The Journal of Cell Communication and Signaling (JCCS) is dedicated to advancing understanding of how intracellular and extracellular signaling coordinate environmental sensing, gene regulation, and tissue homeostasis and how their dysregulation or misinterpretation contributes to disease. Reflecting on my first year as editor-in-chief, I am pleased to highlight the journal's continued progress and strategic development. Submissions, readership, and article diversity have grown steadily, driven by the commitment of authors, reviewers, editors, and publishing staff. JCCS remains selective yet inclusive in scope, emphasizing high-quality studies that illuminate signaling processes in health and disease. Ongoing initiatives to reduce decision times and enhance the expertise and global representation of our editorial and reviewer communities reinforce peer review as a rigorous collaborative enterprise. A key milestone ahead is the transition of JCCS manuscript handling to Wiley's Research Exchange (REX) platform, which integrates submission, integrity screening, and peer review within a unified system. This platform leverages artificial intelligence tools, metadata extraction, and ORCID integration to improve efficiency, transparency, and ethical oversight. Looking forward, JCCS aims to strengthen peer review, introduce special issues on emerging topics in cell communication, and foster greater international engagement to advance the field's scientific and collaborative frontiers.
Lung adenocarcinoma (LUAD) frequently harbors activating mutations in the epidermal growth factor receptor (EGFR), making EGFR tyrosine kinase inhibitors (EGFR-TKIs) a critical component of targeted therapy. Although third-generation EGFR-TKIs, such as Furmonertinib, have improved outcomes for patients with EGFR-mutant LUAD, drug resistance and tumor adaptation remain major challenges. The cellular and molecular mechanisms underlying response and adaptation to Furmonertinib, particularly within the tumor microenvironment (TME), are not fully understood. We performed single-cell RNA sequencing on tumor and paired paracancerous tissues from EGFR-positive LUAD patients before and after Furmonertinib treatment, integrating both public and in-house datasets. We systematically analyzed changes in cellular composition, gene expression profiles, pathway enrichment, and ligand-receptor-mediated cell-cell communication. Furmonertinib treatment led to a marked reduction in tumor cell proportion and profound remodeling of the TME. There was an increase in T cell infiltration, particularly CD4+ T cells, and a decrease in exhausted CD8+ T cells, indicating a shift toward a less immunosuppressive microenvironment. Cancer-associated fibroblasts and monocytes were also enriched post-treatment. Tumor cells exhibited increased EGFR expression, along with transcriptomic reprogramming characterized by upregulation of signaling, immune, and differentiation pathways, and downregulation of metabolic and protein synthesis genes. Cell-cell communication analysis revealed attenuation of immunosuppressive signaling (such as MIF axis) and enhancement of alternative ligand-receptor interactions, including LAMC1- and EGFR-related pathways. Our integrative single-cell analysis reveals that Furmonertinib therapy induces significant cellular and molecular changes in EGFR-positive LUAD, including TME remodeling, transcriptomic adaptation, and reprogramming of intercellular communication networks. These findings provide insight into the mechanisms of Furmonertinib response and resistance, and may inform strategies to optimize EGFR-TKI therapy.
The Joint Meeting commemorating the 25th anniversary of the International CCN Society (ICCNS) and the 5th anniversary of the Association for Research on Biosignaling and Communication (ARBIOCOM) will take place on December 13-17, 2025, in Nice, France. This multidisciplinary forum will bring together researchers in molecular and cellular biology, systems biology, translational medicine, and related fields to explore advances in intercellular communication and signal transduction. The program will include keynote lectures, thematic sessions, and attendee presentations spanning juxtacrine and paracrine interactions, extracellular matrix-mediated signaling with emphasis on CCN proteins, endocrine and neuroendocrine regulation, immune-modulatory circuits, extracellular vesicle biology, and systemic regulation by soluble factors. A special focus will address how dysregulated signaling drives cancer, musculoskeletal, cardiovascular, neurodegenerative, and developmental disorders. Sessions will encourage contributions using single-cell and spatial transcriptomics, dynamic proteomics, and systems-level approaches to map signaling dynamics in vivo. The meeting will also highlight pivotal role of the Journal of Cell Communication and Signaling (JCCS), the official ICCNS journal published by Wiley, as a leading platform for disseminating impactful research in biosignaling. This joint anniversary event will provide an international venue for advancing knowledge, fostering collaborations, and shaping the future of research in cell communication and signaling.
