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PubMed2026

Cell Type-Resolved Causal Inference and Spatial Transcriptomic Integration Reveal Immune-Specific Genetic Drivers of Autoimmune and Malignant Thyroid Disease.

BACKGROUND: Thyroid diseases, including autoimmune thyroid disease (AITD) and thyroid cancer, are characterized by immune dysregulation, yet the cell type-specific genetic mechanisms underlying these conditions remain poorly understood. Most genome-wide association studies (GWAS) have relied on bulk tissue expression quantitative trait loci (eQTL), which cannot resolve the heterogeneity of immune cell populations. METHODS: We performed two-sample Mendelian randomization (MR) analyses using single-cell cis-eQTLs from 14 immune cell subtypes (OneK1K cohort) as instrumental variables against GWAS summary statistics for four thyroid outcomes: autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid cancer and autoimmune thyroiditis. Causal associations were validated through Bayesian colocalization, phenome-wide association analysis (PheWAS) and multi-layered transcriptomic validation encompassing spatial transcriptomics of AITD tissue (GSE248205), bulk RNA-seq of thyroid cancer (GSE3678) and single-cell RNA-seq of thyroid tumours (GSE250521). gsMap spatial LD score regression was applied to map disease heritability onto spatial tissue architecture. RESULTS: We identified six Bonferroni-significant causal gene-cell type pairs for autoimmune hyperthyroidism, including protective effects of ABHD16A in naïve/immature B cells (OR = 0.440), HIST1H3H in CD8 NC T cells (OR = 0.324), HMGN4 in NK recruiting cells (OR = 0.556) and ZKSCAN4 in CD8 S100B T cells (OR = 0.427), with five pairs showing strong colocalization (PP.H4 ≥ 86%). Three pairs reached significance for autoimmune hypothyroidism, including a risk association of HLA-F in CD4 NC T cells (OR = 1.139). For autoimmune thyroiditis, FAM134B/RETREG1 showed consistent suggestive protective associations across both CD4 and CD8 NC T cells (PP.H4 ≥ 90% for both), suggesting a possible involvement of ER phagy regulation in thyroiditis susceptibility. Thyroid cancer showed a suggestive association with HLA-G in classical monocytes (OR = 1.899, PP.H4 = 53%). Spatial transcriptomic validation demonstrated progressive immune infiltration from control tissue to Graves' disease to Hashimoto's thyroiditis (7.7%-15.7%, 46.1%-54.1%, respectively) and strong spatial correlation between target gene expression and corresponding cell type enrichment (e.g., plasma cell-HLA-DQB1: r = 0.491, p < 10-300). HLA-G was independently validated in thyroid cancer bulk (log2fc = 0.542, p = 9.51 × 10-3, AUC = 0.857) and single-cell datasets. PheWAS revealed no significant associations detected for the core candidates. gsMap identified significant enrichment of autoimmune hypothyroidism heritability in gastrointestinal tract, adrenal gland and adipose tissue (all Bonferroni p < 0.002). CONCLUSIONS: This study establishes a multi-scale analytical framework integrating cell type-resolved genetic inference with spatial tissue validation, revealing distinct immunogenetic architectures underlying autoimmune versus malignant thyroid disease. Protective genetic programs in autoimmune hyperthyroidism converge on chromatin remodelling (HIST1H3H, HMGN4, ZKSCAN4) and lipid metabolism (ABHD16A) across lymphocyte subsets, whereas thyroid cancer risk involves immune escape mediated by HLA-G in myeloid cells. The ER-phagy receptor RETREG1 represents a candidate pathway warranting further investigation in autoimmune thyroiditis. These findings provide genetically supported, cell type-specific therapeutic targets and demonstrate a generalizable strategy for dissecting the immune-mediated mechanisms of complex thyroid diseases.

