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PubMed2026

Epigenetic and immunological alterations in umbilical cord blood of overweight/obese women with gestational diabetes mellitus: insights into DNA methylation signatures and immune cell dysregulation.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse maternal and neonatal outcomes. Epigenetic modifications may reflect intrauterine metabolic exposure and contribute to immune and metabolic alterations. This study aimed to explore DNA methylation profiles in umbilical cord blood from overweight and obese women with and without GDM. METHODS: Umbilical cord blood samples from 30 overweight/obese pregnant women (with and without GDM) were analyzed using the Illumina 850 K methylation array to identify differentially methylated positions (DMPs) and regions (DMRs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to assess the functional relevance of methylation changes. Immune cell composition was estimated using deconvolution analysis and further examined in an independent single-cell RNA sequencing (scRNA-seq) cohort. Lasso regression was applied to identify CpG sites associated with GDM status and construct a preliminary methylation-based classification model. RESULTS: A total of 23,331 hypermethylated and 29,501 hypomethylated DMPs were identified between women with and without GDM, with hypomethylation predominating. Enrichment analyses indicated associations with neurodevelopmental pathways, metabolic processes, immune regulation, and epigenetic modification. Immune deconvolution analysis suggested reduced proportions of CD4+ T cells (p < 0.05) and a trend toward decreased NK cells in the GDM group, alongside increased CD8+ T cells and neutrophils. Seven CpG sites were selected for model construction and demonstrated strong discriminatory performance within this cohort. CONCLUSION: This exploratory study identifies distinct cord blood DNA methylation patterns associated with GDM in overweight/obese pregnancies. The findings suggest potential links between epigenetic alterations and immune cell composition in GDM-exposed offspring. The identified CpG signature warrants further validation in larger, prospective cohorts to determine its clinical applicability.

Humans↗

PubMed2026

FZD5 drives macrophage-mediated immunomodulation and predicts prognosis in glioma: evidence from single-cell sequencing.

BACKGROUND: Gliomas are highly malignant brain tumors characterized by an immunosuppressive microenvironment, which limits therapeutic efficacy and contributes to poor clinical outcomes. The WNT/β-catenin signaling pathway is critically involved in tumor progression, and FZD5, a key receptor within this pathway, may participate in immune regulation. However, its specific role and underlying mechanisms in glioma remain unclear. METHODS: RNA-seq and microarray datasets from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA), together with single-cell RNA sequencing (scRNA-seq) datasets from GEO, were comprehensively analyzed. The Seurat package was used to identify macrophage-related clusters and mitophagy-associated pathways. Cox and LASSO regression analyses, along with a prognostic nomogram, were applied to evaluate the prognostic significance of FZD5. Immune infiltration, functional enrichment, and immunotherapy response analyses were conducted, followed by validation using spatial transcriptomics, immunohistochemistry, and in vitro assays. RESULTS: In bulk glioma transcriptomes, FZD5 emerged as an independent predictor of poor prognosis. Crucially, single-cell and spatial analyses revealed that the biologically significant FZD5 signal originated predominantly within tumor-associated macrophages (TAMs), where it colocalized with the M2 marker CD163. Consistently, elevated FZD5 levels correlated with increased myeloid infiltration and an immunosuppressive tumor microenvironment. Functionally, macrophage-expressed FZD5 was associated with mitophagy-related programs and promoted an M2-skewed phenotype, thereby enhancing glioma cell proliferation, migration, and invasion via macrophage-glioma crosstalk. CONCLUSION: FZD5 is a TAM-enriched marker in glioma tissues and a potential regulator of macrophage-associated immunosuppressive programs, supporting its utility as a prognostic biomarker and a candidate target for microenvironment-oriented interventions in glioma.

Humans↗

PubMed2026

Hepatic metabolic adaptation to endurance exercise: temporal and sex differences by multiomics integration and validation.