Neonatal necrotizing enterocolitis (NEC) continues to be the most severe gastrointestinal emergency affecting preterm infants, with reported mortality rates ranging from 20% to 30%. The absence of distinct early biomarkers results in delayed intervention and unfavorable outcomes, and the molecular mechanisms underlying the dysregulated immune response in NEC remain incompletely defined. We integrated five gene expression omnibus datasets (36 NEC cases and 34 controls) using weighted gene co-expression network analysis and systematically evaluated 113 machine learning algorithm combinations. The best-performing model (RF + XGBoost) identified candidate diagnostic genes, which were validated through independent bulk RNA-sequencing cohorts, single-cell RNA sequencing (11,308 intestinal cells), single-cell virtual gene knockout (scTenifoldKnk), and experimental models including mice and the intestinal epithelial cells cell line. Combinatorial in silico perturbation was further performed using Geneformer, and a ferroptosis gene panel was validated by qRT-polymerase chain reaction in the mouse NEC model. The RF + XGBoost model achieved high diagnostic accuracy (area under the curve = 0.979, 95% CI: 0.940-1.000). Three key biomarkers were identified: SLC26A3, CCL20, and CXCL5. Multi-platform validation showed consistent downregulation of SLC26A3 and upregulation of CCL20 and CXCL5 in NEC (all p < 0.001). Single-cell analyses revealed cell-type-specific dysregulation, with CCL20 markedly elevated in macrophages (log2FC = 3.85) and CXCL5 broadly upregulated across enterocytes, macrophages, and fibroblasts. Immune profiling demonstrated elevated proportions of M0 macrophages and activated mast cells, alongside reduced naive B cells and naive CD4 T cells, and CXCL5 expression was strongly correlated with neutrophil infiltration (r = 0.88, p < 0.001). Virtual knockout analysis revealed that perturbation of CCL20 and CXCL5 produced overlapping downstream networks converging on major histocompatibility complex class II-related antigen presentation genes, whereas SLC26A3 knockout perturbed a distinct set of epithelial barrier and innate immune genes. FTH1 was the sole gene perturbed across all three knockouts, implicating ferroptosis as a potential convergence point in NEC pathogenesis. Geneformer-based combinatorial perturbation indicated subadditive rather than synergistic interactions among the three biomarkers, with SLC26A3 appearing as the dominant node. Extension to a 9-gene ferroptosis panel showed coordinated directional shifts across the tested genes, and qPCR measurements in the NEC mouse ileum were consistent with the predicted expression changes for the five measured genes. SLC26A3, CCL20, and CXCL5 constitute a candidate molecular signature for early NEC diagnosis. Combinatorial perturbation analysis suggests subadditive rather than synergistic interactions among the three biomarkers, with SLC26A3 appearing as the dominant node. Virtual knockout network analyses suggest that CCL20 and CXCL5 share downstream regulatory circuits linked to antigen presentation, while SLC26A3 primarily perturbs the epithelial barrier and innate immune genes. Ferroptosis emerged as a coordinated multi-node convergence point, with computational predictions corroborated by qPCR measurements in a mouse NEC model. These findings provide a framework for a mechanistic study and potential targeted intervention in NEC.
Trauma to the spinal cord initiates an inflammatory response causing secondary damage, which collectively can result in loss of function below the level of the injury. The unbalanced risk-benefit ratio of methylprednisolone led to development of therapeutic nanoparticles (NPs) that associate with circulating monocytes and neutrophils to reduce inflammation and secondary damage and improve functional recovery in a female mouse model of cervical hemisection spinal cord injury. Herein, we investigate the mechanisms occurring during the acute phase of injury by which NPs directly and indirectly modulate the phenotype and trafficking of monocytes and neutrophils and computationally catalog the communication network among cell types within the injury microenvironment. Using adoptive transfer to monitor trafficking, NP treatment reduced the extent of myeloid cell recruitment to the injury yet did not impact the composition of adoptively transferred monocytes or neutrophils. The proportion of inflammatory monocytes was reduced with NP treatment, and single-cell sequencing analysis indicated increased polarization toward pro-regenerative phenotypes. Sequencing analysis also demonstrated that outgoing signals from monocytes and neutrophils influenced the phenotype of numerous cell types, including endothelial cells, fibroblasts, oligodendrocyte progenitor cells, and Schwann cells. Signaling between cell compartments involves a combination of soluble and matrix signals, with NP treatment enhancing expression of genes associated with anti-inflammatory phenotypes, angiogenesis, neuroprotection, and promotion of axon outgrowth or decreasing expression of inhibitors to regeneration. Collectively, NP delivery leads to direct and indirect effects on monocytes and neutrophils, which subsequently influence gene expression and intercellular signaling networks that promote a pro-regenerative environment.
