J Transl Med [JOURNAL]
Sun
200 papers
The lncRNA-m6A axis in cancer: a bidirectional regulatory network in tumor progression and therapeutic resistance.
Wang Z, Li T, Li K
J Transl Med · 2026 Jul · PMID 42400056 · Full text
BACKGROUND: Long non-coding RNAs and N6-methyladenosine RNA methylation represent two pivotal layers of gene regulation. Their extensive crosstalk forms a sophisticated bidirectional network that is fundamentally rewired...
BACKGROUND: Long non-coding RNAs and N6-methyladenosine RNA methylation represent two pivotal layers of gene regulation. Their extensive crosstalk forms a sophisticated bidirectional network that is fundamentally rewired in cancer. MAIN BODY: This review synthesizes current knowledge to elucidate the principles and consequences of this synergistic axis. We detail how m6A modification dictates long non-coding RNA stability, splicing, localization, and function through recruitment of distinct "reader" proteins, with one "reader" family primarily mediating decay while another promotes stabilization. Conversely, we examine how long non-coding RNAs act as scaffolds, guides, and decoys to modulate the activity and specificity of the m6A machinery, establishing powerful feedforward and feedback loops. This reciprocal regulation converges on multiple cancer hallmarks, including proliferation, metabolic reprogramming, immune evasion, stemness, and therapeutic resistance. We critically discuss experimental strategies to establish causal relationships, including site-directed mutagenesis, CRISPR-based editing, and rescue assays. We also evaluate current methodological limitations in m6A detection, from antibody-dependent approaches to emerging nanopore sequencing, and highlight how single-cell and spatial transcriptomic technologies can resolve cell-state-specific networks within the tumor microenvironment. From a translational perspective, we compare small molecule inhibitors targeting m6A "writers" with RNA-based therapies, addressing their respective delivery challenges and toxicity concerns. Finally, we outline how m6A-related long non-coding RNA signatures serve as prognostic biomarkers and liquid biopsy tools for non-invasive cancer monitoring. CONCLUSION: By integrating molecular mechanisms with clinical perspectives, this review charts a roadmap for targeting the epitranscriptomic-long non-coding RNA circuit in precision oncology.
Repurposing cepharanthine as a radiosensitizer in esophageal squamous cell carcinoma through dual metabolic intervention and direct targeting of p70s6K.
Hao Z, Su X, Li J … +9 more , Jin J, Li Z, Yan Z, Jiao W, Jiao W, Wang Y, Ji C, Wang X, He Y
J Transl Med · 2026 Jul · PMID 42400032 · Full text
BACKGROUND: Metabolic reprogramming underpins the acquisition of radioresistance in esophageal squamous cell carcinoma (ESCC); however, the specific bioenergetic vulnerabilities and direct pharmacological targets remain...
BACKGROUND: Metabolic reprogramming underpins the acquisition of radioresistance in esophageal squamous cell carcinoma (ESCC); however, the specific bioenergetic vulnerabilities and direct pharmacological targets remain to be fully elucidated. This study defines a distinct metabolic phenotype conferring radioresistance and evaluates the natural alkaloid Cepharanthine (CEP) as a mechanism-driven radiosensitizer. METHODS: Matched clinical cohorts of radiosensitive and radioresistant ESCC patients were analyzed using untargeted and targeted metabolomics. Bioenergetic profiling (ECAR/OCR) was performed on established isogenic radioresistant cells. The mechanistic interactions between CEP and its target were mapped via network pharmacology, surface plasmon resonance (SPR), cellular thermal shift assays (CETSA), ubiquitin-proteasomal degradation assays, and Q347A site-directed mutagenesis. In vivo efficacy was validated across human cell-derived xenografts (CDX) and immunocompetent syngeneic (AKR/C57BL/6) mouse models. RESULTS: Clinical multi-omics revealed a "metabolic duality" in radioresistant ESCC, characterized by the concurrent hyperactivation of glycolysis and oxidative phosphorylation (OXPHOS). CEP administration disrupted this metabolic network, significantly sensitizing ESCC cells to irradiation [Dose-modifying factor at 37% survival (DMF) > 1]. Mechanistically, CEP directly engages the kinase domain of p70S6K-a structural interaction dependent on the Q347 residue-and triggers its ubiquitin-proteasomal degradation. This targeted clearance disrupts the upstream PI3K/Akt/mTOR survival axis. Genetic overexpression of wild-type p70S6K, but not the Q347A mutant, rescued the dual hypermetabolic phenotype and reinstated radioresistance. Clinically, elevated p70S6K expression correlated with poor disease-free survival and therapeutic failure. In vivo, CEP synergized with radiotherapy to suppress tumor kinetics in both CDX and syngeneic models, while concurrently enhancing CD8 T cell infiltration in the immunocompetent microenvironment, with no observable systemic toxicity. CONCLUSIONS: Radioresistant ESCC relies on a dual hypermetabolic state driven by the PI3K/Akt/mTOR/p70S6K cascade. CEP overcomes this radioresistance by physically binding to and degrading p70S6K, thereby inducing bioenergetic exhaustion and reshaping the anti-tumor microenvironment. These findings provide a solid mechanistic rationale for translating CEP into clinical radiotherapeutic regimens.
Cellular crosstalk and signaling networks in the rheumatoid arthritis synovial microenvironment.
Feng M, Chen H, Liao L … +5 more , Huang D, Shen J, Xiao L, Lu Q, Xie P
J Transl Med · 2026 Jul · PMID 42400001 · Full text
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive cartilage and bone destruction. Within the RA synovial microenvironment, resident synovi...
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive cartilage and bone destruction. Within the RA synovial microenvironment, resident synoviocytes, mesenchymal stem cells, fibroblasts, adipocytes, vascular-associated cells, and diverse immune cell populations form a dynamic interaction network through direct contact and paracrine mediators, including cytokines, chemokines, complement components, and extracellular vesicles. This review summarizes how these cellular interactions drive RA along a pathological continuum from early autoimmune initiation, through middle-stage inflammatory amplification and synovial hyperplasia, to late fibrosis, pannus formation, dysregulated bone remodeling, and irreversible structural damage. Particular emphasis is placed on the dynamic balance between pathogenic cellular circuits and immunoregulatory programs within the synovial microenvironment, which helps determine whether the joint remains in an inflammatory-active state, re-enters a remission-associated and relatively rebalanced state, or progresses toward remission failure and structural injury. We further discuss the major signaling pathways that mediate these interactions, especially NF-κB, MAPK, JAK-STAT, TGF-β/Smad, and Wnt/β-catenin signaling, highlighting how pathway crosstalk contributes to inflammatory persistence, loss of tissue plasticity, and progressive remodeling. Importantly, because key cellular subsets and interaction programs may still retain partial plasticity during the early and middle stages of disease, stage-adapted modulation of these pathogenic networks may help restore synovial immune homeostasis, promote remission, delay disease progression, and reduce irreversible tissue damage. A deeper understanding of stage-specific cellular programs and interaction networks may therefore provide a stronger theoretical basis for mechanism-informed precision therapies in RA.
