectories or definitive disease convergence.
Restoring neuroplasticity after CNS trauma: cell therapy approaches in spinal cord and traumatic brain injury.
Palha AT, Lima MF, Carvalho M … +3 more , Campos J, Sampaio-Marques B, Salgado AJ
J Transl Med · 2026 Jun · PMID 42286677 · Full text
BACKGROUND: The central nervous system (CNS) has a limited regenerative capacity, rendering traumatic injuries such as spinal cord injury (SCI) and traumatic brain injury (TBI) highly disabling and difficult to treat. Th...
BACKGROUND: The central nervous system (CNS) has a limited regenerative capacity, rendering traumatic injuries such as spinal cord injury (SCI) and traumatic brain injury (TBI) highly disabling and difficult to treat. These insults trigger complex pathophysiological cascades, including extensive cell death, sustained inflammation, and the formation of a hostile inhibitory microenvironment that compromises neural plasticity and hampers tissue regeneration. The multifactorial nature of these mechanisms, together with a fragmented understanding of CNS plasticity, has hindered the development of effective therapeutic interventions. MAIN BODY: In recent years, cell-based therapies have emerged as promising strategies to support neural repair and induce pro-regenerative processes. This approach encompasses multiple cell types, including bone marrow-derived mesenchymal stem cells (BMSCs), adipose-derived stem cells (ASCs), umbilical cord mesenchymal stem cells (UCMSCs), as well as neural progenitor cells (NPCs) and olfactory ensheathing cells (OECs). Clinical studies in SCI have reported functional improvements, particularly following treatment with BMSCs and peripheral blood-derived stem cells, although substantial methodological heterogeneity limits definitive conclusions. In TBI, clinical evidence remains more limited; however, preclinical studies consistently demonstrate the neuroprotective and regenerative potential of mesenchymal stem cell-based therapies. Beyond direct cell transplantation, increasing attention has been given to cell-free approaches, including secretome and extracellular vesicle-based strategies, which recapitulate many of the beneficial effects while potentially overcoming safety and logistical constraints. CONCLUSIONS: Overall, both cell-based and cell-free therapeutic strategies show significant potential to enhance neuroplasticity, attenuate secondary injury, and promote functional recovery following CNS trauma. Nevertheless, successful clinical translation will require larger, well-controlled trials and the establishment of standardized protocols addressing optimal timing, dosage, and routes of administration.
Endothelial glycocalyx perturbation in obstructive sleep apnea is associated with repetitive hypoxemia and immunothrombotic endothelial dysfunction.
Müller MB, Kammerer T, Khan H … +12 more , Schmid A, Hirschberger S, Hübner M, Barth TK, Mitsigiorgi R, Stihl C, Holzer M, Jira D, Patscheider M, Weiss BG, Reichel CA, Uhl B
J Transl Med · 2026 Jun · PMID 42286659 · Full text
BACKGROUND: Obstructive sleep apnea (OSA) is associated with cardiovascular disease. The endothelial glycocalyx (eGCX) is a shear-sensitive intravascular barrier. The relevance of OSA and intermittent hypoxia (IH) for eG...