Perineural invasion (PNI) is an aggressive feature in head and neck squamous cell carcinoma (HNSCC), but its molecular basis and neuroimmune implications, including potential links to immunotherapy response, remain unclear. We performed an integrative multi-omics analysis using public datasets and an independent clinical cohort. Transcriptomic, proteomic, single-cell, and spatial transcriptomic data were jointly analyzed to identify PNI-associated molecular patterns, construct prognostic signatures, and characterize immune infiltration and cell-cell communication. Regulatory elements were further explored by super-enhancer mapping and target-gene prediction. Pharmacologic inhibition experiments using the TLR2 inhibitor C29 were performed in FaDu cells for functional validation. PNI was associated with extracellular matrix and neuroactive signaling changes. A protein-based signature (ADIPOQ, MB, PLIN1, ADH1B) stratified survival risk. PNI-positive/high-risk tumors showed an immune-suppressed phenotype with lower predicted immunotherapy sensitivity and reduced CD8+ T-cell, B-cell, and Tfh-cell infiltration. Spatial analysis showed higher PNI scores at the invasive front, positive correlations with neural programs, and enrichment of TLR2-related signaling. TLR2 expression was associated with the PNI score, neural markers, and immune exclusion. In FaDu cells, C29 suppressed proliferation, migration, and invasion. Super-enhancer analysis identified candidate SE-target genes, including MYL4, CMYA5, and TNNT3, linked to PNI-associated biology. PNI in HNSCC is associated with coordinated extracellular-matrix, neuroimmune, and immune-suppressive remodeling. These findings support PNI-related molecular signatures for risk stratification and identify TLR2-related signaling and SE-associated programs as candidate mechanisms for further study.
The rising global incidence of clear cell renal cell carcinoma (ccRCC) often coincides with metabolic disorders like type 2 diabetes mellitus (T2DM). However, the association between these two conditions remains unclear. This study aimed to identify common molecular pathways and novel biomarkers for the comorbidity of T2DM and ccRCC. Utilizing single-cell transcriptomic datasets from the GEO public database, this study identified heterogeneous cell characteristics and core subpopulations in T2DM and ccRCC. Immune infiltration was assessed using the GSEA algorithm, and a prognostic model was optimized through machine learning algorithms. Key genes were pinpointed in conjunction with the optimal model's score. Subsequently, in vivo and in vitro comorbidity models were established to validate the pivotal role of these key genes in the comorbidity. Single-cell sequencing analysis revealed that efferocytosis was notably active in dead cell clearance in T2DM. In ccRCC, macrophages regulated efferocytosis to facilitate antigen presentation, modulate inflammation, and promote intercellular communication. Integrating machine learning and transcriptome analysis, we identified LST1 as a pivotal regulatory gene in both T2DM and ccRCC (AUC> 0.745). This result suggests that LST1 is involved in regulating macrophage-mediated efferocytosis and immune communication. Analysis of immune infiltration suggests that LST1-mediated efferocytosis may influence ccRCC susceptibility or disease progression by sustaining immune signaling activation and disrupting regulatory balance, potentially stemming from early inflammation in T2DM. Validation through in vitro and in vivo experimental models further underscores the critical role of LST1 in disease advancement. This study initially identified LST1 as a pivotal regulatory factor in the co-occurrence of T2DM and ccRCC, emphasizing its essential involvement in the immune interaction within the hyperglycemia-induced microenvironment of ccRCC. These results not only elucidated the immunomodulatory role of LST1 in individual diseases but also delineated an immunological continuum bridging diverse conditions, providing a novel framework for investigating the immune pathways implicated in the concurrent presence of diabetes and malignancies.