Pilot spatial transcriptomics of dental pulpitis suggests immune-fibroblast profiling linked to reversibility.
Zaky S, Rajasundaram D, Lee AL … +7 more , Summersgill K, Levine S, Boulos O, Dunn S, Intini G, Sfeir C, Silva R
J Transl Med · 2026 Jul · PMID 42399991 · Full text
BACKGROUND: Diagnostic protocols in endodontics rely heavily on subjective pain assessments and sensibility testing, which may not reflect the underlying histopathological and molecular state of the dental pulp. This lim...
BACKGROUND: Diagnostic protocols in endodontics rely heavily on subjective pain assessments and sensibility testing, which may not reflect the underlying histopathological and molecular state of the dental pulp. This limitation can contribute to discordance between clinical diagnosis (reversible (RP) vs. irreversible (IP) pulpitis) and tissue biology, potentially leading to overtreatment of teeth that might respond to conservative, pulp-preserving approaches. Spatial transcriptomics offers an opportunity to explore the cellular and molecular heterogeneity of inflamed pulp in a spatially resolved manner. OBJECTIVE: To explore spatial transcriptomic heterogeneity across healthy pulp and clinically diagnosed reversible and irreversible pulpitis samples, and to identify candidate immune-fibroblast features associated with an RP-like versus IP-like molecular profile. METHODS: Spatial transcriptomics (Visium-CytAssist-V2) was performed on four human dental pulp tissues (n = 4). Cell deconvolution, differential gene expression, and pathway/module scoring were used to characterize spatial gene-expression patterns in healthy pulp and in clinically diagnosed RP and IP, with attention to coronal regions adjacent to carious lesions. RESULTS: Despite meeting clinical criteria for symptomatic IP, an IP sample exhibited spatial transcriptomic features more similar to the RP sample, including a comparable immune-to-fibroblast ratio and similar activation patterns of TLR4 and neuroinflammation-related pathways. Across clinically diagnosed IP samples, genes involved in immune signaling, cell migration, and tissue remodeling were differentially expressed. Increased PTN and CXCL14, together with lower expression of ENG (CD105), SELE, COL4A1, CXCL1, and CXCL13, emerged as candidate markers associated with an RP-like molecular profile in this pilot dataset. Overall, spatial patterns suggested that immune-fibroblast composition and interactions may contribute to transcriptomic differences across samples. CONCLUSION: In this hypothesis-generating pilot study, spatial transcriptomics highlighted substantial molecular heterogeneity within clinically diagnosed pulpitis and demonstrated that clinical labels may not consistently align with transcriptomic status. Candidate immune-fibroblast features identified here warrant validation in larger cohorts to determine the utility of spatial transcriptomics for refining pulpitis classification and guiding pulp-preserving treatment decisions.
Beyond semen analysis: in men with normal semen parameters telomere attrition and oxidative imbalance distinguish those fertile from those with infertility.
Rocca MS, Di Nisio A, Cosci I … +5 more , Assalve G, Grande G, Graziani A, Ferramosca A, Ferlin A
J Transl Med · 2026 Jul · PMID 42399968 · Full text
BACKGROUND: Standard semen analysis has little prognostic value in distinguishing fertile from infertile men. Furthermore, in men with semen parameters within the reference ranges, it cannot distinguish fertile men from...
BACKGROUND: Standard semen analysis has little prognostic value in distinguishing fertile from infertile men. Furthermore, in men with semen parameters within the reference ranges, it cannot distinguish fertile men from infertile men, i.e. partners of couples with idiopathic infertility. Oxidative stress, mitochondrial dysfunction, sperm telomere shortening, and DNA fragmentation have been proposed as contributors to impaired male fertility. However, these biomarkers have not been evaluated as a whole in subjects with normal semen parameters, partners of fertile and infertile couples. OBJECTIVE: To characterise a multidimensional panel of sperm biomarkers-including sperm telomere length (STL), mitochondrial DNA copy number (mtDNAcn), reactive oxygen species (ROS), lipid peroxidation (LP), sperm chromatin dispersion (SCD), and respiratory control ratio (RCR)-and to identify whether these parameters might discriminate, in men with normal semen parameters, infertile men from fertile controls. METHODS: A total of 150 men with semen parameters within the normal ranges were enrolled: 47 male partners of couples with idiopathic infertility and 103 fertile controls. STL and mtDNAcn were quantified by qPCR; ROS were assessed using OxiSperm®II with semiquantitative imaging; LP was measured spectrophotometrically in seminal plasma; SCD was used to determine DNA fragmentation; and mitochondrial function was evaluated by oxygen consumption and RCR. Correlations between biomarkers and semen parameters were analysed using Pearson or Spearman coefficients, and intergroup comparisons were adjusted for age. RESULTS: Semen parameters did not differ significantly between male partners of fertile and infertile couples. compared to men of fertile couples, men of infertile couples exhibited significantly shorter STL (0.57 ± 0.59 vs 1.21 ± 1.13, p_adj = 0.001) and higher oxidative stress, with both ROS (8300.9 ± 4214.8 vs 6555.3 ± 3394.3, p_adj = 0.027) and LP (88.33 ± 55.50 vs 40.29 ± 46.98, p_adj < 0.001) markedly elevated. mtDNAcn, SCD, and RCR showed no difference between the groups. Across the entire cohort, STL correlated negatively with ROS and LP and positively with RCR. ROS correlated negatively with total sperm count, motility and RCR, and positively with LP. LP displayed the strongest pattern of associations, correlating negatively with concentration, total count, motility, STL and RCR, and positively with age and volume. CONCLUSIONS: Among men with normal semen analysis, partners of couples with idiopathic infertility exhibit a distinct sperm molecular profile characterised by telomere shortening and oxidative imbalance. STL, ROS and LP emerged as age-independent biomarkers associated with infertility status and showed promising discriminatory ability in this cohort, supporting their integration as second-level tests to complement routine semen analysis in cases of normozoospermia.
Dual-block HER2 assessment reveals clinically relevant intratumoral heterogeneity in gynecologic cancers: a single-center landscape analysis.