Mendelian randomization↗

PubMed2026

High-Content CRISPR Screening: Methods and Applications.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening has become a central technology in functional genomics, enabling genome-scale interrogation via pooled perturbations. Early CRISPR screens employed survival or simple phenotypic readouts to identify essential genes and drug resistance mechanisms. However, as biological questions have shifted toward understanding regulatory networks, cellular heterogeneity, and context-dependent gene functions, there has been increasing demand for screening strategies capable of capturing complex cellular phenotypes beyond cell fitness. Recent advances in single-cell sequencing, high-content imaging, and spatial transcriptomics have expanded the resolution of CRISPR screening by enabling multidimensional phenotypic characterization following genetic perturbation. By integrating pooled perturbations with diverse readouts, these approaches systematically map targeted gene edits to transcriptional states, cellular phenotypes, and microenvironmental contexts. Meanwhile, innovations in library design, delivery, and computational pipelines have further improved the robustness and interpretability of high-content screening platforms. This review synthesizes the methodological evolution of CRISPR screening, emphasizing advances in perturbation strategies, delivery systems, and multimodal readouts. Representative applications spanning oncology, immunotherapy, developmental biology, neurobiology, and infectious diseases are delineated to demonstrate refined gene network annotations. Additionally, existing technical bottlenecks, such as scalability, cost constraints, and in vivo limitations, are critically assessed. Finally, future directions are proposed to facilitate the development of precise medicine.

CRISPR screening↗

PubMed2026

A single-cell meta-analysis evidences transposable element dysregulation in sex-based differences in Parkinson's disease.

Transposable elements (TEs) (mobile genetic elements comprising ∼45% of the human genome) have recently emerged as potential contributors to Parkinson's disease (PD); however their role and sex-specific impact remain poorly understood. Here, we present the first integrative meta-analysis of TE expression across 4 substantia nigra single-nucleus RNA-seq datasets, comprising a total of 66 donors, generating a cell-type-resolved atlas of TE dysregulation in PD. We identified widespread TE activation across major brain cell types (i.e. neurons, astrocytes, oligodendrocytes and microglia), with marked upregulation of L1s in neurons and HERVs in oligodendrocytes. Sex-stratified analyses revealed distinct male- and female-biased TE signatures, indicating regulatory programs uniquely affected in each sex, including MIR elements in microglia and Alu subfamilies in neurons. Correlation and genomic proximity analyses also uncovered TE-gene associations linked to important PD pathways such as neuroinflammation or myelination. Collectively, our study positions TEs as potential sex-modulated contributors to PD pathology and also provides a public web resource (PATOSS) to explore PD-associated TE transcriptional deregulation.

Parkinson's disease↗

PubMed2026

Follicular Lymphoma Transformation is Characterized by Cytokine-associated Remodeling of Stromal and Macrophage Compartments.

Across cancer, one of the most frequent examples of histologic transformation is the evolution of follicular lymphoma (FL) to an aggressive large cell lymphoma. Despite recent progress, understanding of the molecular and cellular underpinnings of transformation remains incomplete. Here, we dissect the interplay of tumor and microenvironment cell populations across transformation through a multimodal investigation of 95 FL and transformed FL (tFL) samples, including single-cell and bulk RNA-sequencing alongside spatial transcriptomics and proteomics, and validate findings across independent FL-tFL pairs. Upon transformation, fibroblasts and GPNMB+ macrophages increase while lymph-node organizing follicular dendritic and CCL21+ fibroblastic reticular cells were lost, resulting in an altered spatial distribution of cytokines that impacts T cell infiltration and macrophage differentiation and function. Secreted stromal and macrophage signals were further evident by non-invasive plasma proteomics. Taken together, our data reveal expansion of macrophages and fibroblasts as key features of transformation with potential diagnostic and therapeutic implications.

Journal Article↗

PubMed2026

Multi-level Transcriptomic and Machine-learning Analyses Identify MZT1 as a Proliferation-associated Prognostic Marker in Lung Adenocarcinoma.

BACKGROUND/AIM: Lung adenocarcinoma (LUAD) exhibits substantial molecular heterogeneity and variable clinical outcomes, highlighting the need for biomarkers that reflect core tumor biological processes. Centrosome-associated proteins regulate mitotic fidelity and genome stability, yet their roles in LUAD remain incompletely defined. In this study, we systematically characterized mitotic spindle organizing protein 1 (MOZART1; MZT1) and related family members in LUAD. MATERIALS AND METHODS: We performed integrated analyses combining bulk transcriptomic datasets, survival modeling, gene set enrichment, immune deconvolution, machine-learning based prognostic modeling, and single-cell RNA sequencing. Expression patterns and clinical associations of MZT family genes were evaluated across pan-cancer and LUAD cohorts. RESULTS: MZT family genes were consistently upregulated in tumor tissues, with MZT1 showing the most robust expression pattern. Elevated MZT1 expression was significantly associated with reduced overall survival. Functional analyses revealed coordinated activation of proliferative and genome maintenance pathways, including G2/M checkpoint regulation, E2F and MYC signaling, and DNA repair. A multivariable analysis indicated that the prognostic association of MZT1 was reduced after adjusting for canonical proliferation markers, suggesting partial overlap with established proliferation signals. The LASSO-based Cox model demonstrated stable time-dependent predictive performance at 1-, 3-, and 5-year survival. Immune analyses indicated associations between MZT1 expression and tumor microenvironmental features. Single-cell analysis showed that MZT1 expression was predominantly enriched in malignant epithelial cells and associated with proliferative cellular states. Protein-level validation supported concordance with transcriptomic findings. CONCLUSION: MZT1 is a proliferation-associated marker that integrates clinical risk, transcriptional programs, cellular heterogeneity, and predictive modeling in LUAD, providing a potential framework for biomarker development and risk stratification.