Cellular senescence is a hallmark of cancer and induces senescence-associated inflammatory responses in the tumor microenvironment (TME). CDKN1A, an important cellular senescence marker, plays significant roles in cell proliferation, invasion, migration, and apoptosis. Previous studies have implied its drug resistance role in certain cancer types. However, its impact on immunotherapy efficacy in advanced LUAD remains unclear. Using TCGA and SU2C-MARK cohorts, we investigated CDKN1A's biological features in advanced LUAD, analyzing pathway regulation, immune infiltration, and immunotherapy associations. Single-cell RNA sequencing (GSE148071) validated TME and cellular communication differences between CDKN1A high/low expressing tumors in advanced LUAD. CDKN1A expression was positively associated with immunosuppressive environment including extracellular matrix, cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs) in advanced LUAD for both TCGA and SU2C-MARK cohorts (P < 0.05). CDKN1A showed significantly positive correlations with many senescence genes in advanced LUAD (P < 0.05), which were also positively associated with endothelial cells, epithelial cells, fibroblast cells and macrophages, but negatively associated with immune cells (P < 0.05). In multivariable cox regression, patients with high CDKN1A expression had worse OS (HR = 2.74, 95% CI = 1.31-5.73, P = 0.007) and PFS (HR = 1.78, 95% CI = 1.01-3.11, P = 0.045) than those with low CDKN1A expression when treated with immunotherapy. In contrast, the high CDKN1A expression was not associated with PFS and OS in the TCGA cohort, in which the LUAD patients received standard chemotherapy, suggesting the immunotherapy predictive role instead prognostic role of CDKN1A. Moreover, single-cell analysis revealed that CDKN1A highly expressed tumors were accompanied by an enrichment of stromal and endothelial cells within the tumor microenvironment, along with enhanced activity of SMAD3/4, the downstream transcription factors of TGFB signaling. These tumors exhibited increased cell-cell communication with stromal cells (COL1A1/COL1A2-ITGA1/ITGB1/SDC1) and endothelial cells (NAMPT-ITGAS/ITGB1/INSR). CDKN1A expression was associated with cellular senescence, immunosuppressive environment and exhibited resistance to immunotherapy in advanced LUAD, suggesting a potential combination strategy with senolytic or senomorphic therapies to overcome immunotherapeutic resistance in the future.
Cellular communication network (CCN) proteins are key matricellular regulators of cartilage development, yet their species-specific roles and network-level context remain unclear. This study integrated bulk RNA sequencing from chicken and mouse embryonic limb bud micromass cultures and human mesenchymal stem cell chondrogenesis with co-expression, protein-protein interaction, and ortholog analyses to construct CCN-centered regulatory networks across models. CCN1 and CCN2 emerged as dominant, conserved hubs enriched in collagen-containing extracellular matrix, cartilage development, and growth factor signaling modules, whereas CCN3-CCN6 showed lower context-dependent expression and connectivity. Functional and ortholog analyses revealed moderate pathway conservation, with high conservation of IGF, EGFR, and HIF-1 signaling, but reduced overlap in hypoxia and mechanosensing/Hippo categories, indicating species-specific tuning of environmental sensing. A focused ortholog screen identified multifunctional conserved hubs, including COL2A1, TGFBR1, SMAD3, RUNX2, HIF1A, IGF1, SPP1, and CD44. Single-cell RNA-seq meta-analysis of human iPSC-derived chondrogenesis and embryonic limb datasets showed CCN1/2 expression and homologous network activity peaking in mesenchymal and early chondrocyte populations, consistent with model-dependent persistence into hypertrophic and ossification stages in vivo. Overall, this work defines a conserved CCN1/2-centered axis integrating extracellular matrix formation with growth factor and mechanical cues, providing a framework for model selection and CCN-targeted cartilage regeneration strategies.