Zhou X, Gao J, Cui L … +10 more , Li H, Ge H, Yu L, Lv J, Zuo K, Tian T, Wang Y, Sun H, Cheng Y, Bi R
J Transl Med · 2026 Jul · PMID 42399958 · Full text
BACKGROUND: Gynecologic cancers remain a substantial clinical challenge, particularly in advanced stages, where treatment options are often associated with limited efficacy and poor prognosis. Given the emerging success...
BACKGROUND: Gynecologic cancers remain a substantial clinical challenge, particularly in advanced stages, where treatment options are often associated with limited efficacy and poor prognosis. Given the emerging success of HER2-targeted antibody-drug conjugates (ADCs) across solid tumors, accurate evaluation of HER2 status is essential. This study investigated intratumoral HER2 heterogeneity in gynecologic cancers to refine detection accuracy and improve patient stratification for targeted therapy. METHODS: A retrospective cohort of 416 patients with gynecologic malignancies was analyzed using immunohistochemistry (IHC) testing on separate dual formalin-fixed paraffin-embedded (FFPE) tumor blocks. HER2 expression was scored according to ASCO/CAP gastric criteria, and heterogeneity was defined as discordant IHC scores across blocks. Statistical analyses were performed using McNemar's test, and clinical predictors of discordance were identified through multivariate logistic regression. RESULTS: Across all tumors, HER2 IHC scores were distributed as 0 (49.5%), 1+ (33.9%), 2+ (15.6%), and 3+ (1.0%). HER2 overexpression was most frequent in uterine serous carcinoma, uterine endometrioid carcinoma, and ovarian clear cell carcinoma in our cohort. Intratumoral discordance was observed in 20.7% of cases, with the highest rates in uterine (23.9%, 21/88), ovarian (21.4%, 39/182), and cervical (18.2%, 26/143) tumors. Dual-block assessment revealed that most discrepancies resulted from incremental shifts in HER2 expression, primarily from 0 to 1 + or 1 + to 2+. This approach reclassified 13.5% of tumors originally reported as HER2-0 to HER2 expression. CONCLUSION: Intratumoral HER2 heterogeneity is common in gynecologic cancers and frequently results in underestimation of HER2 expression when single-block assessment is used. Dual-block evaluation improves detection sensitivity and may refine patient selection for HER2-targeted antibody-drug conjugates.
Positive TAZ-TDG feedback loop drives proneural-to-mesenchymal transition to promote glioblastoma progression.
Yu W, Xie J, Peng L … +7 more , Cai S, Gui S, Wang D, Tao Z, Xiao J, Cheng Z, Luo H
J Transl Med · 2026 Jul · PMID 42399932 · Full text
BACKGROUND: Glioblastoma multiforme (GBM) is the most prevalent malignant tumor of the central nervous system, featuring high heterogeneity and invasiveness. Proneural-mesenchymal transition (PMT) has garnered extensive...
BACKGROUND: Glioblastoma multiforme (GBM) is the most prevalent malignant tumor of the central nervous system, featuring high heterogeneity and invasiveness. Proneural-mesenchymal transition (PMT) has garnered extensive attention as a crucial driving mechanism for glioblastoma invasion and progression; however, its molecular regulatory network remains ill-defined. METHODS: The expression and prognostic significance of TAZ were analyzed using bioinformatics tools. The function of TAZ was evaluated using in vitro and in vivo experiments. MeDIP and McrBC analyses were used to investigate the effect of TDG on methylation levels in the WWTR1 promoter region. ChIP-qPCR and Luciferase reporter assays were used to evaluate the binding affinity of TEAD4 to the TDG promoter. RESULTS: Aberrantly expressed TAZ promotes PMT in GBM cells. Mechanistically, the high expression of TAZ is caused by thymine DNA glycosylase (TDG), which maintains the low methylation state of its promoter region. TDG is transcriptionally regulated by TAZ-TEAD4, forming a TAZ-TDG positive feedback loop that promotes PMT. Importantly, we confirmed the significant inhibitory effect of dual targeting of TAZ and TDG, both in vitro and in vivo. CONCLUSION: Our data strongly indicate that the self-amplifying TDG-TAZ loop represents a previously unrecognized key participant in the progression of glioblastoma (GBM) via PMT, suggesting that TAZ and TDG may serve as potential therapeutic targets for GBM.
Immuno-metabolic biomarkers for 90-day prognostication after acute ischemic stroke: a classically solved QUBO-COPE modeling and biological contextualization study.
Tan H, Zhao L, Zhang J … +5 more , Huang M, Tulapu A, Zhu C, Feng Q, Li Y
J Transl Med · 2026 Jul · PMID 42399908 · Full text
BACKGROUND & OBJECTIVE: Early and accessible prognostication after acute ischemic stroke (AIS) is critical for risk stratification, yet translating systemic immuno-metabolic responses into bedside tools remains challengi...
BACKGROUND & OBJECTIVE: Early and accessible prognostication after acute ischemic stroke (AIS) is critical for risk stratification, yet translating systemic immuno-metabolic responses into bedside tools remains challenging. This study aimed to develop and externally validate an interpretable prognostic framework based on routine immuno-metabolic biomarkers for predicting 90-day functional outcomes after AIS. METHODS: In this dual-center retrospective cohort study, consecutive AIS patients from two tertiary hospitals in the Huaibei Economic Zone were enrolled. The primary endpoint was unfavorable functional outcome at 90 days, defined as a modified Rankin Scale score ≥ 3. After feature selection via classically solved Quadratic Unconstrained Binary Optimization (QUBO) with simulated annealing, a CRITIC-Optimized Poly-Ensemble (COPE) model integrating six base learners was constructed. A Full Model (including cellular population data) and a Core Model (excluding cellular population data) were internally locked and then evaluated in a held-out external validation cohort. Model interpretation was performed using CRITIC-weighted SHapley Additive exPlanations. Supporting biological contextualization utilized Mendelian randomization, single-cell RNA sequencing, and unsupervised clustering. RESULTS: A total of 3,812 patients were included (3,093 in the development cohort, 719 in external validation, including 107 with an unfavorable outcome). The QUBO algorithm identified a 10-feature panel comprising neurological severity, inflammatory, and metabolic indices. In external validation, the Full COPE Model achieved an area under the receiver operating characteristic curve of 0.860 (95% CI = 0.815-0.898), a Brier score of 0.118 (95% CI = 0.106-0.130), a specificity of 0.931, and a positive predictive value of 0.592. The Core Model retained comparable discrimination (AUC = 0.870). SHAP analysis revealed that admission neurological severity and inflammatory burden dominated predictions, and unsupervised clustering identified two reproducible sub-phenotypes with divergent outcomes. Mendelian randomization and transcriptomic data provided supportive biological context linking neuroinflammatory signals to prognosis. CONCLUSION: The framework offers an interpretable, laboratory-based prognostic tool for 90-day AIS outcomes by integrating routine immuno-metabolic biomarkers. Its balanced performance and clinical accessibility support potential utility in risk stratification, though prospective multicenter validation across diverse populations is required before clinical implementation.