BACKGROUND: Although endurance exercise benefits liver health, sex-specific adaptive trajectories remain unclear. This study mapped dynamic liver adaptation in males and females during prolonged training and identified underlying molecular programs. METHODS: Using publicly available time-resolved liver multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we established a computational pipeline for differential analysis of transcriptomic, proteomic, phosphoproteomic, and metabolomic data with FDR correction, followed by FGSEA pathway enrichment. Kinase activities were inferred through ortholog mapping and PhosphoSitePlus. Cross-omics co-expression networks were constructed using WGCNA and topological overlap to link omics features with physiological phenotypes. For experimental validation, liver tissues were collected from endurance-trained Sprague-Dawley rats, and key nodes were confirmed by Western blotting, qRT-PCR, and immunofluorescence/immunohistochemical staining. Public scRNA-seq data were further integrated to map multi-omics signals to single-cell resolution and assess functional changes in specific cell types. RESULTS: The hepatic response to exercise stress was stage-specific, shifting from early transcriptional activation to later proteomic and metabolic remodeling. Multi-omics integration revealed distinct sex-associated adaptive trajectories: males were more strongly associated with energy metabolism, redox-related programs, and amino acid/organic acid catabolism, whereas females showed prominent membrane lipid remodeling, proteostasis -related programs, and mitochondrial/ribosomal translational features. Single-cell analysis showed that tissue remodeling occurred without major lineage turnover, instead involving altered communication among pre-existing cell communities. Validation of PPP1R3G identified a protein-dominant exercise-responsive marker, supporting the contribution of post-transcriptional or protein-level regulation. CONCLUSIONS: Hepatic adaptation to endurance stress follows a cross-omics evolutionary pattern with sex-specific reprogramming of energy supply and homeostatic maintenance. This time-resolved framework clarifies how exercise improves liver function and supports sex-oriented metabolic interventions and therapeutic target discovery.

Animals↗

PubMed2026

Increased IL4I1 expression predicts poor survival and modulates the immune microenvironment in acute myeloid leukemia.

BACKGROUND: The immunometabolic enzyme Interleukin-4-induced-1 (IL4I1) is implicated in cancer pathogenesis, yet its specific function and clinical relevance in acute myeloid leukemia (AML) remain unclear. METHODS: Comparative analysis of IL4I1 mRNA levels between AML patients and normal controls was performed using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The Kaplan–Meier survival analysis was conducted to evaluate the prognostic value of IL4I1. Functional insights were derived from analyses of differentially expressed genes (DEGs), Gene Set Enrichment Analysis (GSEA), and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Immune infiltration was evaluated using the ssGSEA, ESTIMATE, quanTIseq and single-cell RNA sequencing (scRNA-seq) analysis. Finally, in vitro and in vivo functional experiments were perfromed to explore the impact of IL4I1 on AML progression and immunoregulation. RESULTS: IL4I1 expression was significantly elevated in AML compared to normal controls (p = 0.0004) and associated with poorer overall survival (p = 0.003). Bioinformatic analysis revealed that IL4I1 was linked to immune-related pathways—including humoral immune response, leukocyte interactions, and chemokine signaling—and to cellular amino acid metabolism. Its expression correlated with immune cell infiltration and checkpoint molecule expression. Experimentally, IL4I1 promoted leukemia cell proliferation in vitro and in vivo (p < 0.05). Furthermore, silencing IL4I1 suppressed M2 macrophage polarization and reduced secretion of inflammatory factors (p < 0.05). CONCLUSIONS: IL4I1 may serve as a potential biomarker for poor prognosis and an attractive target for immune-based therapeutic interventions in AML.

