J Transl Med [JOURNAL]
Sun
200 papers
Gestational diabetes mellitus and maternal-infant microbiome axis: mechanistic insights and therapeutic interventions.
Choi J, Keum J, Kwak MJ … +4 more , Kim SH, Hoh JK, Jeon BH, Park HK
J Transl Med · 2026 Jun · PMID 42332788 · Full text
BACKGROUND: Gestational diabetes mellitus (GDM) alters maternal metabolism and the gut microbiota, thereby significantly affecting neonatal health. This narrative review synthesizes current clinical and translational evi...
BACKGROUND: Gestational diabetes mellitus (GDM) alters maternal metabolism and the gut microbiota, thereby significantly affecting neonatal health. This narrative review synthesizes current clinical and translational evidence on temporal changes in the maternal gut microbiota across the three pregnancy trimesters in women with GDM and examines its subsequent impact on neonatal microbiome composition, immune development, and long-term disease risk. MAIN BODY: GDM-associated dysbiosis has been reported early in pregnancy, but human evidence remains heterogeneous and does not establish direct vertical transmission; instead, maternal metabolic status and perinatal exposures may jointly shape early neonatal microbial patterns and immune-metabolic trajectories. These microbial alterations are closely associated with immune dysregulation and increased risks of inflammatory and metabolic disorders in offspring. Although diet, obesity, and probiotics influence microbial composition, their clinical efficacy in GDM remains inconsistent. Importantly, the available evidence remains heterogeneous, reflecting differences in cohort characteristics, sequencing methods, and study design, which limits definitive causal interpretation. CONCLUSIONS: Advances in microbiota-based diagnostics and personalized microbial interventions-including microbiome-guided dietary modulation, targeted probiotic strategies, and metabolite-focused approaches tailored to individual maternal metabolic and microbial profiles-offer promising strategies to mitigate adverse outcomes by targeting the maternal-neonatal microbiome axis, highlighting microbiome-based approaches as an emerging translational direction. CLINICAL TRIAL NUMBER: Not applicable.
Sodium-glucose cotransporter 2 inhibitors in breast cancer patients on endocrine therapy: a targeted strategy to mitigate long-term cardiometabolic risk.
Quagliariello V, Berretta M, Bisceglia I … +14 more , Barbato M, Arianna R, Forte P, Santagata J, Maurea C, Canale ML, Paccone A, Inno A, D'Ambrosio C, Oliva S, Dessalvi CC, Di Matola T, Gabrielli D, Maurea N
J Transl Med · 2026 Jun · PMID 42332771 · Full text
BACKGROUND: Hormone receptor-positive breast cancer (HR+ BC) represents the most common breast cancer subtype and is increasingly characterized by long-term survivorship complicated by substantial cardiometabolic and car...
BACKGROUND: Hormone receptor-positive breast cancer (HR+ BC) represents the most common breast cancer subtype and is increasingly characterized by long-term survivorship complicated by substantial cardiometabolic and cardiovascular morbidity. Endocrine therapies, including aromatase inhibitors, selective estrogen receptor modulators and degraders, and ovarian suppression, remain central to disease control but promote metabolic dysfunction, vascular injury, and systemic inflammation, thereby increasing cardiovascular disease (CVD) risk and potentially contributing to endocrine resistance. These alterations are also associated with adverse changes in adipose tissue distribution, increased visceral fat accumulation, and dysregulated lipid metabolism, further amplifying cardiometabolic risk. Consequently, CVD has emerged as a leading cause of non-cancer mortality among breast cancer survivor. METHODS: We performed a comprehensive narrative review of mechanistic, preclinical, and clinical evidence evaluating the cardiometabolic and oncologic effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the context of breast cancer and cardio-oncology. Literature from experimental models, observational and real-world studies was synthesized to delineate the biological pathways through which SGLT2i may influence cardiovascular risk, metabolic health, and endocrine therapy resistance in HR + BC. MAIN BODY: SGLT2 inhibitors, originally developed as glucose-lowering agents, confer robust cardiovascular and renal protection that extends beyond glycemic control. Emerging evidence indicates that SGLT2i modulate key biological pathways relevant to HR+ BC survivorship, including insulin-IGF-1 signaling, PI3K-Akt-mTOR and AMPK pathways, adipose tissue inflammation, hepatic steatosis, endothelial dysfunction, myocardial energetics, and systemic inflammatory tone. In addition, SGLT2i promote favorable adipose tissue remodeling, with preferential reduction in visceral adiposity and improvement in adipokine profiles, and induce lipid metabolism reprogramming characterized by enhanced fatty acid oxidation and reduced hepatic lipogenesis, contributing to improved cardiometabolic homeostasis. Observational and propensity-matched studies in oncology populations associate SGLT2i use with reduced incidence of heart failure, attenuation of cancer therapy-related cardiac dysfunction, and improved cardiovascular outcomes, including in breast cancer survivors exposed to cardiotoxic therapies. Beyond cardiovascular protection, converging data suggest that SGLT2i may indirectly mitigate or delay resistance to endocrine therapy by suppressing hyperinsulinemia-driven growth signaling, remodeling adipokine and inflammatory networks, and altering tumor-host metabolic interactions. CONCLUSION: SGLT2 inhibition represents a promising systems-level strategy at the intersection of cardio-oncology, metabolism, and endocrine resistance in HR+ breast cancer. By simultaneously targeting glucose homeostasis, adipose tissue dysfunction, and lipid metabolism, SGLT2i may improve both cardiovascular outcomes and long-term cancer control. Dedicated prospective trials are urgently needed to define their clinical role in breast cancer survivorship and precision cardio-oncology.
Transcription factor, E4BP4, inhibits autophagy and apoptosis in multiple myeloma and promotes the HDAC3-mediated suppression of the Beclin1 promoter to reduce dexamethasone sensitivity.
Li L, Li M, Liu H … +7 more , Chen T, Yang W, Cheng W, Kang Z, Yang X, Luo Y, Li Q
J Transl Med · 2026 Jun · PMID 42332765 · Full text
BACKGROUND: Multiple myeloma (MM) is a plasma cell malignancy prone to drug resistance, with unclear autophagy/apoptosis interactions in its etiology. This study explored transcription factor E4BP4's role in MM autophagy...