Improving pancreatic adenocarcinoma prognosis models through ligand receptor interactions and histopathological integration.
Liu K, Tan Z, Tang Y … +2 more , Lv Y, Bu Y
J Transl Med · 2026 Jul · PMID 42399741 · Full text
BACKGROUND: Pancreatic adenocarcinoma (PAAD) has an extremely poor prognosis, and existing prognostic markers fail to fully capture the complex heterogeneity of the tumor microenvironment. This study aimed to integrate l...
BACKGROUND: Pancreatic adenocarcinoma (PAAD) has an extremely poor prognosis, and existing prognostic markers fail to fully capture the complex heterogeneity of the tumor microenvironment. This study aimed to integrate ligand-receptor (L-R) interactions, multi-omics data, and deep learning-based pathological images to construct an interpretable multimodal prognostic model and to elucidate the mechanisms underlying the cancer-associated fibroblast (CAF) microenvironment. METHODS: Significant L-R interactions were identified using BulkSignalR, followed by sequential Cox, least absolute shrinkage and selection operator (LASSO)-Cox, and random survival forest analyses to construct a prognostic model. Multi-omics profiling characterized molecular distinctions between risk groups. Key L-R pairs were evaluated with single-cell and spatial transcriptomics, validated in 39 paired clinical specimens via immunofluorescence, and linked to histopathological features through deep learning on hematoxylin and eosin-stained whole-slide images. RESULTS: We identified 236 significant L-R pairs, with 47 associated with prognosis. Integration of LASSO-Cox and random survival forest analyses yielded five key pairs: IL16_KCND1, PLAU_ITGA5, FN1_ITGB3, GNAS_ADCY1, and CALM1_PDE1B. The resulting risk model effectively stratified overall survival. The high-risk group showed higher tumor mutational burden, more frequent KRAS and TP53 mutations, and enrichment of extracellular matrix remodeling, transforming growth factor‑β signaling, and glycolysis pathways. Single-cell and spatial analyses revealed preferential enrichment of PLAU_ITGA5 and FN1_ITGB3 in fibroblast-related compartments. Immunofluorescence confirmed upregulation of these pairs in tumor tissues, and deep learning identified fibroblast-associated histopathological features with strong concordance to the risk axes. CONCLUSIONS: This study established the first multimodal prognostic framework integrating L-R interactions and histopathological features, revealing the central role of CAF-mediated L-R signaling in remodeling the PAAD microenvironment and providing a novel strategy for precise prognostic stratification and targeted microenvironmental therapy.
Pathology-derived clinical micro-architectural diagnostics of tumour-microbiome interactions in colorectal cancer.
Steele S, Mazengenya P, Chambuso R
J Transl Med · 2026 Jul · PMID 42399737 · Full text
BACKGROUND: Classical tumour pathology reports contain a largely untapped layer of information that may indicate tumour-microbial interactions. However, routine colorectal cancer pathology staging does not take into acco...
BACKGROUND: Classical tumour pathology reports contain a largely untapped layer of information that may indicate tumour-microbial interactions. However, routine colorectal cancer pathology staging does not take into account microbiome-associated tumour micro-architecture signatures, thus limiting insights into intratumoral microbial ecology, prognostic stratification and treatment-relevant microbial information. In this study, we analysed scanned USA pathology reports to quantify likely intratumoral microbiome-associated micro-architectural signatures. METHODS: We studied 1,978 TCGA colorectal cancer pathology reports from 1,249 colon adenocarcinomas, 559 rectal adenocarcinomas and 170 reports without a definitive anatomic site using rule-based natural language processing to extract microbiome-linked micro-architectural features. Barrier-disruption and invasion-access signatures were identified from the reports as microbiome-associated pathology micro-architecture signatures that occur with microbial-related necrosis, hypoxia, toxins, colonisation, persistence, metabolic activity and/or tumour interaction. We developed a z-scored composite index called Report-based Microbial Ecology Likelihood Score (RMELS) and used Kaplan-Meier log-rank analyses, multivariable Cox regression, Kruskal-Wallis tests and receiver operation characteristic curves with bootstrap confidence intervals. Proportional hazards assumptions were tested for statistical significance at two-sided p < 0.05. RESULTS: Microbiome-associated pathology micro-architectural signatures were highly prevalent in the pathology reports. Barrier-disruption features, including ulceration (41.1%) and mucin alteration (16.7%), were common and increased with tumour stage (Kruskal-Wallis p < 0.0001). Prominent invasion-access features included infiltrative growth (59.4%, 95% CI 57.2-61.5), lymphovascular invasion (18.6%, 95% CI 17.0-20.4) and perineural invasion (22.9%, 95% CI 21.1-24.8). All showed heterogeneous, non-monotonic distributions across pathologic stages, indicating activation of microbial injury and invasion programmes. Integration of these features into our signature score, ordered tumours along a continuous microbiome-permissiveness gradient independent of pathological stage. With limited information, our signature score discriminated early (T1) from advanced (T4) disease more effectively than barrier or invasion features alone (AUC = 0.66, 95% CI 0.58-0.74, p < 0.0001). Right-sided colonic tumours exhibited significantly higher scores than left-sided colonic and rectal tumours (FDR q < 0.001), aligning with known microbial biogeography. In multivariable Cox models adjusted for pathological stage, our signature score RMELS showed modest but directionally consistent association with overall and progression-free survival, capturing microbiology-relevant risk not resolved by pathological staging. CONCLUSIONS: Routine classical colorectal cancer pathology reports contain intratumoral microbiome-associated pathology micro-architectural signatures. Quantifying these exploratory tumour-microbial signatures using digital pathology will enable scalable, microbiology-informed risk stratification and prognostic modelling to complement the current pathological staging.
Association between light exposure patterns and multidimensional health outcomes in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: findings from an observational cross-sectional cohort study.
Cambras T, Domingo JC, Sanmartín-Sentañes R … +2 more , Alegre-Martín J, Castro-Marrero J
J Transl Med · 2026 Jul · PMID 42399727 · Full text
BACKGROUND: Light is a major environmental factor regulating circadian rhythms, sleep- wake cycles, and mood-related behaviors. Patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often experience c...