Humans↗

PubMed2026

Cell type resolved MR based on brain single cell eQTLs corroborated by single cell RNA sequencing uncovers neuroimmune and vascular programs in intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) lacks effective neuroprotective therapies. We integrated cell type–resolved genetic inference with single-cell profiling to map putative causal programs and multicellular circuitry relevant to ICH. METHODS: Cis-eQTLs from eight human brain cell types were used as instruments for two-sample Mendelian randomization (MR), with an ICH meta-analysis from large biobanks and a stroke consortium as the outcome. Instruments were LD-pruned and restricted to strong variants (F > 10). Inverse-variance weighting (IVW) was the primary estimator, supported by robustness methods, heterogeneity/pleiotropy diagnostics, and false discovery rate control. Experimental validation used mouse collagenase ICH single-cell RNA-seq at 24 h (n = 3 sham; n = 3 ICH) with Seurat integration, composition testing, Slingshot pseudotime, and CellChat. An independent mouse cohort underwent qRT–PCR for selected genes. RESULTS: The ICH meta-analysis showed acceptable genomic control, supporting downstream MR. We identified 524 nominal gene–cell type associations, with a glia-weighted signal landscape. Enrichment implicated autophagy/mitophagy, antigen processing, cytoskeletal and vesicular trafficking, endothelial matrix–adhesion programs, ferroptosis, and myelin stress pathways. In mouse scRNA-seq, disease-associated microglia expanded with reciprocal loss of homeostatic microglia and increased neutrophils and T cells. Prioritized genes showed directional concordance; qRT–PCR confirmed ARPC3 and EIF2AK2 upregulation and TBCK and SPECC1 downregulation in ICH versus sham. Pseudotime supported a shift toward disease-associated microglial states, and CellChat indicated increased network interaction strength with microglia and endothelium as hubs. CONCLUSIONS: Cell type–specific MR combined with single-cell validation highlights neuroimmune and neurovascular programs in ICH and links genetic signals to state transitions and inferred intercellular communication.

Animals↗

PubMed2026

MX1+ effector T cells hyperactivation at the maternal-fetal interface in unexplained recurrent pregnancy loss.

BACKGROUND: Immune tolerance breakdown at the maternal-fetal interface is implicated in unexplained recurrent pregnancy loss (URPL), but the interplay between T cell hyperactivation and dendritic cells (DCs)-mediated signaling remains poorly defined. METHODS: First-trimester decidual tissues from 5 healthy controls and 6 URPL patients underwent single-cell RNA sequencing (scRNA-seq, 10× Genomics). Computational analyses included clustering (Seurat), trajectory inference (scTour), intercellular communication (CellChat) and metabolic pathway enrichment (Gene Ontology and scMetabolism). Flow cytometry was performed from 11 patients and 11 healthy controls. Spatial validation was performed via multiplex immunohistochemistry and immunohistochemistry on 12 additional controls and 12 URPL cases. Statistical significance was assessed using Student’s t-test. RESULTS: URPL decidua exhibited marked CD3+ T cells and MX1+effector T (Tem) cells infiltration and activation. Flow cytometry analysis confirmed a significant decidua-specific upregulation of T cell activation markers CD25 and CD69 specifically on the MX1+Tem subset in URPL patients compared to controls. MX1+Tem cell subset demonstrated interferon hyperactivation, proliferative hyperactivity and lipid-biased immunometabolism. Pseudotemporal analysis positioned MX1+ Tem cells between classical Tem and exhausted T cell states, suggesting progressive differentiation. CellChat identified DCs as key regulators of MX1+ Tem expansion via aberrant ICOSL signaling, validated by spatial co-localization of ICOSL+ DCs and MX1+ Tem cells in URPL tissues. CONCLUSION: Our findings demonstrate that the aberrant activation and proliferation of MX1+Tem cells as a key immunological feature associated with URPL patients.