Humans↗

PubMed2026

Big data analytics for CLEC5A dynamics based on single cell genomics and proteomics reveal its diverse functions in human diseases.

BACKGROUND: CLEC5A (C-type lectin domain family 5 member A) is an innate immune receptor implicated in inflammatory signaling, contributing to hyperinflammatory responses in infections and sterile inflammation. However, CLEC5A dynamics in human diseases remain to be identified. Here, we systematically characterized CLEC5A dynamics in humans across cells, tissues, and disease states, and to explore the functional significance of CLEC5A in macrophage activation based on single-cell genomics. METHODS: With multi-omics (scRNA-seq, proteomics and big data analytics), we analyzed extensive human transcriptomic datasets (>42,000 samples) to profile CLEC5A expression by cell type, tissue, and disease. Single-nucleus RNA-seq (snRNA-seq) from pediatric congenital heart disease and a virtual CLEC5A gene knockout were also performed to characterize CLEC5A dynamics in humans. RESULTS: CLEC5A is highly enriched in innate immune cells, particularly in macrophages and neutrophils. Baseline CLEC5A in most tissues is low, but it is markedly upregulated in inflammatory and infectious diseases. CLEC5A expression has sex-specific differences in certain organs. Single-cell analysis showed that CLEC5A can be considered novel marker of proinflammatory macrophages with elevated cytokine production, antigen presentation, and impaired phagocytosis. Virtual CLEC5A knockout analysis identified coordinated perturbation of immune-regulatory pathways and overlapping genes linking CLEC5A to macrophage activation networks. CONCLUSION: CLEC5A is predominantly expressed in myeloid cells and acts as a key amplifier of inflammation in human diseases. Our findings highlight CLEC5A as a potential biomarker and therapeutic target in myeloid-driven hyperinflammatory conditions, warranting further experimental and translational validation.

Humans↗

PubMed2026

Myeloid landscape of BRAF-mutant papillary thyroid cancer and thyroiditis.

Papillary thyroid cancer (PTC) is less aggressive when associated with lymphocytic thyroiditis (LT), even in the presence of oncogenic BRAF, including smaller tumours, less lymph node involvement and reduced extrathyroidal extension. To investigate possible immune mechanisms underlying this association, we compared the tumour microenvironment of PTC-BRAF with LT and that without LT using single-cell RNA sequencing (scRNA-seq). Single-cell libraries were generated from fresh and fixed tumour samples with post-dissociation viability >70% using the 10x Genomics Chromium Platform and sequenced on an Illumina NovaSeq 6000. We analysed scRNA-seq data from 11 PTC-BRAF tumours: four with LT (one publicly available sample) and seven without LT. Downstream analyses included quality control, batch correction, dimensionality reduction, and differential gene expression analysis. We found that neutrophils were the predominant myeloid cell type in PTCs without LT. Thyrocytes without LT showed significant expression of the neutrophil recruitment chemokine ECRG4. In the absence of LT, neutrophils expressed oncogenic genes with poor clinical outcomes. In contrast, thyrocytes from tumours with LT showed increased expression of MHC-II antigen presentation, consistent with effective immune surveillance. Thyrocytes and macrophages in the presence of LT showed enrichment of interferon gamma response pathways. Our data suggest that LT in thyroid cancer is associated with enhanced antigen presentation and fewer features of pro-tumourigenic innate immune activity. These results identify previously under-recognised innate immune cell population and associated transcriptomic features, which suggest new mechanisms to target immune treatments in PTC refractory to other therapies.

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

ScRNA-seq analysis reveals the effects of nitrite stress on the endocrine system of the eyestalk in Litopenaeus vannamei.