Extracellular vesicles (EVs) derived from pluripotent stem cells have been reported to reprogram cancer cells to a more benign phenotype, due to its provision of an embryonic microenvironment. Here, we show that the effect of the EVs on the tumorigenicity of the cancer cell lines is cell type-dependent. First, we characterized the complement of transcription factors contained in EVs derived from human embryonic and induced pluripotent stem cell lines and subsequently treated MCF7, A431, MDA-MB-231, and DLD-1 cancer cell lines with the EVs derived from these pluripotent stem cell lines. For EV-treated MDA-MB-231 and DLD-1 cells, we found a decrease in the protein expression of CD44 and C24, which are accepted markers for cancer cell populations enriched with tumor-initiating cells, a result that corresponds to the previous reports. However, for EV-treated MCF7 and A431 cells, there was an increase in the protein expression of CD44 and C24 instead, with a corresponding increase in clonogenicity and resistance to a panel of anticancer drugs, when compared to non-exosome-treated cells. When subcutaneously implanted in nude mice, EV-treated MCF7 cells gave rise to tumors of larger size than untreated cells. The cell type-dependence of the effect of hPSC-derived EV treatment was postulated to be due to occurrence of an EMT for cells located at different locations along the epithelial-mesenchymal spectrum, leading to either an increase or decrease in tumorigenicity. Therefore, exposure to EVs does not always reduce the tumorigenicity of cancer cells but is cell type-dependent.
BACKGROUND: Lung adenocarcinoma (LUAD), a molecularly complex and aggressive malignancy, has a dismal 5-year survival rate. N6-methyladenosine (m6A) associated factors regulates cancer progression, but its role in LUAD prognosis and immune regulation remains unclear. METHODS: By integrating LUAD gene expression data and clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we analyzed the expression differences and genetic variations of m6A regulators. Clustering analysis identified distinct m6A modification patterns, while various regression algorithms were employed to construct a risk model based on m6A-related differentially expressed genes, and assessed its clinical relevance, genetic mutations and sensitivity to immunotherapy. PHLDA2 function was assessed by RT-qPCR, proliferation, migration and invasion assays. Its role in immune regulation was tested via MIF promoter luciferase reporter and MIF neutralization followed by STAT3/PD-L1 analysis. Single-cell RNA sequencing and tools including CellChat and NicheNet were used to map gene expression and cell–cell communication in the tumor microenvironment. RESULTS: Consensus clustering analysis based on 15 differentially expressed m6A regulatory factors identified two m6A clusters. 40 key genes closely associated with m6A modification were identified and a two-gene (PHLDA2 and RGS13) risk model correlated with the prognosis of LUAD patients was constructed. High-risk scores were linked to poor prognosis, advanced TNM(Tumor-Node-Metastasis) stage, and higher mutation frequency. Furthermore, PHLDA2 was found to be highly expressed in LUAD, predominantly localizing in epithelial and T cells, influencing late-stage T cell functions, and regulating LUAD cell proliferation, migration and invasion. Additionally, PHLDA2 was positively correlated with Programmed Death-Ligand 1 (PD-L1) and associated with the initiation or activation of immune cycle processes. Experimental validation shows that PHLDA2 promotes MIF transcription, and that MIF signaling is required for PHLDA2-induced PD-L1 upregulation via STAT3 activation. CONCLUSION: m6A modification patterns and the PHLDA2-RGS13 signature predict LUAD prognosis and immunotherapy response. PHLDA2 contributes to tumor progression and immune evasion through MIF-dependent signaling in mediating PHLDA2-driven PD-L1 expression, highlighting this axis as a potential therapeutic target.
Glucocorticoids (GCs) are key regulators of stress responses and fetal maturation, and their physiological rise during pregnancy supports coordinated organ development. Clinically relevant GC exposure during sensitive windows of brain development occurs in several contexts, including antenatal treatment for risk of preterm birth to promote lung maturation, prolonged maternal therapy for chronic inflammatory or autoimmune conditions, and postnatal GC treatment in preterm infants, including regimens used to prevent or treat bronchopulmonary dysplasia. Although these contexts differ in timing, dose, and duration, they share the capacity to engage a glucocorticoid receptor (GR) signaling during critical windows of neurodevelopment, with possible long-term consequences for brain development and stress responsiveness. This review synthesizes clinical, experimental, and stem cell-based evidence to examine how GC signaling can shape brain structure and function across the lifespan. We discuss GR signaling in the central nervous system (CNS) and summarize evidence that sustained activation can be associated with paradoxical pro-inflammatory and neurotoxic phenotypes. We highlight epigenetic mechanisms through which GC signals may produce persistent changes in gene regulation, and we integrate data from prenatal exposure together with evidence on maternal metabolic and inflammatory context as modifiers of developmental risk. Finally, we propose an integrated view in which CNS outcomes attributed to GCs reflect a composite of direct neural actions and indirect effects shaped by peripheral tissues. We discuss adipose- and muscle-linked pathways as candidate mediators of systemic-to-central communication. This perspective links stress endocrinology, metabolism, and brain vulnerability, and highlights key mechanistic gaps and translational priorities for future research.