Humans↗

PubMed2026

Multi-omics characterization of a GPRC5A+ epithelial subpopulation associated with malignant features in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) exhibits marked cellular heterogeneity, and the cellular context of malignancy-associated epithelial programs remains incompletely defined. METHODS: We integrated 2,993 CRC samples spanning bulk RNA-seq (n = 2,568; two OS/RFS cohorts), scRNA-seq (281,961 cells/152 specimens), spatial transcriptomics (n = 6), and proteomics (n = 267). Analyses included single-cell integration/annotation, GSVA/HALLMARK, interactome, pseudotime, and ligand-receptor mapping; functional CRISPR assays, EMT immunoblotting, and xenografts; TF profiling (SCENIC/JASPAR/ChIP-qPCR); and exploratory drug-response prediction (OncoPredict), cell-sensitivity assays, and docking/MD modeling. RESULTS: We constructed a stage-stratified single-cell atlas and resolved eleven malignant epithelial subsets, characterizing Epi_4 as late-stage-enriched with EMT, hypoxia, and inflammatory programs and adverse OS/RFS. GPRC5A marked this subset, which we define as GPRC5A+Epi; its expression rose from stage I→IV and was associated with poor outcomes across cohorts, with concordant spatial/proteomic observations. GPRC5A perturbation affected CRC proliferation, migration/invasion, EMT, and xenograft tumorigenicity, supporting a functionally important role in the tested models. SCENIC and ChIP-qPCR supported FOSL1 as an upstream regulator that occupies the GPRC5A promoter. Spatial and ligand-receptor analyses predicted close association and potentially reciprocal signaling between GPRC5A+Epi and POSTN+fibroblasts (COL1A1-SDC4, COL1A1/1A2-ITGA2/ITGB1, PPIA-BSG); concurrent high GPRC5A+Epi/POSTN+Fib signatures were associated with inferior OS/RFS. Drug-response analyses identified an association between GPRC5A status and trametinib sensitivity. Docking/MD produced a computational model of a possible trametinib-GPRC5A interaction, which remains experimentally unvalidated. CONCLUSIONS: GPRC5A⁺Epi is a malignancy-associated epithelial state in CRC, and GPRC5A is functionally important for malignant phenotypes in the tested models. Its inferred relationships with POSTN⁺ fibroblasts and the trametinib findings should be regarded as hypothesis-generating pending functional crosstalk, direct-binding, and therapeutic validation.

Humans↗

PubMed2026

Integrated single-cell transcriptomics, Mendelian randomization, and machine learning identify CEBPZ as an immune-related biomarker in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a chronic, immune-mediated oral mucosal disease with complex pathophysiology and potential for malignant transformation. Understanding its molecular basis is critical for the development of precise diagnostic and therapeutic strategies. OBJECTIVES: We aimed to identify key immune-related biomarkers and characterize cellular dynamics in OLP, with a particular focus on the role of CEBPZ in disease pathogenesis. MATERIAL AND METHODS: We analyzed single-cell RNA sequencing (scRNA-seq) data from OLP lamina propria samples (GSE211630) to identify disease-specific T-cell subpopulations using high-dimensional weighted gene co-expression network analysis (hdWGCNA) for oxidative stress-related gene modules.-data-based Mendelian randomization (SMR) integrated FinnGen genome-wide association study (GWAS; 342,499 Europeans) data with Genotype-Tissue Expression (GTEx) expression quantitative trait loci (eQTL) data to identify causal genes. Machine learning (ML) models (least absolute shrinkage and selection operator (LASSO) and convolutional neural network (CNN)) were developed using bulk RNA-seq datasets (GSE52130 and GSE38616) for diagnostic purposes. RESULTS: We identified OLP-specific T-cell populations (clusters 0, 3, 5, 7, 13, and 15) with enhanced migration inhibition factor (MIF) pathway signaling toward B cells and monocytes. Two oxidative stress-associated modules contained hub genes, including CEBPZ. Summary-data-based Mendelian randomization analysis identified 231 OLP-associated genes, with CEBPZ uniquely intersecting LASSO-selected markers (odds ratio (OR) = 1.057, 95% confidence interval (95% CI) = 1.013-1.102, p = 0.010). Machine learning models achieved area under the curve (AUC) values ranging from 0.653 to 0.745, with the CNN model reaching a validation accuracy of 0.735. CEBPZ showed elevated expression in OLP T cells and correlated with enhanced MIF-(CD74+CXCR4) signaling. CONCLUSIONS: This integrative approach identifies CEBPZ as a pivotal biomarker linking genetic susceptibility, oxidative stress, and immune dysregulation in OLP. Our diagnostic models offer promising tools for OLP management.