BACKGROUND: Obstructive sleep apnea (OSA) is associated with cardiovascular disease. The endothelial glycocalyx (eGCX) is a shear-sensitive intravascular barrier. The relevance of OSA and intermittent hypoxia (IH) for eGCX perturbation and cardiovascular disease in humans remains unclear. METHODS: In a prospectively recruited observational cohort with cross-sectional biomarker analysis in men (n = 60), polysomnography quantified apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and hypoxic burden (HB). Using single-time-point plasma sampling, eGCX glycosaminoglycans hyaluronan (HA) and heparan sulfate (HS) and the proteoglycan syndecan-1 (SDC-1) were related to OSA severity and repetitive hypoxemia, including multivariable adjustment for cardiometabolic, inflammatory, and renal determinants. Plasma proteomics defined pathways associated with OSA and HA/HS. Shear-matured primary human endothelial cells were exposed to OSA-characteristic IH cycles under arterial flow to assess eGCX structure, oxidative stress, nitric oxide (NO) signaling, thromboinflammatory status, and antioxidant treatment with N-acetylcysteine. RESULTS: Plasma HA and HS were higher in OSA than in non-OSA individuals and increased stepwise with disease severity, tracking AHI, ODI, and HB. These associations persisted in multivariable analyses adjusting for age, BMI, hypertension, hs-CRP, fasting glucose, and eGFR. Plasma SDC-1 did not differ between groups and remained non-associated in adjusted analyses. Proteomics revealed enrichment of inflammatory, coagulation, and oxidative stress-related pathways that strengthened with increasing OSA burden and higher HA/HS levels. Experimentally, IH caused loss of endothelial surface HA/HS with increased shedding, increased reactive oxygen species, reduced redox capacity, impaired NOS3/eNOS signaling and reduced NO bioavailability. IH or enzymatic eGCX digestion each enhanced monocyte and platelet adhesion, tissue factor expression, and fibrin deposition under shear, while N-acetylcysteine attenuated oxidative stress and partially restored surface HA expression. CONCLUSIONS: Integrated patient and IH-model data show that OSA severity and repetitive hypoxemia are associated with circulating markers consistent with eGCX perturbation, while the endothelial IH model supports induction of oxidative-inflammatory stress and a proadhesive, prothrombotic phenotype by intermittent hypoxia. Together, circulating HA and HS emerge as candidate biomarkers associated with OSA-related eGCX perturbation, warranting further evaluation in longitudinal and interventional studies of eGCX-stabilizing adjunct therapies. These findings derive from an all-male cohort and require validation in women and more diverse populations.
Macrophage immunometabolism in stroke: a view from single-cell and nano technologies.
Zhu Y, Huang Z, Li X … +7 more , Zhou J, Lei X, Liang F, Yan J, Deng H, Sun X, Guo Z
J Transl Med · 2026 Jun · PMID 42286638 · Full text
BACKGROUND: Stroke induces profound neuroinflammation in which macrophages play a complex dual role, contributing to both injury and repair. The traditional M1/M2 classification is increasingly recognized as oversimplifi...
BACKGROUND: Stroke induces profound neuroinflammation in which macrophages play a complex dual role, contributing to both injury and repair. The traditional M1/M2 classification is increasingly recognized as oversimplified. Advances in single-cell RNA sequencing (scRNA-seq) have revealed a spectrum of dynamic macrophage subpopulations with distinct functional and metabolic states, fundamentally reshaping our understanding of post-stroke immunity. MAIN BODY: This review synthesizes recent insights into macrophage heterogeneity from a single-cell perspective, highlighting novel subsets such as an LCP1⁺ population defined by coupled glycolipid metabolism. We discuss how metabolic reprogramming, including glycolysis, oxidative phosphorylation, cholesterol metabolism, hypoxia‑driven gradients, and mitochondrial dynamics, critically underpins macrophage polarization. Glycolysis fuels pro-inflammatory (M1-like) responses, whereas oxidative phosphorylation and fatty acid oxidation support anti-inflammatory and reparative (M2-like) functions. We further explore innovative nano‑therapeutic strategies, including engineered liposomes, exosomes, and responsive polymeric nanoparticles, that enable spatiotemporally precise modulation of macrophage activity. Based on these advances, we propose an integrative framework that directly links scRNA‑seq‑defined macrophage subsets to their metabolic pathways, druggable targets, and tailored nano‑interventions. We also critically examine clinical translation barriers and prioritize actionable targets (e.g., CCR2, PPARγ, Nrf2) for future stroke therapy. CONCLUSIONS: The convergence of single‑cell genomics, immunometabolism, and nanotechnology offers a transformative path toward precision immunomodulation in stroke. Moving beyond the static M1/M2 dichotomy to target macrophage subpopulations and their metabolic drivers guided by an integrated framework holds significant promise for developing more effective therapies.
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