BACKGROUND: Multiple myeloma (MM) is a plasma cell malignancy prone to drug resistance, with unclear autophagy/apoptosis interactions in its etiology. This study explored transcription factor E4BP4's role in MM autophagy and apoptosis. METHODS: Transcriptomic data from GEO and TCGA assessed E4BP4 expression and clinicopathological correlations. E4BP4 expression in MM cell line U266 and normal PBMCs was analyzed via western blotting, RT-qPCR, and immunohistochemistry. Autophagy/apoptosis markers were measured using CCK-8, flow cytometry, electron microscopy, and immunofluorescence. Molecular docking identified E4BP4 DNA-binding sites. Co-immunoprecipitation, luciferase reporter assays, and ChIP-qPCR analyzed E4BP4 transcriptional activity. E4BP4 knockdown effects were tested in mouse xenografts. RESULTS: E4BP4 was overexpressed in MM tumor tissues versus non-cancerous tissues, and in U266 cells versus PBMCs. High E4BP4 suppressed apoptosis and autophagy in MM cells. E4BP4 overexpression upregulated HDAC3 transcription, activated mTOR signaling, and reduced H3K9Ac/H3K27Ac association with Beclin1 promoter, decreasing Beclin1 expression. E4BP4 overexpression reduced U266 sensitivity to dexamethasone, while knockdown enhanced drug sensitivity. E4BP4 knockdown inhibited U266 xenograft growth in mice, with combined knockdown and dexamethasone yielding additive effects. CONCLUSION: E4BP4 promotes MM progression by upregulating HDAC3, reducing histone acetylation and Beclin1 transcription to suppress autophagy/apoptosis. Its role in dexamethasone resistance highlights E4BP4 as a potential therapeutic target.
RUNX1-regulated ITGB1-enriched extracellular vesicles drive pancreatic cancer liver metastasis via fibrotic pre-metastatic niche formation.
Wang Y, Wang R, Zhu Q … +8 more , Liao S, Zhou Y, Xiao S, Wang H, Zhang Z, Sun P, Song Q, Dong M
J Transl Med · 2026 Jun · PMID 42332760 · Full text
BACKGROUND: Liver metastasis (LM) is the predominant distant metastatic target of pancreatic ductal adenocarcinoma (PDAC) and a major contributor to poor patient outcomes, with pre-metastatic niche (PMN) formation as its...
BACKGROUND: Liver metastasis (LM) is the predominant distant metastatic target of pancreatic ductal adenocarcinoma (PDAC) and a major contributor to poor patient outcomes, with pre-metastatic niche (PMN) formation as its critical prerequisite. However, its mechanisms remain incompletely elucidated. METHODS: RNA sequencing was performed on primary tumor tissues and paired adjacent non-tumor tissues from PDAC patients, combined with the analysis of a GEO dataset related to PDAC liver metastasis (PDAC-LM), followed by validation using in vitro assays and mouse orthotopic liver metastasis models. Transcription factor database screening coupled with dual-luciferase reporter assays identified downstream molecules. Mass spectrometry was conducted on plasma extracellular vesicles (EVs) from PDAC patients and healthy controls, with validation by ELISA. The hepatic effects of EVs were assessed using mouse models, and in vitro EV uptake assays were performed to dissect the underlying molecular mechanisms. RESULTS: Transcriptomic sequencing of PDAC patients showed that elevated primary-tumor runt-related transcription factor 1 (RUNX1) expression correlates with PDAC-LM. In orthotopic murine models, RUNX1 knockdown significantly reduced liver metastasis rate from 61.54% to 8.33%. Mechanistically, RUNX1 transcriptionally upregulated integrin beta 1 (ITGB1), which was enriched in PDAC cell-secreted EVs and internalized by hepatic stellate cells (HSCs), activating the NF-κB pathway to induce HSC activation and secretion of ECM proteins, inflammatory factors and chemokines. This EV-induced HSC activation thereby promoted fibrotic hepatic PMN formation and facilitated LM, as validated in murine models. Clinically, ITGB1 in plasma EVs correlated with PDAC-LM and poor prognosis, with favorable diagnostic efficacy in distinguishing PDAC-LM patients. CONCLUSIONS: Here, we first demonstrate that ITGB1 upregulated by RUNX1 in primary PDAC cells is enriched in tumor-derived EVs and contributes to fibrotic PMN formation, thereby accelerating PDAC-LM. These pivotal findings not only unravel the intricate molecular circuitry governing PDAC-LM but also pinpoint promising biomarkers to facilitate the diagnosis and therapy of this lethal metastatic cascade.
LAK to CIK continuum in glioma immunotherapy: a systematic review of efficacy and safety outcomes.
Hamidi S, Morsali S, Ghannadikhosh P … +6 more , Darvishi A, Nour MA, Zafarabadi S, Rahmani M, Doustvandi MA, Aghebati-Maleki L
J Transl Med · 2026 Jun · PMID 42332740 · Full text
BACKGROUND: Immunotherapy against gliomas, including Glioblastoma multiform (GBM) as the most lethal type combines innate and adaptive immune responses to strengthen systemic and host-specific immunity. Among various cel...
BACKGROUND: Immunotherapy against gliomas, including Glioblastoma multiform (GBM) as the most lethal type combines innate and adaptive immune responses to strengthen systemic and host-specific immunity. Among various cell-based immunotherapies, activated cell therapies utilize autologous immune cells activated ex vivo-such as lymphokine-activated killer (LAK) cells, cytokine-induced killer (CIK) cells, and cytotoxic T lymphocytes. Despite challenges, LAK laid the groundwork for further progress in activated killer cell therapies, such as CIK cells. CIK cells with their MHC-independent lytic activity, can be rapidly expanded ex vivo and administered as promising anticancer agents. This systematic review aims to assess CIK and LAK-based immunotherapy in glioma patients, their biological evolutionary path, and to compare these therapies across several parameters. METHODS: Following the PRISMA guideline, a thorough literature search was implemented using four major online databases up to August 2025. Screening and data extraction was performed by two independent reviewers and the quality assessment was evaluated using the Joanna Briggs Institute critical appraisal tool. RESULTS: Out of 930 initial papers, 21 studies including 18 quasi-experimental studies, 2 randomized controlled trials, and 1 cohort were selected. GBM was the predominant glioma subtype. LAKs and CIKs were mostly administered intracavitary and intravenously, respectively. LAK therapy increased survival; however, they presented more complications compared to CIK therapy, attributed to factors such as co-administration of IL-2. Bispecific antibodies were administered alongside LAK cells in two studies, which reported a higher survival rate. Hishi et al. demonstrated that 50% of the patients survived after three years, and 40% were free from recurrence. Studies evaluating CIK therapy demonstrated significant improvements in progression-free survival (PFS) and an increased disease control rate based on MRI findings. Kong et al. showed that PFS rose from 5.4 months in the control group to 8.1 months in the intervention group, while overall survival improved from 16.9 months to 22.5 months. No inflammatory cytokine storm or severe allergic reactions were observed in the CIK therapy groups. CONCLUSIONS: Both LAK and CIK therapies could be beneficial for glioma patients, with CIK being safer and associated with higher efficacy. Although larger clinical trials are needed to consolidate observed outcomes.