Nitrite is a harmful substance generated in Litopenaeus vannamei farming systems, largely originating from the inadequate breakdown of surplus feed and shrimp feces. Its accumulation in the water can affect the growth and physiological functions of shrimp, damage the immune system, and even cause mass mortality, thus becoming a key environmental factor restricting the green development of the industry. Under nitrite stress, the eyestalk, as an important neuroendocrine regulatory center in crustaceans, participates in the stress adaptation of the organism and exerts a protective effect by regulating energy metabolism and immune function. However, the molecular regulatory mechanism of the eyestalk in response to nitrite stress remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) technology was used to analyze the heterogeneity of eyestalk cells in L. vannamei under nitrite stress. A total of 18, 394 high-quality cells were obtained, and six major cell subpopulations, including Neurosecretory cell, Motor neuron, Sensory neuron, Interneuron, Neurogliocyte, and Support cell, were identified. Differential expression analysis identified 839 differentially expressed genes, and different cell types showed distinct specific responses to nitrite stress. Functional enrichment analysis indicated that pathways such as glycolysis, oxidative phosphorylation, ribosome function, and endoplasmic reticulum protein processing were significantly activated, while signal transduction and DNA repair-related pathways were inhibited. Further analysis revealed that nitrite stress could induce mitochondrial function changes and trigger oxidative stress, thereby affecting the neuroendocrine system function of the eyestalk. This study provided insights into transcriptomic responses of the eyestalk to nitrite stress at the single-cell level, laying a theoretical foundation for the management of aquaculture environments.

Animals↗

PubMed2026

Machine learning identifies ac4C-related prognostic signature and TUBA1C as therapeutic target in COAD.

To explore the role of N4-acetylcytidine (ac4C)-related genes (acRGs) in colon adenocarcinoma (COAD) and identify reliable prognostic biomarkers and potential therapeutic targets. Multi-source transcriptomic datasets (TCGA-COAD, GSE39582, GSE17536) and single-cell RNA-seq data were analyzed. Ten machine learning algorithms were integrated to construct an acRG-based prognostic signature (acRGBS). Immune microenvironment (TME) and genomic profiling were performed, with in vitro functional experiments validating TUBA1C's role. acRGBS, comprising four hub genes (SARAF, CDC42SE2, TSPYL2, TUBA1C), effectively stratified COAD patients into high- and low-risk groups with distinct survival outcomes and was an independent prognostic factor. High-risk patients exhibited increased genomic instability and immunosuppressive TME, while low-risk patients had favorable immunotherapy response. TUBA1C was overexpressed in COAD cells, and its knockdown inhibited proliferation/migration and induced apoptosis. The acRGBS is a robust prognostic tool for COAD, and TUBA1C serves as a candidate therapeutic target, providing new insights for personalized COAD management.

Humans↗

PubMed2026

Urinary clusterin as a biomarker of human kidney disease progression and response to the endothelin receptor antagonist atrasentan: An exploratory analysis from the SONAR trial.

The endothelin receptor antagonist atrasentan improved kidney outcomes in the SONAR trial for type 2 diabetes and chronic kidney disease (NCT01858532), though individual responses varied. To identify molecular biomarkers of atrasentan response and outcome, we conducted a nested case-control proteomics study (N = 180) within the SONAR trial population and identified urinary clusterin (uCLU) as the top candidate. Transcriptomic analyses of human kidney biopsies at tissue and single cell level from independent cohorts revealed higher CLU mRNA levels associated with worse kidney function and outcomes. An endothelin signaling activation score derived from pathway genes was reduced by atrasentan in mice with diabetic kidney disease. In the SONAR trial (N = 3,060) population, higher uCLU predicted worse outcomes, while atrasentan reduced uCLU by 42.6% over six weeks. Early uCLU changes independently predict improved kidney outcomes. In summary, uCLU is associated with kidney disease progression and response to atrasentan treatment, supporting its potential as a pharmacodynamic biomarker to target therapy.

Humans↗

PubMed2025

Impaired natural killer cell maturation in lung adenocarcinoma driven by FABP4 and SPON2 downregulation through disrupted lipid metabolism.