BACKGROUND: Light is a major environmental factor regulating circadian rhythms, sleep- wake cycles, and mood-related behaviors. Patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often experience circadian disruption and poor sleep quality, which severely compromise their quality of life; however, the relationship between light exposure and illness severity remains largely unknown. METHODS: An observational cross-sectional cohort secondary study used collected data from 100 ME/CFS patients and 56 healthy controls to explore the impact of spontaneous light exposure on multidimensional health status and circulating biochemical parameters. Demographic and clinical features were assessed using validated patient-reported outcome measures. Light intensity, wrist temperature, and physical activity were continuously monitored at home over one week using wrist-worn actigraphy. Light intensity during predefined intervals and rhythmic variables of light cycle were calculated. Principal component analysis (PCA) was applied to reduce dimensionality of light variables. Multivariable analysis was performed adjusting for age, sex, body mass index, and physical activity. RESULTS: Following PCA of the light patterns, two components emerged across groups with high consistency: PC1 (explaining 61.7% of the total variance) reflected higher daytime light and rhythm stability, and PC2 (explaining 16.1%) represented nocturnal/early-morning light and rhythm instability. In ME/CFS patients, light variables were more extensively associated with clinical outcomes measures (FIS-40, PSQI and SF-36) than in healthy controls (all p < 0.05). Furthermore, PC2 was associated with higher levels of VCAM-1 and triglycerides, and lower serotonin concentrations (all p < 0.05). Four distinct light patterns were identified based on PCA scores: nocturnal light, healthy, adverse, and low diurnal light. ME/CFS patients exhibiting the healthy light pattern showed significantly lower fatigue, fewer sleep complaints, reduced autonomic dysfunction, and higher quality of life compared to those with the adverse light pattern (all p < 0.05). No significant differences were observed among healthy controls. CONCLUSIONS: Light exposure patterns show distinct associations with symptom variability in ME/CFS compared to healthy controls. More stable daytime light appears to relate to better symptom profiles, whereas irregular exposure and nocturnal light are linked to poorer health outcomes. Although causality cannot be inferred, these findings highlight light exposure as a potentially modifiable, non-invasive target for behavioral interventions aimed at improving the quality of life in ME/CFS, representing a promising emerging for future translational research.
The mitochondrial protease, LonP1, is a potential cardioprotective target for attenuating doxorubicin-induced cardiomyocyte death.
O'Dwyer KP, Bauer PE, Dziadowicz SA … +14 more , Pal S, Eminhizer M, Bandaru A, Myers E, Awad M, Murshid A, Santer M, Wang L, Hu G, Brundage K, DeVallance E, Hollander JM, Patel B, Venkatesh S
J Transl Med · 2026 Jul · PMID 42393712 · Full text
BACKGROUND: Doxorubicin (DOX), a first-line chemotherapeutic agent, has been linked to severe off-target cardiotoxicity in the clinic. Previous works suggest that mitochondria are key mediators of this cardiotoxicity. Le...
BACKGROUND: Doxorubicin (DOX), a first-line chemotherapeutic agent, has been linked to severe off-target cardiotoxicity in the clinic. Previous works suggest that mitochondria are key mediators of this cardiotoxicity. Leakage of mitochondrial contents after DOX treatment, including mitochondrial DNA (mtDNA), is thought to activate apoptotic and inflammatory signaling pathways implicated in cardiomyocyte cell death. Whether the master mitochondrial protease, LonP1, can dampen these pathways and improve cardiomyocyte viability following DOX treatment remains unknown. METHODS: Human cardiac cells (AC-16) and primary (1°) human cardiomyocytes were subjected to DOX treatment, followed by bulk RNA-Seq, RT-qPCR, qPCR, and immunoblotting to assess apoptotic signaling, inflammatory signaling, mtDNA release, and LonP1 expression, respectively. Lentivirus transduction of AC-16 cells was used to generate both knockdown (KD) and overexpression (OE) LonP1 cell lines to determine the effects of altered LonP1 levels on DOX-induced apoptosis and mtDNA release. Further, levels of mitochondrial DNA (mtDNA) were measured using qPCR from serum samples obtained from patients undergoing DOX treatment to assess the clinical relevance of released mtDNA as a potential biomarker for the development of DOX cardiotoxicity. RESULTS: DOX treatment of AC-16 cells, as well as 1° human cardiomyocytes, upregulated both apoptotic and inflammatory signaling in both cell models. Increased LonP1 levels were also observed under DOX treatment in AC-16 cells and 1° human cardiomyocytes. Likewise, DOX increased mtDNA release from both cell lines, both prior to, and as a sequel to cell death. Decreasing LonP1 levels exacerbated DOX-mediated apoptotic signaling and mtDNA release, whereas overexpression of LonP1 attenuated these effects. Furthermore, DOX treatment in cancer patients increases plasma mtDNA levels. CONCLUSIONS: These findings suggest LonP1 plays a protective role in the heart following DOX treatment, supporting LonP1 as a potential novel therapeutic target for prevention of DOX cardiotoxicity. Patterns of mtDNA release within patients undergoing DOX treatment also highlight the potential of mtDNA as a potential biomarker and target for prevention of DOX cardiotoxicity, justifying the need for more extensive, prospectively monitored cohort studies to expand upon these findings and statistically model mtDNA release patterns.
Enhancing the positive predictive value of early-stage ovarian cancer detection using a two-step machine learning framework.
Mikami M, Tanabe K, Nagaki S … +21 more , Nogami Y, Imanishi T, Ikeda M, Yoshida H, Hasegawa M, Shimada M, Shigeta S, Ishikawa M, Kato M, Saji H, Kobayashi Y, Morisada T, Suzuki N, Ohhara T, Tanaka K, Murakami I, Katahira T, Hayashi C, Grubbs BH, Yamagami W, Matsuo K
J Transl Med · 2026 Jul · PMID 42387536 · Full text
BACKGROUND: Early detection of epithelial ovarian cancer (EOC) remains a major clinical challenge. Although serum tumor markers are widely used for detection, their diagnostic performance remains limited. We previously d...