Hypoxia-induced lnc-IRP drives oxaliplatin resistance in colorectal cancer through IRP2 sequestration and iron metabolism reprogramming.
Yang H, Wang X, Li S … +6 more , Zhang M, Zhou Z, Yang J, Zhang X, Gao M, Zhang H
J Transl Med · 2026 Jun · PMID 42332736 · Full text
BACKGROUND: Hypoxic microenvironment is an important characteristic of solid tumors. A series of adaptations associated with hypoxia occur in cancer cells, including reprogramming of multiple metabolic pathways. Gastroin...
BACKGROUND: Hypoxic microenvironment is an important characteristic of solid tumors. A series of adaptations associated with hypoxia occur in cancer cells, including reprogramming of multiple metabolic pathways. Gastrointestinal bleeding is a common clinical symptom of CRC, resulting in anemia and iron deficiency. CRC patients have unbalanced iron homeostasis due to blood loss, chronic inflammation, etc. However, the molecular mechanisms underlying the effect of hypoxia-induced reprogramming of iron metabolism on chemosensitivity in CRC remain unclear. METHODS: RIP-seq combined with lncRNA-seq was conducted on hypoxia or normoxia CRC cells, to screen a profile of lncRNAs. Based on the characteristics of IRE elements, the sequence alignment and secondary structure analysis of the above screened lncRNAs were carried out by using open-access databases. Then lnc-IRP was obtained. RNA pull-down, RIP, RNA FISH and IF were used to confirm the binding and co-localization relationship between lnc-IRP and IRP2. Subsequently, the role of lnc-IRP in the chemosensitivity of CRC was verified both in vitro and in vivo. RESULTS: lnc-IRP relied on its IRE-like element to competitively bind IRP2, which disrupted intracellular iron regulatory network, leading to a tendency of iron to be stored in a ferric form rather than converted to LIP, and ultimately inhibiting apoptosis and ferroptosis. CONCLUSIONS: lnc-IRP is a potential therapeutic target to restore iron homeostasis under hypoxia, thereby increasing the sensitivity of CRC to oxaliplatin, which is expected to provide a new choice for clinical treatment, and thus improve the prognosis of patients.
Circulating CD28KLRG1CD8 T cells involve in systemic and local immunity that predicts chemoimmunotherapy outcomes in advanced NSCLC.
Zhou J, Bie H, You Y … +16 more , Li J, Liu J, Li S, Huang H, Zhou L, Hui Z, Zhang W, Meng Y, Lin H, Zheng L, Qi Y, Ji Z, Yu W, Wang M, Ren X, Yan C
J Transl Med · 2026 Jun · PMID 42332718 · Full text
BACKGROUND: Chemoimmunotherapy has become the standard first-line treatment for advanced non-small cell lung cancer (NSCLC). Deciphering the T-cell subset responsible for chemoimmunotherapy and easily tested conveniently...
BACKGROUND: Chemoimmunotherapy has become the standard first-line treatment for advanced non-small cell lung cancer (NSCLC). Deciphering the T-cell subset responsible for chemoimmunotherapy and easily tested conveniently is critical in predicting the treatment outcomes. METHODS: Based on peripheral blood collected from patients enrolled from a phase 2 clinical study (ClinicalTrials.gov NCT04836728), we performed multi-color flow cytometry and unsupervised analysis to explore correlations with therapeutic outcomes. We integrated single-cell RNA and T-cell receptor (TCR) sequencing in 36 samples, including peripheral blood, tumors and non-tumor tissues, from 8 NSCLC patients to interpret the correlation, which was further verified using blood samples, orthotopic and subcutaneous lung cancer mouse model. RESULTS: The baseline CD28KLRG1CD57 and on-treatment CD28KLRG1 CD8 T cells in peripheral blood were independent factors which indicated improved treatment outcomes in advanced NSCLC patients receiving first-line chemoimmunotherapy. While being in a late-differentiated T-cell status, these cells were clonally expanded and reinvigorated during chemoimmunotherapy, serving as a peripheral T-cell pool for supplying potential tumor-reactive T cells in tumors, and reversely differentiating into less-differentiated subsets. The zinc-metallothionein pathway regulated the CD28KLRG1 CD8 T-cell subset. Zinc supplementation combined with chemoimmunotherapy improved both local and systemic antitumor immune responses in mouse model. CONCLUSIONS: Circulating CD28KLRG1 CD8 T cells are valuable and convenient biomarkers for first-line chemoimmunotherapy in advanced NSCLC and provide insight into how late-differentiated or senescent T cells engage in the antitumor immunity when immunotherapy is added to conventional therapies.
Low-dose MyoAAV 2A-mediated delivery of engineered micro-utrophin achieves pan- muscle tissue distribution with elevated muscle function in Duchenne muscular dystrophy.
Li N, Li Z, Zhang Z … +7 more , Xiahou Z, Xiao H, Wu S, Xu F, Liu Q, Wu Y, Song Y
J Transl Med · 2026 Jun · PMID 42332716 · Full text
BACKGROUND: The pathogenesis of Duchenne muscular dystrophy (DMD) is driven by a deficiency of functional dystrophin. Although gene therapy is a promising strategy, current approaches face substantial challenges in balan...