CEBPZ↗

PubMed2026

Non-structural maintenance of chromosome condensin I complex subunit H knockdown suppresses malignant progression of esophageal squamous cell carcinoma via the Wnt/β-catenin signaling pathway.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) remains a major cause of cancer-related mortality, and effective therapeutic targets are still limited. Non-structural maintenance of chromosome condensin I complex subunit H (NCAPH) has been implicated in tumorigenesis; however, its clinical relevance, functional roles, and underlying mechanisms in ESCC are not fully defined. We aimed to characterize the expression pattern, prognostic value, biological functions, and mechanistic basis of NCAPH in ESCC. METHODS: Public datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to evaluate NCAPH expression and clinical associations. Single-cell RNA sequencing (scRNA-seq) data were used to map cell-type-specific distribution of NCAPH in tumor and adjacent tissues. NCAPH was silenced in KYSE150 and KYSE510 cells using lentiviral short hairpin RNAs (shRNAs), followed by Cell Counting Kit-8 (CCK-8), colony formation, wound-healing, and Transwell migration/invasion assays. A nude mouse xenograft model was established to assess the effect of NCAPH knockdown in vivo. RNA sequencing (RNA-seq), quantitative polymerase chain reaction (qPCR), western blotting, and enzyme-linked immunosorbent assay (ELISA) were performed to explore potential mechanisms. RESULTS: NCAPH was consistently upregulated in ESCC across multiple cohorts and was associated with unfavorable clinicopathological features and poorer survival. Functional assays demonstrated that NCAPH knockdown significantly inhibited ESCC cell proliferation, migration, invasion, and clonogenic growth. In vivo, NCAPH silencing suppressed xenograft tumor growth. Mechanistically, transcriptomic profiling and molecular validation indicated attenuation of Wnt/β-catenin signaling following NCAPH depletion, accompanied by reduced β-catenin and downstream targets. CONCLUSIONS: NCAPH promotes malignant progression of ESCC, at least in part through activation of the Wnt/β-catenin pathway, and may serve as a potential biomarker and therapeutic target.

Esophageal squamous cell carcinoma (ESCC)↗

PubMed2026

Construction of molecular signatures based on the co-expression network of NECSO-related gene TRPM4 and its prognostic value in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) demonstrates significant prognostic variability that is not entirely accounted for by traditional staging systems. Necrosis by sodium overload (NECSO) is an emerging programmed cell death pathway, but its clinical relevance in HCC remains undefined. Therefore, this study aimed to identify TRPM4-associated core genes, develop and validate a prognostic signature, and investigate its relationship with the tumor immune microenvironment, tumor mutational burden, and single-cell expression patterns in HCC. METHODS: We integrated transcriptomic, clinical, and mutational datasets from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) (n=421) and Gene Expression Omnibus (GEO) cohorts (n=115) to identify genes co-expressed with TRPM4-a key NECSO mediator-and those differentially expressed in HCC. A prognostic signature was developed using least absolute shrinkage and selection operator (LASSO)-Cox regression and validated through survival analysis, time-dependent receiver operating characteristic (ROC) curves, and multivariate Cox regression analysis. The immune landscape was characterized using CIBERSORT, somatic mutation data were used to calculate tumor mutational burden (TMB) and assess its correlation with the risk score, and single-cell RNA sequencing (scRNA-seq) resolved cell-type-specific expression patterns. RESULTS: From 294 TRPM4-associated core genes, we identified an 11-gene signature (BRSK1, MMP1, GRIN2D, GP6, MYOM2, N4BP3, CCDC112, TSEN54, MAP3K9, SPP1, B3GNT4) that independently predicted overall survival (OS) (hazard ratio =5.419, P<0.001) with areas under the curve (AUCs) of 0.779, 0.693, and 0.701 at 1, 3, and 5 years. These values were superior or comparable to conventional clinicopathologic variables after direct comparison. High-risk patients exhibited an immunosuppressive microenvironment, characterized by enrichment of M0 macrophage, a higher M2/M1 ratio (P<0.001) and distinct immune checkpoint profiles. When integrated with TMB, the prognostic stratification was further refined: high-TMB/high-risk patients had poorest outcomes (median OS, 15.3 months), while low-TMB/low-risk patients had the most favorable survival (median OS, 68.7 months). Single-cell analysis revealed that MMP1 was induced in cancer-associated fibroblasts (CAFs) and SPP1 was downregulated in macrophages, single-cell risk scores confirmed TAFs and macrophages as the main contributors to the prognostic model. CONCLUSIONS: The TRPM4-centered 11-gene signature provides robust and independent prognostic stratification in HCC by integrating immune, mutational, and single-cell features. This signature serves as a potential tool for prognostic evaluation and may help inform immunotherapeutic strategies for HCC.