BACKGROUND: Although natural killer (NK) cells play a crucial role in antitumor immunity, the metabolic changes driving their dysfunction in lung adenocarcinoma remain poorly understood. This study investigates how these metabolic modifications impact NK cell function within the lung adenocarcinoma microenvironment. METHODS: A total of 13 pairs of lung adenocarcinoma samples were obtained from The Cancer Genome Atlas. Differential gene expression, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and single-cell metabolic quantification analyses were used to characterize the transcriptomic, pathway, and metabolic signatures of NK cells. The developmental trajectory was reconstructed via pseudotime analysis. The fatty acid-binding protein 4 (FABP4) and spondin2 (SPON2) expression was examined using immunofluorescence (IF) and immunohistochemistry (IHC) in patients with lung adenocarcinoma. In NK cells with FABP4 downregulation, FABP4 function was analyzed using antibody-independent cell-mediated cytotoxicity assays, flow cytometry (FCM), and liquid chromatography-mass spectrometry. RESULTS: The number of NK cells was significantly decreased in the lung adenocarcinoma microenvironment. FABP4 and SPON2 expression was significantly lower in NK cells within tumor tissues than in the adjacent tissues. FABP4 expression was significantly lower in tumor tissues than in the adjacent tissues, whereas no significant difference in SPON2 expression was observed. The cytotoxic function of NK cells with decreased FABP4 levels was impaired. Non-targeted lipid metabolism analysis indicated that differentially expressed lipids in NK cells with low FABP4 levels were functionally enriched in the glycerophospholipid metabolism pathway compared to those in normal NK cells. CONCLUSIONS: The study findings present new evidence showing that low FABP4 and SPON2 gene expression may impair NK cell maturity by affecting lipid metabolism in lung adenocarcinoma. These results provide a new perspective on restoring immune function in patients with lung cancer.

FABP4↗

PubMed2025

Scalable single-cell total RNA-seq reveals non-coding programs in immunity, infection, and brain development.

Non-coding RNAs represent a widespread and diverse layer of post-transcriptional regulation across cell types and states, yet much of their diversity remains uncharted at single-cell resolution. This gap stems from the limitations of widely used single-cell RNA-sequencing protocols, which focus on polyadenylated transcripts and miss many short or non-polyadenylated RNAs. Here, we adapted single-cell RNA-sequencing on the 10x Genomics platform to capture a broad complement of coding and non-coding RNAs-including miRNAs, tRNAs, lncRNAs, histone RNAs, and non-adenylated viral transcripts. This approach enabled the discovery of rich, dynamic non-coding RNA programs across immune cells, virally infected hepatocytes, and the developing human brain. In dengue virus-infected hepatocytes, we detect non-adenylated viral transcripts and distinguish active from transcriptionally quiescent infected states, each with distinct host regulatory signatures. In brain tissue, we identify biotype-specific, cell-type-restricted non-coding RNAs, including miRNAs whose expression anticorrelates with predicted targets, consistent with post-transcriptional regulatory relationships. We show that MIR137, one of the strongest GWAS loci associated with schizophrenia and intellectual disability, is expressed specifically in Cajal-Retzius cells, an early-born but transient population that guides subsequent cortical neuron migration. These findings demonstrate the importance of non-coding RNAs in defining cell identity and state, and show how expanded transcriptome coverage can reveal additional layers of gene control-now accessible through practical and scalable single-cell profiling.

Journal Article↗

PubMed2026

Identification of immune cell type-specific susceptibility genes in multiple cancers using transcriptome-wide association studies.

BACKGROUND: Transcriptome-wide association studies (TWAS) integrate gene expression and genome-wide association studies (GWAS) to identify disease susceptibility genes. Because gene expression varies substantially across cell types within tissues, cell type-specific prediction models may enhance the power of TWAS. METHODS: We conducted cell type-specific TWAS leveraging single-cell RNA sequencing data from the OneK1K cohort (14 immune cell types, 1.27 million cells) and GWAS summary statistics for 7 cancers (>290 000 cases in total). To improve prediction accuracy, we developed a modeling framework that incorporates shared gene expression effects across cell types. RESULTS: At a false discovery rate of 5%, we identified 106 (Bonferroni 5%: 13) previously unreported loci for breast cancer, 51 (4) loci for prostate cancer, 11 (4) loci for lung cancer, 39 (5) loci for melanoma, 9 (1) loci for ovarian cancer, and 2 (1) loci for diffuse large B-cell lymphoma, with most genes exhibiting cell type specificity. Gene set analyses confirmed joint associations of unreported genes with breast and prostate cancer risk in UK Biobank data. Additional lung tissue single-cell RNA sequencing data with 113 individuals validated 18 of 32 (56.3%) statistically significant genes for lung cancer. Across cancers, 139 statistically significant genes were shared by at least 2 cancer types and were primarily enriched in specific immune cell types. CONCLUSION: Cell type-specific TWAS improve the identification of novel cancer susceptibility loci and provide insights into the immune landscape of cancer etiology.