BACKGROUND: The pathogenesis of Duchenne muscular dystrophy (DMD) is driven by a deficiency of functional dystrophin. Although gene therapy is a promising strategy, current approaches face substantial challenges in balancing therapeutic efficacy with toxicity, largely owing to the requirement for high-dose adeno-associated virus (AAV) administration. METHODS: We employed a low-dose strategy in neonatal mdx mice, using a muscle-targeted MyoAAV 2 A capsid to deliver a rationally designed, codon-optimized micro-utrophin construct (ΔR4-R22/ΔC + H3/H4) at 1 × 10¹² vg/kg via intraperitoneal injection. Four weeks post-injection, micro-utrophin expression and localization, as well as γ- and α-sarcoglycan recruitment, were assessed by western blotting and immunofluorescence. Vector genome distribution was quantified by real-time quantitative PCR. Tissue histology was evaluated using Evans blue dye uptake, H&E staining, and Masson's trichrome staining. Muscle function was measured by grip strength and treadmill exercise tests. Serum biomarkers of cardiac injury, heart failure, and systemic inflammation were detected by ELISA. RESULTS: Robust micro-utrophin expression was detected in skeletal muscles, diaphragm, and myocardium, with minimal off-target expression in the liver. Sarcolemmal localization and functional recruitment of γ- and α-sarcoglycan confirmed restoration of the dystrophin-glycoprotein complex. In treated animals, serum creatine kinase levels, Evans blue dye uptake, and central nucleation in multiple muscles were significantly reduced, accompanied by improvements in relative grip strength, running time, and distance to exhaustion. No cardiac or hepatic toxicity was observed, as indicated by unchanged cTnI, NT-proBNP, ALT, and AST levels. Additionally, serum IL-6 and C5a concentrations were significantly decreased, and fibrosis and inflammation in the diaphragm and myocardium were markedly attenuated. CONCLUSIONS: These findings demonstrate that combining a functional micro-utrophin construct with an advanced muscle-tropic MyoAAV 2 A capsid constitutes a promising strategy to overcome the efficacy-toxicity trade-off that has hindered the clinical translation of DMD gene therapies.
Nrf2 deficiency converts the ESCC microenvironment into an immunologically active state via the GPX2-ICD-DC signaling path.
Liu Y, Guo Q, Liu M … +7 more , Ai D, Chen Y, Liu Q, Hao S, Li C, Su F, Zhao K
J Transl Med · 2026 Jun · PMID 42332706 · Full text
BACKGROUND: Radiotherapy (RT) resistance remains a significant challenge in esophageal squamous cell carcinoma (ESCC). While Nrf2 is known to mediate antioxidant defense, its role in modulating the immunogenicity of radi...
BACKGROUND: Radiotherapy (RT) resistance remains a significant challenge in esophageal squamous cell carcinoma (ESCC). While Nrf2 is known to mediate antioxidant defense, its role in modulating the immunogenicity of radiotherapy-induced cell death is poorly understood. METHODS: We established a spontaneous esophageal cancer model using genetically engineered mice with conditional knockout of Nrf2, and analyzed the tumor immune microenvironment by single-cell RNA sequencing. In vitro, we performed co-culture experiments using CRISPR/Cas9-mediated Nrf2-knockout esophageal cancer cell lines with dendritic cells and T cells to validate immune activation. In addition, in vivo validation was conducted using a mouse subcutaneous tumor model. RESULTS: ScRNA-seq revealed that Nrf2 deficiency significantly remodeled the myeloid compartment, characterized by a population shift from Folr2 + to Mrc1 + macrophages and an expansion of effector T cells. Mechanistically, Nrf2 deletion downregulated the expression of Gpx2, impairing antioxidant defenses. This sensitized ESCC cells to RT, triggering the release of immunogenic cell death (ICD) markers, including ATP, HMGB1, and surface calreticulin (CRT). In tumor-DC-T cell co-culture systems, Nrf2-deficient cells stimulated dendritic cells (DCs) to secrete IP-10 (CXCL10), which was indispensable for the recruitment and activation of CD8 + T cells. Finally, in vivo experiments confirmed that Nrf2 deficiency enhanced radiosensitivity and promoted CD8 + T cell infiltration. CONCLUSION: Our findings identify the Nrf2-Gpx2 axis as a master regulator of immunogenicity in ESCC. Targeting this axis represents a promising strategy to convert "cold" tumors into "hot" environments, thereby improving the efficacy of radiotherapy and immunotherapy.
The expression landscape and clinical significance of cancer-specific RNA transcripts across human cancers.
Li H, Ding J, He X … +1 more , Chen Z
J Transl Med · 2026 Jun · PMID 42324541 · Full text
BACKGROUND: Transcript-level analyses allow for the precise characterization of gene expression and its functional role in cancer. However, most of these studies rely on reanalyses of next-generation sequencing data, who...
BACKGROUND: Transcript-level analyses allow for the precise characterization of gene expression and its functional role in cancer. However, most of these studies rely on reanalyses of next-generation sequencing data, whose incomplete or inaccurate assemblies limit the comprehensive and faithful characterization of transcripts. To systematically elucidate transcriptomic expression in tumors and define broadly applicable therapeutic strategies, we investigated cancer-specific RNA transcripts (cancer-SRTs) expressed across multiple cancer types based on long-read sequencing data. METHODS: We characterized the expression profiles of 44,405 cancer-SRTs across multiple cancer types using t-SNE and correlation analyses. Transcripts expressed in more than 10 cancer types were further investigated through enrichment, survival, and correlation analyses to elucidate their functions and clinical relevance. To explore the mechanisms driving cancer-SRT generation, we analyzed alternative splicing events within these transcripts and integrated copy number variation, DNA methylation, and ATAC-seq data from matched TCGA tumor samples. Using the expression of 131 transcripts strongly associated with tumor hallmarks, we developed a risk-score model to evaluate associations with patient survival, tumor stage, immune characteristics, and responses to immune checkpoint blockade. Finally, the in vitro anti-tumor effects of siRNAs targeting two cancer-SRTs were evaluated using CCK-8 assay, colony formation, and transwell assays. RESULTS: Cancer-SRTs exhibit substantial structural diversity and are enriched in malignancy-associated pathways. The expression of these transcripts is associated with multiple genomic and epigenetic processes. We identify 131 transcripts that are strongly associated with tumor hallmarks and develop a risk-score model for evaluating patient prognosis and tumor progression. The model also exhibited strong associations with features of immune evasion. CONCLUSIONS: Cancer-SRTs are widely expressed yet highly heterogeneous across tumor types, and are subject to multiple regulatory mechanisms underlying their functional and clinical significance. These findings advance our understanding of tumor biology and lay the groundwork for developing diagnostic, prognostic, and therapeutic strategies based on these transcripts. Future studies investigating their underlying mechanisms and applications in immunotherapy will be critical for precision cancer treatment.
PD-1 H (VISTA) drives immunosuppressive reprogramming of glioma-associated myeloid cells to promote glioma progression.