BACKGROUND: Early detection of epithelial ovarian cancer (EOC) remains a major clinical challenge. Although serum tumor markers are widely used for detection, their diagnostic performance remains limited. We previously developed a comprehensive serum glycopeptide spectrum analysis (CSGSA) approach that integrates tumor marker measurements and enriched glycopeptides (EGPs) using convolutional neural networks. In this study, we evaluated whether a two-step LightGBM framework incorporating cancer antigen 125 (CA125), human epididymis protein 4 (HE4), cancer antigen 72 - 4 (CA72-4), and EGPs could improve the diagnostic specificity and projected positive predictive value (PPV) for EOC detection compared with conventional biomarker-based approaches. METHODS: The study included 553 patients with EOC and 1,144 non-EOC controls (healthy individuals or patients with benign conditions). Serum levels of CA125, HE4, and CA72-4 were measured along with 1,712 EGPs. Diagnostic models were developed using machine learning algorithms and evaluated for accuracy, area under the receiver operating characteristic curve (ROC-AUC), PPV, and negative predictive value (NPV). RESULTS: The highest diagnostic performance was achieved using a two-step classification framework. First, patients were stratified into high-, intermediate-, and low-risk groups based on tumor markers and age. Second, the intermediate-risk group was reclassified using a model incorporating EGP-derived features. Among the evaluated algorithms, LightGBM achieved the best performance, yielding a prevalence-adjusted (projected) PPV of 18.7% and an NPV of 99.99%. At a predefined specificity of 99.5%, the corresponding sensitivity was 65%. CONCLUSIONS: The CSGSA method combined with a two-step LightGBM framework demonstrated promising diagnostic performance in an internally validated cohort, with improved specificity and prevalence-adjusted PPV compared with conventional biomarker-based approaches. However, prospective external validation in independent populations is required before clinical implementation or generalizability can be established.
CTSS regulates macrophage lipid metabolic reprogramming and white matter repair after intracerebral hemorrhage.
Yu X, Huang H, Mao D … +16 more , Wu J, Pan J, Kuang Y, Wu Y, Chen H, Fan L, Zheng Y, Zhou J, Jiang S, Wu X, Zhou H, Yan W, Zheng H, Chen J, Chen G, Gu C
J Transl Med · 2026 Jun · PMID 42381008 · Full text
BACKGROUND: Intracerebral hemorrhage (ICH) causes secondary white matter injury, which contributes substantially to long-term neurological disability. Although macrophages accumulate in the perihematomal region and parti...
BACKGROUND: Intracerebral hemorrhage (ICH) causes secondary white matter injury, which contributes substantially to long-term neurological disability. Although macrophages accumulate in the perihematomal region and participate in tissue remodeling after ICH, the molecular programs that link macrophage responses to white matter repair remain poorly understood, and no current strategies specifically target macrophage‑mediated white matter restoration. Cathepsin S (CTSS), a lysosomal cysteine protease involved in immune regulation and tissue remodeling, is strongly induced after brain injury; however, its role in post‑ICH white matter pathology has not been defined. METHODS: A collagenase-induced mouse model of intracerebral hemorrhage (ICH) was established, followed by pharmacological inhibition of Cathepsin S (CTSS) using LY3000328. Single-cell RNA sequencing was performed on perihematomal tissues from Vehicle- and CTSS inhibitor-treated mice to explore CTSS-responsive cell populations and transcriptional programs. Macrophage lipid handling was assessed using flow cytometry, immunofluorescence, and fluorescent myelin debris-based uptake and lipid-transfer assays. A bone marrow-derived macrophage (BMDM)-oligodendrocyte precursor cell (OPC) co-culture system was used to determine whether CTSS inhibition alters macrophage-derived lipid support for OPC differentiation. The LXR agonist GW3965 was applied as a rescue intervention. White matter repair and neurological recovery were evaluated by myelin-associated protein analysis, immunofluorescence, behavioral testing, and transmission electron microscopy. RESULTS: Single-cell analysis identified infiltrating macrophages, particularly adaptive lipid-associated macrophages (aLAMs), as a major CTSS-expressing population after ICH, displaying a transcriptional state related to lipid metabolism and tissue repair. CTSS inhibition attenuated this lipid-associated macrophage program and reduced ApoE, ABCA1, and ABCG1 expression. Mechanistically, CTSS inhibition reduced Npc1/Npc2 expression and disrupted lysosomal cholesterol trafficking, leading to lysosomal cholesterol retention. These changes suggest impaired Npc1/Npc2-associated cholesterol mobilization and attenuation of the LXR-associated macrophage lipid efflux program. In BMDM-OPC co-cultures, CTSS inhibition reduced the transfer of fluorescent macrophage-processed myelin-derived lipids to OPCs and limited OPC differentiation, whereas GW3965 partially restored Npc1/Npc2 expression, macrophage-derived lipid support, and OPC differentiation. Consistently, in vivo CTSS inhibition reduced MBP expression and MBP⁺ axonal wrapping, increased g-ratio values, aggravated myelin ultrastructural abnormalities, and delayed neurological recovery after ICH. CONCLUSIONS: CTSS in macrophages supports white matter repair after ICH by maintaining lysosomal cholesterol trafficking and macrophage lipid efflux. CTSS inhibition limits macrophage-derived lipid support for OPCs and impairs remyelination, whereas LXR activation partially restores these reparative responses.
High glucose promotes aggressive progression of PR-negative endometrial cancer via CD146.
Li W, Mao W, Zhang Q … +5 more , Zeng X, Ke D, Wang Y, Tan J, Yi C
J Transl Med · 2026 Jun · PMID 42380907 · Full text
BACKGROUND: Hyperglycemia is a risk factor for endometrial cancer (EC) progression, especially in the high-risk progesterone receptor‑negative (PR‑) subtype. A high‑glucose environment can induce epithelial‑mesenchymal t...
BACKGROUND: Hyperglycemia is a risk factor for endometrial cancer (EC) progression, especially in the high-risk progesterone receptor‑negative (PR‑) subtype. A high‑glucose environment can induce epithelial‑mesenchymal transition (EMT) to promote tumor aggressiveness. However, the regulatory mechanism of EMT‑related molecules like CD146 in PR‑ EC under hyperglycemic conditions remains unclear, and its therapeutic potential is undefined. This study aimed to elucidate the role and mechanism of CD146 in this context. METHODS: This study integrated bioinformatics, cellular experiments, and clinical validation. Bioinformatics analysis of the TCGA database assessed CD146 expression in EC, focusing on the PR-low subgroup to evaluate its associations with prognosis, EMT, and glucose metabolism. A high-glucose-induced PR-negative JEC cell model was established for in vitro validation. Gene knockdown and overexpression assays elucidated CD146's functional role in high-glucose-driven EMT, invasion, and metastasis. Clinical tissue validation was performed using immunohistochemistry (IHC). Finally, drug sensitivity screening combined with molecular docking was employed to identify potential therapeutic compounds targeting CD146. RESULTS: The results showed that CD146 was markedly downregulated in endometrial cancer (EC) tissues, an effect exacerbated in PR‑negative EC cells under high‑glucose conditions. Low CD146 expression correlated with poor prognosis in PR‑negative EC patients. Mechanistically, CD146 suppression activated epithelial-mesenchymal transition (EMT), accompanied by enhanced cell migration and invasion. Functional studies demonstrated that CD146 knockout accelerated high‑glucose-induced EMT and malignant progression, whereas its overexpression attenuated this process. Immunohistochemical analysis confirmed significantly lower CD146 expression in EC tissues. Furthermore, drug sensitivity screening and molecular docking revealed that CD146‑low EC cells exhibit heightened sensitivity to the TGF‑β pathway inhibitor SB505124, suggesting its pharmacological inhibition as a promising therapeutic strategy for this EC subtype. CONCLUSION: In summary, high glucose may promote the progression of PR-negative EC by downregulating CD146 expression and inducing EMT, suggesting that CD146 represents a promising therapeutic target for precision treatment strategies in EC, particularly in patients with concurrent glucose metabolism dysregulation.