Extracellular matrix (ECM) remodeling is a critical component of colorectal cancer (CRC) progression and tumor microenvironment organization. Members of the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) metalloproteinase family are known regulators of ECM structure; however, the transcriptional regulation of ADAMTS14 and its potential role in inflammation-associated ECM remodeling remain poorly understood. In this study, we investigated whether inflammatory signaling regulates ADAMTS14 expression and explored its association with ECM organization in CRC. Interleukin-6 (IL-6) stimulation significantly increased ADAMTS14 expression at both mRNA and protein levels in CRC cells. Promoter deletion analyses identified a critical IL-6-responsive region between -145 and -43 bp upstream of the transcription start site, suggesting transcriptional responsiveness of ADAMTS14 to inflammatory signaling. Inhibition experiments demonstrated that Extracellular Signal-Regulated Kinase, c-Jun N-terminal Kinase, Phosphatidylinositol 3-Kinase, and Nuclear Factor Kappa B pathways were associated with IL-6-induced ADAMTS14 expression. Transcriptomic analyses of The Cancer Genome Atlas CRC datasets revealed that ADAMTS14 expression is elevated in tumors and is associated with inflammatory signaling, stromal activation, fibroblast-related gene expression, and ECM organization pathways. Functional enrichment analyses indicated that ADAMTS14-correlated genes are primarily involved in ECM organization, collagen fibril organization, and connective tissue development. Together, these findings identify ADAMTS14 as an inflammation-responsive ECM-associated metalloproteinase and suggest that IL-6 signaling may be associated with ECM-related transcriptional programs through regulation of ADAMTS14 expression. Our findings further suggest that ADAMTS14 expression may be associated with inflammatory and stromal-related transcriptional programs in CRC.
Glucose deprivation (Glu-D) is a critical feature of the tumor microenvironment. Under such conditions, tumor cells seek alternative metabolic resources to maintain rapid growth and proliferation. Glutamine serves as a key alternative resource for cancer cells, yet the metabolic mechanisms involving its transporters in non-small cell lung cancer remain poorly understood. Lentiviral vectors for overexpression and knockdown of phosphoenolpyruvate carboxykinase 2 (PCK2), solute carrier family 38 member 2 (SLC38A2), and CEBPB were constructed. Transwell, flow cytometry, Western blotting, and dual-luciferase reporter assays were used to investigate the regulatory relationship between PCK2 and SLC38A2 under Glu-D, as well as their effects on cellular glutamine metabolism, glycolysis, and malignant cell behaviors. PCK2 and SLC38A2 were highly expressed in human adenocarcinomas tissues. PCK2 upregulated SLC38A2 expression, though this effect was indirect. Under Glu-D, knockdown of PCK2 or SLC38A2 significantly reduced cellular glutamine utilization, inhibited glycolysis, and suppressed malignant cell behaviors. Treatment with an AMP-activated protein kinase (AMPK) inhibitor or knockdown of CEBPB produced similar effects. PCK2 activated AMPK, which increased downstream SLC38A2 expression by activating the transcription factor CEBPB. PCK2 upregulates SLC38A2 expression via the AMPK-CEBPB axis, enhancing glutamine utilization to promote glycolysis and malignant behaviors in A549 cells under Glu-D.