Guo Y, Zhao C, Liu H … +7 more , Ning W, Zhao J, Chen Y, Li H, Li Y, Wang S, Zhang H
J Transl Med · 2026 Jun · PMID 42324467 · Full text
BACKGROUND: Glioma is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that severely limits immune checkpoint blockade efficacy. Glioma-associated myeloid cells (GAMs), including resident micr...
BACKGROUND: Glioma is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that severely limits immune checkpoint blockade efficacy. Glioma-associated myeloid cells (GAMs), including resident microglia and infiltrating macrophages, constitute the dominant immune population within gliomas and shape antitumor immune responses. While immune checkpoint pathways have been extensively studied in T lymphocytes, the contribution of myeloid-restricted immune checkpoints to glioma progression remains poorly defined. Programmed death-1 homolog (PD-1 H/VISTA) is an inhibitory immune checkpoint predominantly expressed by myeloid cells, yet its functional role in GAMs has not been systematically investigated. METHODS: PD-1 H expression in human glioma was analyzed using immunohistochemistry, bulk transcriptomic datasets, and single-cell RNA sequencing. Associations between PD-1 H expression, immune cell composition, and patient survival were evaluated in clinical cohorts. The functional role of PD-1 H in GAMs was examined using genetically manipulated myeloid cells in vitro and orthotopic glioma mouse models in vivo. Transcriptomic profiling was performed to identify PD-1 H-associated biological pathways. The therapeutic potential of PD-1 H blockade was assessed using monoclonal antibody treatment in glioma-bearing mice. RESULTS: PD-1 H was highly expressed in human glioma tissues and was predominantly enriched in GAMs. Elevated PD-1 H expression was associated with an immunosuppressive tumor microenvironment characterized by increased infiltration of immunosuppressive myeloid populations, reduced cytotoxic T-cell presence, elevated expression of multiple immune checkpoint molecules, and unfavorable clinical outcomes. Functionally, PD-1 H promoted immunosuppressive myeloid polarization, enhanced malignant behaviors of glioma cells, and suppressed CD8 T-cell proliferation in vitro. In orthotopic glioma models, PD-1 H expression in GAMs accelerated tumor progression, promoted T-cell exhaustion, and shortened survival, whereas PD-1 H deficiency restrained tumor growth and prolonged survival. Mechanistic studies revealed that the AKT/NF-κB pathway mediates PD-1 H-dependent myeloid reprogramming. Importantly, therapeutic blockade of PD-1 H significantly suppressed glioma growth and improved survival in vivo. CONCLUSIONS: PD-1 H functions as a myeloid-restricted immune checkpoint that drives immunosuppressive reprogramming of glioma-associated myeloid cells, promotes glioma progression, and impairs antitumor T-cell immunity. Targeting PD-1 H represents a promising myeloid-focused immunotherapeutic strategy to overcome immune suppression in glioma.
Irisin treatment counteracts bone loss and muscle atrophy in aged mice by reducing sclerostin expression in bone and skeletal muscle.
Suriano C, Zerlotin R, Taurino M … +11 more , Dicarlo M, Storlino G, Pignataro P, Terrevoli OD, Pellicani L, Oranger A, Mori G, Passeri G, Colucci SC, Colaianni G, Grano M
J Transl Med · 2026 Jun · PMID 42323687 · Full text
BACKGROUND: Over the past decade, the myokine irisin has been identified as the main molecular mediator of physical exercise, with a remarkable effect on muscle and bone. Given its anabolic role, we sought to determine w...
BACKGROUND: Over the past decade, the myokine irisin has been identified as the main molecular mediator of physical exercise, with a remarkable effect on muscle and bone. Given its anabolic role, we sought to determine whether prolonged treatment with irisin could be a therapeutic option to counteract age-related osteosarcopenia. METHODS: To this end, 12-month-old C57BL6 mice were treated with vehicle or irisin (s.c. 100 µg/kg/weekly) for 8 months. Femurs were analyzed by micro-computed tomography, 3-point-bending assay and histomorphometry. Vastus Lateralis muscles were subjected to histological and molecular analysis. To evaluate the effect of irisin on sclerostin, its expression was assessed in bone marrow, cortical bone and skeletal muscle ex vivo, and in C2C12 myoblasts in vitro. RESULTS: The mice treated with irisin showed increase in cortical tissue mineral density (TMD) (p = 0.008), bone surface (BS) (p = 0.036), bone volume/total volume (BV/TV) (p = 0.02), and number of trabeculae (Tb. N) (p = 0.0002) compared with vehicle-mice. Irisin decreased the number of osteoclasts (p = 0.0056), tartrate-resistant acid phosphatase positive (TRAP+) osteocytes (p = 0.0292), and Sost expression in the bone marrow (p = 0.026) and cortical bone (p = 0.032). Furthermore, irisin preserved the morphological organization of muscle fibers and decreased the expression of muscle atrophy genes, Atrogin (p = 0.0168) and Muscle Ring-Finger Protein-1 (Murf1) (p = 0.0452). Notably, we observed a 2-fold lower sclerostin positivity in the muscle of irisin-treated mice than in vehicle mice (p = 0.026). In vitro experiments demonstrated that Sost was downregulated in C2C12 myoblasts treated with irisin either for 8 h (p = 0.0001) or intermittently for 1 week (p = 0.0004). On the other hand, sclerostin treatment in myoblasts affected their differentiation marker genes and downregulated the irisin precursor Fibronectin domain-containing protein 5 (FNDC5) (p = 0.009). CONCLUSIONS: Overall, this study demonstrates that irisin is a systemic mediator capable of counteracting the effects of aging on the musculoskeletal system. Furthermore, our study provides evidence of sclerostin expression in skeletal muscle and the negative effect of this osteokine on myoblast differentiation. Therefore, the ability of irisin to downregulate sclerostin expression in both bone and skeletal muscle highlights its functional versatility, which could find application as a therapeutic approach for the treatment of osteosarcopenia.
Tackling non-canonical splicing in arrhythmogenic cardiomyopathy to reduce the uncertain significance variants burden.
Celeghin R, Tosato G, Pinci S … +5 more , Dalla Zanna F, Bueno Marinas M, Cason M, Basso C, Pilichou K
J Transl Med · 2026 Jun · PMID 42323666 · Full text
BACKGROUND: Splice-altering variants (SAVs), particularly those outside canonical splice sites, are an underappreciated contributor to inherited cardiovascular diseases. In arrhythmogenic cardiomyopathy (ACM), these vari...