Hepatocellular carcinoma (HCC)↗

PubMed2026

Identification of Drug-resistant Cell Subpopulations in Colorectal Cancer Through Single-cell Analysis and Exploration of Potential Therapeutic Strategies.

INTRODUCTION: The therapeutic efficacy of Colorectal Cancer (CRC) is often compromised by resistance to the standard chemotherapy agent oxaliplatin. METHODS: This study obtained single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database. Differentially Expressed Genes (DEGs) between resistant and sensitive epithelial subpopulations were identified, followed by enrichment analysis. Pseudotemporal trajectory and cell-cell communication were analyzed using Monocle2 and CellChat, respectively. The candidate drug was predicted by Connectivity Map (cMAP) analysis. External validation included assessment of the EpC2 signature in an oxaliplatin-resistant cell line dataset (GSE76092), survival analysis using The Cancer Genome Atlas (TCGA) cohorts, and re-analysis of the GSE179784 dataset to assess the reproducibility of EpC2-like subpopulations and their DNA Damage Repair (DDR) scores. RESULTS: Cell subpopulations were divided into 10 clusters. Among them, epithelial cells comprised 5 subpopulations, with EPC2 identified as a potential oxaliplatin-resistant subset. DEGs were enriched in the TNF and IL-17 pathways. External validation confirmed the enrichment of EpC2 in resistant cell lines and its association with poor survival. Pseudotemporal trajectory revealed that epithelial cells underwent state transitions, forming two distinct branches. The resistant group exhibited enrichment in RNA splicing and NF-κB pathways. Cell-cell communication analysis revealed interactions involving MDK- NCL and PPIA-BSG. Dasatinib was predicted as a candidate drug. DISCUSSION: We identified an oxaliplatin-resistant subpopulation of Epithelial Cells (EpC2) in CRC, elucidated its multi-layered resistance mechanisms, and integrated multi- omics and cMAP database analyses to predict a potential intervention drug. CONCLUSION: This study provided potential therapeutic possibilities for oxaliplatin resistance, contributing to CRC treatment.

Humans↗

PubMed2026

PAFAH1B1 governs follicular development by modulating the protein complex of CCNE1-CDK2-CDK1 to induce cell cycle arrest.

BACKGROUND: Ovarian follicle development plays a crucial role in mammalian fertility, which is primarily regulated by granulosa cell (GC) proliferation and cell cycle. Cell cycle dysregulation collectively might drive follicular atresia through GC dysfunction. However, the underlying molecular mechanisms remain largely unexplored. METHODS: The scRNA-seq and integrative analysis revealed that PAFAH1B1 was involved in cell cycle. Functional assays, including overexpression/knockdown, flow cytometry, EdU, HE, and TUNEL, confirmed that PAFAH1B1 regulated cell cycle and follicular development in vitro and in vivo. CoIP showed that PAFAH1B1 bound CCNE1-CDK2-CDK1 to arrest G2/M phase. Chromatin accessibility and CRISPR/dCas9-TET1 demonstrated that DNA methylation modulated PAFAH1B1 transcription. RESULTS: A novel regulator of cell cycle, PAFAH1B1, was identified in Pig Genotype-Tissue Expression (PigGTEx). During GC proliferation, we found that PAFAH1B1 transcription was correlated with the distribution rate of G1 phase in GCs. PAFAH1B1 protein was confirmed to specifically bind to CCNE1-CDK2-CDK1 to arrest G2/M phase. Notably, PAFAH1B1 appeared to hinder the development of follicles. Furthermore, the demethylation significantly promoted the transcription activity and chromatin accessibility of CpG island (-7 bp to +170 bp) of PAFAH1B1. Taken together, PAFAH1B1 physically interacted with the CCNE1-CDK2-CDK1 complex to arrest G2/M phase and inhibit the GCs proliferation and follicular development. Additionally, demethylation of CpG island significantly promoted the transcription of PAFAH1B1. CONCLUSION: These findings not only advance understanding of cell proliferation and cycle regulation but also identify PAFAH1B1 as a candidate gene for further investigation in follicular development.