Multiphasic blood transcriptomic signatures of radioprotection by BIO 300, a synthetic genistein nanosuspension, in a nonhuman primate model of acute radiation syndrome.
Nanoth Vellichirammal N, Wise SY, Fatanmi OO … +5 more , Mingus RC, Carpenter AD, Petrus SA, Kaytor MD, Singh VK
J Transl Med · 2026 Jun · PMID 42380874 · Full text
BACKGROUND: Prophylactic radioprotectors for pre-exposure administration are notably absent, creating a critical gap in radiation emergency preparedness and ARS management. BIO 300, a wet-nanomilled formulation of synthe...
BACKGROUND: Prophylactic radioprotectors for pre-exposure administration are notably absent, creating a critical gap in radiation emergency preparedness and ARS management. BIO 300, a wet-nanomilled formulation of synthetic genistein, is in advanced development as a prophylactic radioprotector with demonstrated survival benefits in murine and nonhuman primate (NHP) models when administered prior to lethal radiation exposure. Longitudinal transcriptomic analysis enables characterization of the molecular mechanisms underlying radioprotective drug action and supports development of potential blood-based monitoring tools for clinical translation. We performed longitudinal blood transcriptome profiling in NHPs receiving 5.8 Gy total-body irradiation to characterize BIO 300's radioprotective mechanisms and identify candidate transcriptional biomarkers of drug activity. RESULTS: BIO 300 demonstrated multiphasic changes in the transcriptome spanning acute cellular preservation (Days 7-10), immune reconstitution (Day 21), and sustained recovery (Day 60), with peak protection spanning 745-865 genes at Days 7-10 and sustained late-phase protection of 558 genes at Day 60. Differential expression analysis revealed four distinct drug-related molecular mechanisms: direct cellular protection, active damage reversal, drug-specific therapeutic responses, and stress attenuation. A core set of 39 genes showing sustained or consistent differential expression was identified, of which 20 carry conventional gene symbols and are functionally interpretable; LOC-designated genes are excluded from functional annotation. Notable annotated genes include SOX2, AKAP11, TIMD4, BTNL10, VNN2, and CLEC1A, representing candidate exploratory transcriptional markers consistent with hematopoietic recovery and immune surveillance. Temporally orchestrated pathway signatures include neuroimmune modulation (Day 7), hemostatic recovery (Day 14), and immunometabolic reconstitution (Day 21). CONCLUSIONS: Our results show that BIO 300 provides multiphasic radioprotection across acute, immune reconstitution, and sustained recovery phases through four distinct mechanisms. Longitudinal transcriptomic signatures identified in this study represent potential blood-based monitoring tools for therapeutic efficacy assessment toward the continued development of BIO 300.
Humanized biparatopic nanobody-based CAR-T cells overcome antigen-heterogeneity in multiple myeloma.
Zhou J, Wu K, Lei B … +8 more , Luo X, Shi F, Zhang Y, Kong X, Wang H, Zhou J, Guo H, He X
J Transl Med · 2026 Jun · PMID 42374531 · Full text
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) shows activity in multiple myeloma (MM), yet relapse remains common owing to heterogeneous BCMA expression and soluble...
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) shows activity in multiple myeloma (MM), yet relapse remains common owing to heterogeneous BCMA expression and soluble BCMA (sBCMA). Improving BCMA-directed CAR-T therapy requires persistence, enhanced antitumor activity, tolerance to low antigen density and resistance to sBCMA-mediated inhibition. METHODS: We identified anti-BCMA VHHs from a humanized phage display library, constructed monospecific and biparatopic CARs, and evaluated their function and optimal designs in preclinical models, including patient-derived MM cells and xenografts. RESULTS: Biparatopic Nab5822 CAR-T cells exhibited superior cytotoxicity and cytokine secretion (IL-2, IFN-γ, TNF-α) against antigen-heterogeneous MM cells in vitro, maintained activity under a supraphysiological sBCMA challenge at 120 ng/mL, and retained function under repeated exposure to clinically relevant sBCMA levels. Under repeated antigen challenge, Nab5822 preserved lysis, reduced exhaustion with an increased stem-cell memory T-cell compartment, and achieved durable tumor control in xenograft models without detectable toxicity. Mechanistic analyses indicated that the VHHs engage non-overlapping BCMA epitopes and promote improved immunological synapse organization together with coordinated proximal signaling, features that are not fully explained by equilibrium affinity alone and may contribute to sustained long-term T-cell function. CONCLUSIONS: Our findings support biparatopic CAR design as a strategy to tolerate low antigen density and resist sBCMA-mediated inhibition, providing a rationale for clinical evaluation of next-generation CAR T-cell therapies.
Acidosis-associated gene signature defines novel subtypes and dual-target therapeutic candidates in breast cancer.
Li Y, Wu D, Shi Z … +7 more , Luo Q, Deng W, Liu Q, Lu A, Chen W, Qin G, Guan D
J Transl Med · 2026 Jun · PMID 42374456 · Full text
BACKGROUND: Breast cancer remains the most common malignancy in women, and substantial heterogeneity in treatment response and prognosis persists despite multimodal therapies. The acidic tumor microenvironment (TME), dri...