BACKGROUND: Splice-altering variants (SAVs), particularly those outside canonical splice sites, are an underappreciated contributor to inherited cardiovascular diseases. In arrhythmogenic cardiomyopathy (ACM), these variants frequently remain classified as of uncertain significance (VUS) due to limited predictive power and lack of transcript-level evidence, constraining genetic yield and clinical management. Our study aimed to determine the functional impact of SAVs in ACM genes and refine their classification using ACMG/AMP and ClinGen SVI criteria. METHODS: SAVs identified in 200 ACM probands underwent SpliceAI prediction, GTEx cardiac exon-usage annotation, and functional assessment using pSPL3-based minigene assays. Aberrant transcripts were quantified using Percent Splicing Alteration (PSA). Segregation data and ACMG/AMP criteria refined by ClinGen SVI were applied to integrate functional and clinical evidence for classification. RESULTS: Aberrant splicing was confirmed in 9/20 variants (45%), including synonymous, missense, and non-canonical intronic changes. SpliceAI scores correlated strongly with PSA values (R²=0.86). Case-control burden testing revealed significant enrichment of splice-altering variants in DSP, DSG2, DSC2 and FLNC. Integrating predictive algorithms with experimental validation and segregation analysis markedly enhances reclassification of 16/20 variants (80%). CONCLUSION: Splicing defects beyond canonical sites significantly shape ACM genetic landscape. Integrating predictive models with experimental validation clarifies uncertain variants bridging the gap between genomic uncertainty and clinical decision-making.
SMN deficiency contributes to osteoporosis in spinal muscular atrophy by impairing Snap23 meditated muscle-derived extracellular vesicle secretion.
Lin W, Sui W, Deng Y … +10 more , Chen J, Shao X, Huang Z, Wei W, Cheng L, Zhang X, Hu R, Yang J, Li B, Yang J
J Transl Med · 2026 Jun · PMID 42321919 · Full text
BACKGROUND: Spinal muscular atrophy (SMA), caused by mutations in survival motor neuron 1 (SMN1), presents with severe muscle atrophy and prevalent osteoporosis. Transcriptomic profiling of patient muscle biopsies reveal...
BACKGROUND: Spinal muscular atrophy (SMA), caused by mutations in survival motor neuron 1 (SMN1), presents with severe muscle atrophy and prevalent osteoporosis. Transcriptomic profiling of patient muscle biopsies revealed enrichment of extracellular vesicle genes, yet the contribution of SMA-EVs to SMA-associated bone loss and their link to SMN deficiency remain undefined. METHODS: Clinical CT/MRI images of SMA and control subjects were acquired to quantify osteoporosis and muscle atrophy. SMA model mice (Smn1ROSA26) were phenotyped at 6 weeks by micro-CT and histology. EVs were isolated from muscles, validated (western blot, transmission electron microscope, nano-flow cytometry, BCA protein assay), and compared between genotypes. DiL-labelled EV biodistribution was tracked in vivo; uptake by BMSCs/BMMs was confirmed by confocal microscopy. Cytotoxicity was assessed by live/dead staining. Dose-response experiments evaluated the osteogenic and anti-osteoclastic activity of SMA-EVs. Comparison of the effects of SMA-EVs and CON-EVs were performed with adequate doses in vitro and in vivo, followed by EV replenishment in SMA mice. Osteogenic and osteoclastogenic gene expression was quantified by qPCR; ALP activity by ELISA. Bone and cell parameters were assessed by HE staining, TRAP staining, COL-1 immunofluorescence staining, and micro-CT. RNA-seq data were validated by Western blot. Lentiviral shRNA and over-expression plasmids were used to generate muscle cells with stable SNAP23 knock-down or up-regulation, and AAV-mediated muscle-specific Snap23 over-expression was employed in mice to define the role of muscular SNAP23 in EV secretion and its impact on bone mass. Mice carrying extra SMN2 transgenic copies were analyzed to delineate the SMN-SNAP23 relationship. RESULTS: SMA patients and mice exhibited a significantly diminished capacity of skeletal muscle to secrete EVs, which were readily internalized by BMSCs and BMMs, dose-dependently promote osteogenic differentiation and suppress osteoclast formation. Adequate-dose SMA-EVs matched CON-EVs efficacy, and SMA-EVs supplementation effectively rescued the osteoporotic phenotype in SMA. Transcriptomics indicated impaired SNARE complex-mediated vesicle secretion pathway. We further demonstrated that deficiency of SMN protein drives downregulation of its downstream key SNARE component, SNAP23, thereby impairing the efficiency of SMA-EV secretion. CONCLUSION: Our work elucidates a novel disease-specific mechanism for SMA osteoporosis-dysfunction of the SMN-SNAP23-EVs axis-and highlights the therapeutic potential of replenishing SMA-EVs or targeting this axis, offering a promising strategy to improve skeletal health in SMA.
Gut microbiota-associated leucine elevation promotes cold-induced atherosclerotic plaque formation and instability.
Yan S, Fang N, Zhang Y … +6 more , Zhang N, Liang Q, Duan Y, Li L, Li Y, Gong Y
J Transl Med · 2026 Jun · PMID 42321866 · Full text
BACKGROUND: Environmental factors such as cold exposure have been increasingly recognized as contributors to atherosclerosis progression, yet the underlying mechanisms linking environmental stress to vascular pathology r...