CCNE1-CDK2-CDK1 complex↗

PubMed2026

Distinct cochlear cell types associated with genetic susceptibility to sensory and metabolic hearing loss in older adults.

Hearing loss is a heterogeneous condition that can be classified into different subtypes with diverse genetic and cellular components. To investigate the cochlear cell types underlying the genetic basis of sensory and metabolic components of age-related hearing loss (ARHL), we integrated human genome-wide association study data with mouse cochlear single-cell RNA sequencing data using the single-cell disease relevance score tool. These analyses revealed that genes associated with the sensory component of ARHL were most highly expressed in hair cells, while genes associated with the metabolic component of ARHL were most highly expressed in spiral ganglion neurons. We also investigated whether ARHL-associated gene expression patterns differed across subpopulations of the same cell type. Sensory hearing loss-associated genes showed differential expression across supporting cell subpopulations in younger mice, whereas metabolic hearing loss-associated genes exhibited differences across intermediate cell subpopulations of the stria vascularis in older mice. These findings provide evidence for the role of distinct genetic and cellular risk profiles for different ARHL subtypes, suggesting that prevention and therapeutic strategies may require targeting specific cell populations at different life stages.

ARHL↗

PubMed2025

Innate immune molecular landscape following controlled human influenza virus infection.

Viral infections can induce prolonged changes in innate immunity. Here, we use blood samples from a human influenza H3N2 challenge study (NCT03883113) to perform comprehensive multi-omics analyses. We detect remodeling of immune programs in circulating innate immune cells that persist after resolution of the infection. We find changes associated with suppressed inflammation, including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also find decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and methylation remodeling show modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the molecular landscape in innate immune cells induced by mild influenza virus infection.

Humans↗

PubMed2026

Early immune dysregulation in Mtb/SIV co-infection resists cART treatment at the single-cell level.

Using single-cell transcriptomics of bronchoalveolar lavage cells from Mtb/SIV co-infected rhesus macaques on cART, we reveal profound immune dysregulation during early SIV co-infection of latent tuberculosis. SIV induces a sharp decline in CD4+ T cells, NK, and NKT cells, with incomplete recovery of Mtb-specific TH1 effector responses despite viral suppression. Instead, a persistent TH17-skewed environment emerges, alongside sustained myeloid inflammation driven by Type I interferon signaling and pro-inflammatory regulators such as KLF6 and NFKB1. Ligand-receptor network analyses demonstrate expanded CD4+ T cell-macrophage crosstalk and loss of immune homeostasis that cART fails to fully restore. These findings expose how SIV remodels the pulmonary immune landscape to impair protective immunity against Mtb, providing a transcriptomic framework to explain TB reactivation in HIV infection. Our work highlights the urgent need for adjunctive immunotherapies to complement cART, aiming to rebalance immune responses and improve TB control in co-infected individuals.