Lung adenocarcinoma (LUAD) remains a major cause of cancer-related mortality, and there are currently few reliable biomarkers available for accurate prognosis and effective targeted therapy. Accumulating evidence demonstrates that senescent cells play an important role in tumor progression and immune evasion; nevertheless, their specific contribution to LUAD pathogenesis has not yet been fully elucidated. Accordingly, a five-gene senescence-related risk model comprising FGF2, GAPDH, CCNA2, ENO1, and DKK1 was established using the Least Absolute Shrinkage and Selection Operator regression applied to bulk RNA sequencing data obtained from The Cancer Genome Atlas (TCGA). Patients stratified as high risk by this model exhibited significantly poorer overall survival and progression-free survival, accompanied by marked activation of pathways associated with immune infiltration, epithelial–mesenchymal transition, and extracellular matrix remodeling. Integrative single-cell RNA sequencing analysis further revealed a distinct epithelial subpopulation (E9) defined by preferential activation of the senescence-associated gene DKK1. This subpopulation, which emerged from integrative single-cell transcriptomic analysis, exhibited pronounced senescence-associated characteristics, significantly increased cellular stemness, and extensive intercellular communication capacity, and uniquely expressed COL17A1 together with transcriptional programs that were strongly associated with epidermal development. Pseudotime analyses consistently positioned E9 cells at an early stage of tumor evolution. At the functional level, DKK1 contributed to senescence-associated phenotypic features, thereby promoting tumor cell migration and metastatic potential. From a clinical perspective, patients with concurrent high levels of COL17A1 and DKK1 expression experienced significantly worse clinical outcomes. Collectively, these findings identify a senescence-driven epithelial subpopulation that contributes to LUAD progression via DKK1-mediated activation of aging-related pathways and highlight DKK1 as a potential therapeutic target.
Oral squamous cell carcinoma, with high global incidence and mortality, requires improved early intervention strategies. Ubiquitination - a critical post-translational modification - has been strongly implicated in tumorigenesis, with particularly significant roles in T-cell regulation. We developed a T Cell-Related ubiquitination risk model that enhances prognostic prediction and immunotherapy response assessment, offering a framework for personalized OSCC manageme. T cell-Related Ubiquitination genes were identified based on scRNA-seq analysis, and key genes were selected using WGCNA and LASSO algorithms to construct a prognostic model. Spearman correlation analysis revealed significant associations between riskScore and immune infiltration levels, checkpoint molecule expression, and MMR activity. Pseudotemporal trajectory and cell-cell communication analyses delineated dynamic gene expression patterns driving OSCC progression. Functional validation through colony formation and Transwell assays confirmed the tumor-suppressive effects of key model genes. Given the high correlation between T cell-Related Ubiquitination genes and the prognosis of OSCC patients, a prognostic model based on patient scRNA-seq data was constructed and validated. The RiskScore derived from our model correlated significantly with expression levels of MMR genes, abundance of immune checkpoint proteins, and immunotherapy response. Cell-cell communication analysis further elucidated epithelial-macrophage crosstalk via MIF and IFN-II signaling, suggesting microenvironment-driven progression mechanisms. In vitro functional assays showed that depletion of MNAT1 impaired Cal27 cell proliferation and migration capacity. Collectively, integrating T cell-Related Ubiquitination genes through advanced computational analyses, we established a robust prognostic model for OSCC and identified MNAT1 as a promoter of malignant progression, highlighting its therapeutic potential.
Vitamin D receptor (VDR) signaling plays a crucial role in hair follicle biology and represents a promising therapeutic target for various forms of alopecia. This review comprehensively examines the molecular mechanisms of VDR signaling in hair follicle development, cycling, and pathology. We discuss key molecular mechanisms of VDR-dependent gene regulation through chromatin remodeling, transcriptional regulation, and recruitment of coregulatory complexes, which collectively regulate hair follicle homeostasis. Recent advances in understanding VDR genetic polymorphisms and their impact on treatment responses have provided new insights into personalized therapeutic approaches. The review explores current therapeutic strategies, from conventional vitamin D supplementation to emerging targeted delivery systems and combination therapies. We also analyze the challenges and limitations in current research, including the need for improved delivery systems and reliable biomarkers for treatment response prediction. The integration of molecular insights with clinical applications suggests promising directions for developing more effective, personalized treatments for various forms of alopecia. This comprehensive analysis underscores the significance of VDR-targeted approaches in the future management of hair disorders and highlights the importance of continued research in this field.