BACKGROUND: Environmental factors such as cold exposure have been increasingly recognized as contributors to atherosclerosis progression, yet the underlying mechanisms linking environmental stress to vascular pathology remain incompletely understood. In particular, the role of the gut microbiota and microbiota-associated metabolites in cold-induced atherosclerosis has not been fully elucidated. METHODS: A cold exposure model was established in ApoE⁻/⁻ mice fed a Western diet. Integrated multi-omics analyses were combined with fecal microbiota transplantation (FMT) and mechanistic cellular assays to investigate gut microbiota remodeling, metabolic alterations, and immune regulation during cold-induced atherosclerosis. RESULTS: In this study, we demonstrate that cold exposure accelerates atherosclerotic plaque growth and instability in parallel with pronounced gut microbiota dysbiosis and alterations in host metabolic profiles. FMT combined with metabolomic analyses showed that cold-associated gut microbiota is closely associated with elevated circulating leucine levels, suggesting that cold-induced microbial remodeling may participate in this process by modulating host systemic leucine availability. Mechanistically, increased leucine suppressed the Zic family member 2 (Zic2) in macrophages, leading to reduced expression of growth arrest-specific 6 (Gas6), a key mediator of efferocytosis. Impaired Gas6-dependent efferocytosis resulted in defective clearance of apoptotic cells, heightened vascular inflammation, and increased plaque instability. Importantly, supplementation with Lactobacillus johnsonii, a commensal bacterium depleted under cold exposure, normalized circulating leucine levels, restored Zic2-Gas6 signaling, enhanced macrophage efferocytosis, and attenuated atherosclerotic plaque progression. Conversely, leucine supplementation recapitulated the effects of cold exposure on plaque development and instability. CONCLUSIONS: Collectively, these findings identify a previously unrecognized cold-microbiota-leucine-Zic2-Gas6-efferocytosis axis that links environmental stress to atherosclerosis progression. Targeting gut microbial regulation of host systemic leucine levels, including L. johnsonii-based interventions, may represent a promising therapeutic strategy for preventing cold-induced atherosclerotic cardiovascular disease.
Pomalidomide significantly enhances the antitumor immune efficacy of dendritic cell-derived exosomes from multiple myeloma patients.
Zhang H, Wang Y, Wang X … +7 more , Duan H, Yu D, Kuang X, He L, Zhang W, Chen J, Dai J
J Transl Med · 2026 Jun · PMID 42321862 · Full text
BACKGROUND: To explore the effect and mechanism of pomalidomide on the immune activity of dendritic cell-derived exosomes (DEXs) from patients with multiple myeloma (MM). METHODS: MoDCs were induced from monocytes obtain...
BACKGROUND: To explore the effect and mechanism of pomalidomide on the immune activity of dendritic cell-derived exosomes (DEXs) from patients with multiple myeloma (MM). METHODS: MoDCs were induced from monocytes obtained from patients with MM and HDs with or without pomalidomide treatment. DEXs were then isolated from culture supernatants via ultracentrifugation and characterized by TEM and NTA. Surface markers (CD63, CD81, CD80, CD86, and HLA-DR) were analyzed using nanoflow cytometry. Functional assays included coculturing DEXs with autologous PBMCs to activate T cells, followed by sorting CD8 T cells and assessing their pro-apoptotic effect on U266 cells via flow cytometry. Mechanistic insights were explored through miRNA sequencing of DEXs and transcriptome sequencing of T cells. RESULTS: Pomalidomide significantly increased the proportion of DEXs derived from patients with multiple myeloma (MM) and increased the expression levels and mean fluorescence intensity (MFI) of surface activation markers, including CD80, CD86 and HLA-DR. Functional assays demonstrated that DEXs treated with pomalidomide promoted the generation of CD8 T cells and markedly increased both early and total apoptosis rates in U266 cells. Mechanistically, miRNAomic analysis indicated that pomalidomide potentially facilitates T-cell activation by modulating signaling pathways such as the MAPK and PI3K-Akt pathways. Transcriptome profiling further verified that this treatment triggered substantial metabolic reprogramming in T cells and significantly activated pathways associated with T-cell activation. CONCLUSIONS: This study provides a new strategy for enhancing the activity of DEXs derived from patients with MM, with the potential to develop DEXs as an antitumor vaccine for MM.
Palbociclib targets β-catenin for degradation and synergizes with KRAS or ERK5 inhibition in colorectal cancer preclinical models.
Villa M, Malighetti F, Villa AM … +5 more , Cordani N, Aroldi A, Zambon A, Ramazzotti D, Mologni L
J Transl Med · 2026 Jun · PMID 42321850 · Full text
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, largely driven by aberrant activation of the WNT/β-catenin and RAS pathways. Despite recent therapeutic advances, effective strategies t...
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, largely driven by aberrant activation of the WNT/β-catenin and RAS pathways. Despite recent therapeutic advances, effective strategies to target these oncogenic signals remain limited. METHODS: A multi-step chemical library screen was performed to identify compounds capable of suppressing β-catenin and RAS signaling. Drug mechanisms and combination effects were investigated through functional assays, in vitro and in vivo experiments, and transcriptomic profiling. Survival analysis of the Sidra-LUMC AC-ICAM CRC cohort (n = 303) was conducted to evaluate the prognostic significance of candidate target genes. RESULTS: We identified the CDK4/6 inhibitor palbociclib as an unexpected suppressor of β-catenin signaling. Uniquely, palbociclib promoted GSK3β-mediated β-catenin degradation by dampening AKT activity, revealing a previously unrecognized mechanism of action and broadening its role beyond canonical cell-cycle inhibition. Building on this mechanism, we found that combining palbociclib with the KRAS-specific inhibitor MRTX1133 elicited potent and selective anti-tumor effects in vitro and in vivo. Parallel screening also revealed the ERK5 inhibitor ERK5-IN-1 as a promising combination partner: co-administration with palbociclib strongly suppressed proliferation across multiple CRC models, showed minimal toxicity in normal cells, and produced durable tumor control in vivo. Transcriptomic profiling indicated that both combinations converge on a common program of cancer cell-state reprogramming, characterized by suppression of proliferative drivers and remodeling of metabolic and mitochondrial pathways. Underscoring the clinical relevance of our findings, survival analysis of the Sidra-LUMC AC-ICAM CRC cohort (n = 303) revealed that ERK5 target genes CREB5 and NUPR1, identified in our dataset, were consistently linked to poor prognosis, thereby connecting this signaling axis to unfavorable patient outcomes. CONCLUSIONS: Together, these findings position palbociclib as a versatile therapeutic backbone in CRC. By simultaneously targeting cell cycle and oncogenic signaling networks, palbociclib-based combinations induce synergistic and durable responses, offering a compelling rationale for tailored therapeutic strategies in molecularly defined CRC.
Bronchoalveolar lavage microbiota signatures and stage-associated alterations in early-stage and advanced-stage non-small cell lung cancer: a pilot study.
Li Y, Chen Q, Bin X … +2 more , Xu S, Ma H
J Transl Med · 2026 Jun · PMID 42321844 · Full text
OBJECTIVES: The aims of this study were to characterize the microbial flora in the bronchoalveolar lavage fluid (BALF) of patients with early-stage (stage I, II, IIIA) and advanced-stage (stage IIIB, IIIC, IV) non-small...