BACKGROUND: Breast cancer remains the most common malignancy in women, and substantial heterogeneity in treatment response and prognosis persists despite multimodal therapies. The acidic tumor microenvironment (TME), driven by metabolic reprogramming and lactate accumulation, is recognized as a key driver of tumor adaptation, immune evasion, and therapeutic resistance. However, the genomic and transcriptomic patterns of acidosis tolerance in human breast cancer, and their implications for subtype stratification and targeted therapy, remain poorly understood. METHODS: We integrated GEO datasets, sgRNA-seq data and breast cancer-associated genes to identified breast cancer acidosis tolerance genes (BCATGs). GO and KEGG enrichment analysis were used to define BCATGs function. We divided breast cancer patients into two subtypes based on BCATGs by consensus clustering. GSEA and GSVA were used to characterized the molecular mechanisms of BCATGs subtypes. CIBERSORT, ESTIMATE, IPS, and TIDE, and oncoPredict were applied to depict the immune microenvironment of BCATGs subtypes. A LASSO-Cox prognostic model was developed and validated, with clinical correlations assessed by Cox regression. Virtual screening against key prognostic genes employed AutoDock Vina, followed by molecular dynamics simulations and MM/PBSA binding energy calculations in GROMACS. RESULTS: Seventeen BCATGs were identified, predominantly enriched in mitotic regulation and cell cycle, with low mutation rates, predominant copy number gains and notable co-occurrence patterns. Consensus clustering revealed two subtypes: Subtype I and Subtype II. Subtype II exhibited marked activation of proliferative signatures and suppression of differentiation pathways, coupled with a pro-inflammatory yet immunosuppressive immune profile. Subtype II showed greater sensitivity to cell-cycle inhibitors, apoptosis inducers, and proteasome inhibitors. A five-gene LASSO risk model (AURKA, CCNA2, CDC45, EXO1, KIF4A) demonstrated robust prognostic performance, particularly for disease-specific survival (1-year AUC 0.731), with CCNA2 and CDC45 retaining independent prognostic significance after multivariate adjustment. Virtual screening and molecular dynamics identified four lead compounds (SBC-115337, CDK2-IN-4, Bractoppin, Corylin) with stable binding to CCNA2 and CDC45. CONCLUSIONS: This study establishes a novel framework linking acidosis adaptation to breast cancer heterogeneity, identifying BCATGs-driven subtypes with distinct molecular, immunological, and pharmacological profiles. The prognostic model highlights CCNA2 and CDC45 as key drivers of adverse outcomes. These findings provide a foundation for patient stratification, risk assessment, and targeted therapy in breast cancer.
Mavacamten alleviates sepsis-induced acute respiratory distress syndrome by modulating the PI3K/AKT/autophagy axis: a spatial transcriptomic-guided investigation.
Chen H, He S, Chen L … +7 more , Zhang Y, Guo X, Lin Y, Ren X, Li W, Lin M, Shen Z
J Transl Med · 2026 Jun · PMID 42374449 · Full text
BACKGROUND: Sepsis-induced acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung condition with high mortality and no specific pharmacological treatments. The complex spatial heterogeneity of...
BACKGROUND: Sepsis-induced acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung condition with high mortality and no specific pharmacological treatments. The complex spatial heterogeneity of the lung during sepsis hinders the discovery of effective therapies. This study aimed to use spatial transcriptomics to map the septic lung's molecular landscape to identify and validate a novel therapeutic agent. METHODS: We performed spatial transcriptomics on lung tissues from mice subjected to cecal ligation and puncture (CLP) to model sepsis. A computational drug screen identified Mavacamten. In vitro, lipopolysaccharide-stimulated murine alveolar epithelial cells were used to assess Mavacamten's effects on inflammation and cell injury. In vivo, CLP mice received Mavacamten, and we assessed survival, lung function, pulmonary edema, histology, and inflammatory markers. The underlying mechanism was investigated by analyzing the PI3K/AKT/mTOR pathway and autophagy markers. Statistical analyses included ANOVA, t-tests, and Kaplan-Meier analysis. RESULTS: Spatial transcriptomics revealed distinct cellular clusters that were dramatically rearranged during sepsis. In vitro, Mavacamten significantly attenuated lipopolysaccharide-induced inflammation, cellular injury, and oxidative stress. In the CLP mouse model, Mavacamten treatment markedly improved 7-day survival, restored arterial oxygenation, reduced pulmonary edema, and lessened histological lung injury. Mavacamten also significantly lowered local and systemic pro-inflammatory cytokine levels. Mechanistically, Mavacamten reversed the sepsis-induced inhibition of autophagy and suppressed the activation of the PI3K/AKT/mTOR signaling pathway in lung tissues. CONCLUSIONS: Mavacamten confers robust protection against sepsis-induced ARDS in a preclinical model by mitigating inflammation and lung injury, leading to improved survival. Its therapeutic action is mediated by inhibiting the PI3K/AKT pathway and restoring protective autophagy. Mavacamten is a promising candidate for repurposing in the treatment of sepsis-induced ARDS.
microRNA-204 as a crucial cancer stem cell related miRNA inhibits stemness of gastric cancer by targeting CD44 and EPCAM.
Li D, Zhou R, Cheng Z … +5 more , Xu H, Zhang H, Li X, Cao L, Li F
J Transl Med · 2026 Jun · PMID 42374430 · Full text
BACKGROUND: Cancer stem cells (CSCs) and normal stem cells share key properties such as self-renewal and differentiation capacity, yet the microRNAs (miRNAs) that are differentially expressed between them remain poorly c...
BACKGROUND: Cancer stem cells (CSCs) and normal stem cells share key properties such as self-renewal and differentiation capacity, yet the microRNAs (miRNAs) that are differentially expressed between them remain poorly characterized. This study aimed to identify such miRNAs, with a focus on microRNA-204 (miR-204), and to investigate its functional role and regulatory mechanisms in gastric cancer. METHODS: Using miRNA microarray data from public databases (GEO and TCGA), we identified miR-204 as a stemness-related miRNA. Its expression was validated in clinical gastric cancer tissues and cell lines. Functional assays, including colony formation, Transwell, tumorsphere formation, and extreme limiting dilution analysis, were performed to assess the effects of miR-204 on proliferation, metastasis, and stemness. Luciferase reporter assays confirmed direct targeting of CD44 and EPCAM. The role of TP53 in miR-204 maturation was investigated using TP53-knockout mice and TP53 overexpression cell models. RESULTS: miR-204 was identified as a crucial miRNA, upregulated in normal stem cells but significantly downregulated in CSCs and multiple human cancers, including gastric cancer. Low miR-204 expression correlated with advanced TNM stage and poor overall survival in gastric cancer patients. Restoring miR-204 expression potently inhibited gastric cancer cell proliferation, metastasis, and stemness properties. Mechanistically, miR-204 directly targeted and suppressed the expression of two key CSC regulators, CD44 and EPCAM. Furthermore, we discovered that TP53 mutation is a major cause of miR-204 downregulation, and demonstrated that TP53 promotes the maturation of miR-204 rather than its primary transcription. CONCLUSIONS: Our study unveils miR-204 as a pivotal tumor suppressor that distinguishes CSCs from normal stem cells. It functions by targeting the CD44/EPCAM axis to inhibit gastric cancer stemness, a process governed by a novel TP53-miR-204 regulatory circuit. These findings position miR-204 as a promising prognostic biomarker and therapeutic target for eradicating CSCs in gastric cancer.
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