Post-COVID syndrome (PCS) affects approximately 3-17% of individuals following acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and poses a potential global health burden. While improved assessment strategies are emerging, mechanistic insights and treatment options remain limited. This study investigates molecular mechanisms underlying PCS using single-cell RNA (scRNA) transcriptomics combined with in vitro validation. scRNA analysis is performed on nasal biopsies from 25 patients with moderate or severe PCS to investigate differential cell types, signalling pathways, and cell-cell communication. Air-liquid interface cultures are used to validate findings, focusing on the TNFα-TGFβ axis. Severe PCS shows reduced numbers of ciliated cells, increased immune cell infiltration, and heightened inflammatory signaling that drives TGFβ and TNFα upregulation, in the absence of a detectable viral load. These changes trigger epithelial-mesenchymal transition, basal cell expansion and a mis-stratified nasal epithelium. In vitro experiments confirm TGFβ and TNFα as causal cytokines promoting ciliated cell loss and increased basal cell abundance. These findings indicate a sustained severe PCS is not driven by ongoing viral load but by immune cell activity and chronic cytokine production. Targeting the TNFα-TGFβ axis may mitigate immune-mediated nasal tissue damage and support epithelium restoration, offering a potential therapeutic strategy for PCS.
Sepsis often has a dysregulated inflammatory response and is accompanied by cardiac dysfunction. This study aimed to explore the mechanism of long non-coding RNA MIR503HG (MIR503HG) in regulating sepsis and the inflammatory responses, and sepsis-induced cardiac dysfunction (SICD). 102 sepsis patients were divided into an SICD group (n = 31) and a non-SICD group (n = 71). A cecal ligation and puncture (CLP) sepsis rat model was constructed. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to evaluate the target gene expression. Enzyme-linked immunosorbent assay was used to measure the levels of myocardial damage markers and inflammatory factors. RNA immunoprecipitation and Dual luciferase assay were used to determine the targeting relationship. Kyoto Encyclopedia of Genes and Genomes analysis was used to predict signaling pathways of target genes. MIR503HG expression was significantly down-regulated in sepsis patients and SICD patients, and it has good diagnostic value for these two types of diseases. Its expression was significantly negatively correlated with myocardial injury markers (cardiac troponin I [cTnI], creatine kinase-MB [CK-MB]), cardiac function indicators (left ventricular ejection fraction), inflammatory factors (interleukin-6, tumor necrosis factor-alpha), and disease severity scores (Sequential Organ Failure Assessment, Acute Physiology and Chronic Health Evaluation II). Furthermore, it exerted a protective effect in sepsis: MIR503HG overexpression could effectively alleviate SICD and mitigate the inflammatory response, as evidenced by decreased left ventricular end-diastolic pressure, increased left ventricular systolic pressure, reduced levels of CK-MB and cTnI, as well as restored myocardial systolic/diastolic capacity (maximal rate of left ventricular pressure rise/fall [±dP/dt]). Mechanistically, MIR503HG functions as a molecular sponge that sequesters microRNA-497-5p (miR-497-5p), thereby lifting brain-derived neurotrophic factor (BDNF). Delivery of miR-497-5p-agomiR partially offset the cardioprotective and anti-inflammatory effects of MIR503HG, whereas overexpression of BDNF partially restored them. MIR503HG relieved sepsis and reduced cardiac dysfunction and inflammatory response by regulating the miR-497-5p/BDNF axis.
Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent malignancy with poor prognosis, largely driven by lymph node metastasis (LNM). Despite its clinical significance, the underlying mechanisms of LNM remain elusive. In this study, we used single-cell transcriptomic data to dissect the cellular and molecular interactions within metastatic lymph nodes (MET). Specifically, we analyzed Single-cell RNA sequencing (scRNA-seq) data from GSE195655, GSE140042, GSE227156, and GSE159929 (n = 41) to delineate cellular heterogeneity, intercellular communication networks, and functional enrichment in primary tumors (PT), MET, and non-metastatic lymph nodes (LN). Our analysis identified a subpopulation of tumor-associated macrophages (TAMs) distinctly enriched in MET, characterized by high expression of SPP1. Functional analysis revealed that this TAM subpopulation promotes angiogenesis through specific ligand-receptor interactions with endothelial cells (ECs), involving the SPP1-ITGa9b1 and FN1-ITGa2b1 signaling axes. Furthermore, we leveraged bulk RNA-seq for prognostic research. Immunohistochemistry (IHC) confirmed the increased density and number of blood and lymphatic vessels in MET. Spatial analysis via multiplex immunohistochemistry (mIHC) confirmed the preferential localization of SPP1+ TAMs near ECs in MET. These results suggest a potential communication between TAMs and ECs that contributes to LNM in HNSCC, providing critical insights for HNSCC prognosis and precision treatment.