OBJECTIVES: The aims of this study were to characterize the microbial flora in the bronchoalveolar lavage fluid (BALF) of patients with early-stage (stage I, II, IIIA) and advanced-stage (stage IIIB, IIIC, IV) non-small cell lung cancer (NSCLC), and to explore the associations between microbial flora and lung cancer stage. METHODS: We collected BALF from NSCLC patients (early-stage group 26 cases; advanced-stage group 31 cases). Absolute quantitative metagenomic sequencing was performed to identify differential taxa, genes, and enriched pathways. Flow cytometry was used to profile T cell subsets. We correlated the microbial species with immune cell and gene expression. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of differential taxa to distinguish advanced-stage from early-stage NSCLC. RESULTS: Dokdonia (q = 0.040, LDA = 5.704) and Cocleimonas (q = 0.026, LDA = 5.329) were enriched in the early-stage group, whereas Barnesiella (q = 0.046, LDA = 4.784), Pedobacter (q = 0.040, LDA = 4.913) and unclassified Bacteroides (q = 0.046, LDA = 4.932) were significantly enriched in the advanced-stage group. The microbial genes gmhD (q < 0.001, LDA = 3.926), rfaD (q < 0.001, LDA = 3.918), nudF (q = 0.004, LDA = 4.283) and sfsA (q = 0.004, LDA = 3.915) were expressed remarkably in the advanced-stage group. The advanced-stage group exhibited altered T cell subset distributions, including a higher proportion of CD8⁺ T lymphocytes (q < 0.001), whereas it showed a lower proportion of CD4⁺ T cells and a decreased CD4/CD8 ratio (q < 0.001; q < 0.001). Bifidobacterium was negatively associated with the CD4/CD8 ratio (q = 0.015) and positively significant correlated with the genes which enriched in the advanced-stage group. CONCLUSIONS: This study delineated the microbial structure and function of early-stage and advanced-stage of NSCLC. We identified discriminating taxa, genes, and pathways linked to cancer progression, characterized the T cell subset distributions in the advanced-stage of NSCLC. Bifidobacterium abundance was associated with altered T cell subset distributions and stage-related microbial genes, providing hypotheses for future mechanistic studies on microbiota-driven NSCLC progression.
Machine learning-driven QSAR modeling combined with single cell transcriptomics identifies novel drug targets for lung cancer.
Nagarajan N, Shakyawar SK, Raheem K … +1 more , Guda C
J Transl Med · 2026 Jun · PMID 42321836 · Full text
BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, largely due to frequent metastasis to the brain and bones. Therapeutic outcomes are often limited by drug resistance, tumor h...
BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, largely due to frequent metastasis to the brain and bones. Therapeutic outcomes are often limited by drug resistance, tumor heterogeneity, and the lack of effective treatment options across different stages and metastatic sites. Identifying druggable targets that are conserved between primary tumors and metastases is critical for advancing precision oncology. METHODS: scRNA-seq expression profiles from primary NSCLC tumors and matched brain and bone metastases were analyzed to identify conserved and site-specific gene expression signatures. Ingenuity Pathway Analysis was used for target prioritization. Potential targets identified from scRNA-seq analysis were used for ligand screening using machine learning (ML)-based quantitative structure-activity relationship (QSAR) modeling. QSAR models were developed using ChEMBL bioactivity data and evaluated across multiple ML algorithms. Large-scale virtual screening was followed by molecular docking and molecular dynamics (MD) simulations for lead optimization. RESULTS: Eight candidate therapeutic targets were prioritized, among which ARPC2, PSMB4, and RAC2 were consistently overexpressed across primary, brain, and bone metastatic sites and were functionally implicated in key cancer-associated pathways. QSAR modeling demonstrated strong predictive performance, with XGBoost and Random Forest models achieving AUROC values greater than 0.97. Virtual screening of approximately 9-15 million compounds per target identified high-affinity candidates. Subsequent docking and MD simulations revealed that the ARPC2-14465616, PSMB4-74833722, and RAC2-57175325 complexes exhibited the highest structural stability and sustained intermolecular interactions. CONCLUSION: This integrative single-cell transcriptomics and ML-driven drug discovery framework identified conserved druggable targets and promising lead compounds for metastatic NSCLC. The results provide a strong foundation for experimental validation and the development of novel therapeutic strategies targeting both primary tumors and metastatic lesions.
Gastrointestinal symptoms correlate with core clinical features and systemic inflammation in myalgic encephalomyelitis/chronic fatigue syndrome.
Brown M, Vernon SD, Indart AC … +2 more , Green PH, Alaedini A
J Transl Med · 2026 Jun · PMID 42321833 · Full text
BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness marked by fatigue, cognitive impairment, and post-exertional malaise. Gastrointestinal (GI) symptoms are frequ...
BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness marked by fatigue, cognitive impairment, and post-exertional malaise. Gastrointestinal (GI) symptoms are frequently reported, yet their relationship to central features of the illness and biological correlates remains poorly understood. OBJECTIVES: We aimed to characterize GI symptom burden in ME/CFS and evaluate its associations with core clinical features and specific immune and inflammatory markers, with attention to potential gut-related contributions to disease expression. METHODS: GI symptoms and 49 additional symptoms across nine domains were assessed in 116 ME/CFS patients and 80 matched controls. Plasma C-reactive protein (CRP) and antibodies against dietary and microbial antigens were measured as indicators of systemic inflammation and putative gut-derived antigen exposure. RESULTS: ME/CFS patients reported significantly elevated GI symptom frequency and severity compared with controls, with 53% of ME/CFS patients versus 8% of controls reporting a prior diagnosis of irritable bowel syndrome. GI symptom burden correlated with fatigue, cognitive difficulties, flu-like symptoms, pain, sleep disturbances, neurological complaints, and sensory sensitivities, independent of illness duration. CRP levels were higher in patients with greater GI symptoms and correlated with GI, fatigue, musculoskeletal pain, and flu-like symptom burden. Patients with greater flu-like symptom expression exhibited higher IgM responses to dietary gliadin and bacterial lipopolysaccharide. These associations were not detected in controls. CONCLUSIONS: GI symptoms are a prominent, clinically relevant dimension of ME/CFS, associated with broader symptom burden and inflammatory heterogeneity. These findings highlight the relevance of gut-related and immune processes in ME/CFS and underscore the value of incorporating GI symptom assessment in translational studies to help refine mechanistic understanding and improve therapeutic stratification.
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