HIV↗

PubMed2026

Integrating single-cell transcriptomics to construct an oncogene-driven prognostic model and elucidate metabolic-immune crosstalk in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, its progression and treatment heterogeneity are mainly influenced by driver gene and tumor micro-environment (TME) interactions. Nevertheless, the mechanisms of this process at the single-cell level remain unclear. This study integrated TCGA and multi-center single-cell transcriptome data to identify a 575 genes HCC-specific core set, developing a single-cell "oncogene scoring" system to quantify individual carcinogenic activity. This score is significantly elevated in malignant and proliferative T cells and is closely associated with metabolic reprogramming, aberrant cell‒cell communication, and immunosuppressive phenotypes. Based on these characteristics, we constructed a machine learning-based Random Survival Forest (RSF) prognostic model validated in multiple independent cohorts, which classifies patients into distinct risk subtypes. The high-risk group exhibits genomic instability, increased tumor stemness, and immune evasion, while the low-risk group was more sensitive to drugs such as sorafenib. This study highlights the potential pathways by which high oncogenic activity is associated with HCC progression, suggesting a profound link with single-cell metabolic‒immune crosstalk. The constructed RSF model offers a promising computational framework for risk stratification and provides hypothesis-generating insights that may inform future personalized treatment strategies for HCC patients.

Hepatocellular carcinoma↗

PubMed2026

Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance mechanism to imipridone therapy.

BACKGROUND: Imipridone ONC201 is the first FDA-approved therapy for H3K27-altered diffuse midline glioma; however, clinical responses remain limited. Defining tumor-intrinsic determinants and microenvironmental, extrinsic factors that shape sensitivity or resistance to imipridones will identify actionable therapeutic opportunities and inform improved clinical strategies. METHODS: To identify mechanisms of imipridone resistance, we obtained postmortem brain tissue from DMG patients who had received imipridones and/or standard care. Single-nucleus RNA and open-chromatin sequencing were performed on N = 22 cases. Immunofluorescence-based myeloid phenotyping was performed on N = 46 cases. Mitochondrial copy-number analysis was performed on N = 19 cases. Validation of imipridone sensitivity, its effect on mitochondrial density, and its synergy with inhibition of mitochondrial biogenesis were assessed in DMG primary cells. RESULTS: We established a single-cell RNA/open-chromatin atlas from postmortem DMG cases and found imipridone treatment resulting in regressed mesenchymal transition, reduced myeloid-derived suppressive cells, and reversed aberrant H3K27-altered enhancer activity. Resistant tumors showed increased mitochondrial density, turnover, and membrane potential. Mitochondrial biogenesis and PPARGC1A emerged as resistance biomarkers and actionable targets. CONCLUSIONS: These studies implicate mitochondrial biogenesis as a biomarker of imipridone resistance and a focus for the development of combinatorial strategies to provide effective therapeutic options for a challenging pediatric brain tumor.

Humans↗

PubMed2025

Cellular imbalance in proximal and distal lung of CFTR-/- sheep in utero and at birth.

BACKGROUND: The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage are still unclear. Inflammation may occur in the CF lung prior to birth in human and several large animal models suggesting an in utero origin for the disease and encouraging further studies prior to birth. METHODS: Here we used the sheep model of CF (CFTR-/-) and age-matched wild-type (WT) sheep of the same breed to investigate the single cell transcriptomes of proximal and distal lung tissue at 80 days and 120 days of gestation and at term (147 days). Single cell RNA-seq was performed on tissues from 4 to 7 animals of each genotype (WT and CFTR-/-) at each time point. RESULTS: At term, FOXJ1-expressing ciliated cells are overrepresented in both lung regions from CFTR-/- lambs, while secretory epithelial and basal cells are underrepresented in proximal lung, as are T cells and monocytes in distal lung. The imbalance in ciliated and basal cells was confirmed by immunohistochemistry. At 120 days of gestation, lymphoid cells are slightly more abundant in proximal and distal lung from CFTR-/- animals compared to WT, consistent with the transient CF-associated inflammatory response in utero. At 80 days of gestation, T and B cells are underrepresented in both lung regions. CONCLUSIONS: The differences in epithelial cell abundance observed in the CFTR-/- lambs at term may reflect sequelae from the loss of CFTR on lung development and differentiation in utero. These findings provide novel insights into the cellular mechanisms of pathology and may be relevant to the design of new therapeutic approaches for CF lung disease.

Animals↗