Humans↗

PubMed2026

Cellular transcriptomic signatures underpinning the heterogeneity of depression in Alzheimer's disease.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) and major depressive disorder (MDD) share genetic etiologies. Here, we investigated brain transcriptomic landscapes to gain insights into shared and divergent molecular and biological etiologies across LOAD and MDD. METHODS: Brain single-nucleus RNA sequencing (snRNA-seq) datasets from cognitively normal older and young individuals and LOAD patients stratified by comorbid MDD were analyzed to identify differential expressed genes (DEGs). Using cell type-specific DEGs we performed biological pathway and intercellular-communication networks analyses. We investigated shared DEGs across MDD and LOAD cohorts and sex-specific DEGs. Results were validated by comparison with four transcriptomic and proteomic studies of MDD and depression. RESULTS: MDD-associated dysregulated genes and pathways were shared between LOAD and cognitive-normal individuals, including JUNB and DUSP1 in glutamatergic neurons, and PRAM1 and SNX9 in microglia. DEGs shared between the MDD and LOAD cohorts included HSPA1A and NDUFB7 in glutamatergic neurons. Sex interaction analysis identified numerous new DEGs in the MDD cohorts, whereas there were ≈5 to 10 times more DEGs in female than in male individuals. LOAD and MDD common microglial pathways included neuronal injury, stress, peroxisome proliferator-activated receptor (PPAR) signaling and interferon alpha/beta signaling. DISCUSSION: LOAD and MDD exhibited common molecular profiles, dysregulated pathways, and cellular communication changes. MDD develops earlier in life, thus, our findings provide a window into early molecular and biological processes preceding LOAD-onset.

Humans↗

PubMed2026

The pseudouridine epitranscriptomic landscape of advanced prostate cancer therapeutic resistance identifies TIMM17A as a key player.

BACKGROUND: Resistance to androgen receptor signaling inhibitors (ARSIs) remains a major barrier of advanced prostate cancer (PCa) treatment. While RNA epitranscriptomic modifications are increasingly recognized as key regulators of tumor biology, the role of pseudouridine (Ψ) in therapeutic resistance is largely unexplored. METHODS: A darolutamide-resistant PCa cell model was established and subjected to integrated multi-omics profiling using bulk RNA sequencing and photo-crosslinking-assisted Ψ sequencing (PA-Ψ-seq). Differential expression and pseudouridylation analyses were combined to identify Ψ-associated genes. Public datasets validated expression and prognosis. Functional assays including RNA knockdown, cell proliferation, colony formation, and xenograft models were conducted. Single-cell RNA sequencing investigated tumor microenvironment (TME) interactions. RESULTS: We identified extensive transcriptomic and pseudouridylation alterations associated with ARSI resistance, with a significant positive correlation between Ψ modification and mRNA expression. Integrated analysis highlighted a subset of "hyper-up" genes enriched in resistance-related pathways. Thus, TIMM17A was identified as a novel candidate. TIMM17A expression was significantly elevated in PCa and correlated with disease progression and poor prognosis. Experimental validations demonstrated that TIMM17A promoted tumor growth and resistance, while its knockdown restored sensitivity to darolutamide both in vitro and in vivo. Mechanistically, TIMM17A expression may be regulated by PUS1‑mediated pseudouridylation. Single-cell analysis further revealed that TIMM17A is enriched in malignant epithelial cells and associated with enhanced cell-cell communication within the TME. CONCLUSIONS: This study delineates the pseudouridine epitranscriptomic landscape in advanced PCa and identifies TIMM17A as a key mediator of therapeutic resistance. Targeting the Ψ-TIMM17A axis may offer a novel strategy to overcome ARSI resistance.

Advanced prostate cancer↗

PubMed2026

Genomic Structural Equation Modeling Identifies a Shared Inflammatory Genetic Dimension Across Inflammatory Arthritis Phenotypes and Biomarkers.

BACKGROUND: Inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout, shares systemic inflammatory features indexed by C-reactive protein (CRP) and interleukin-6 (IL-6), yet the extent of their common genetic basis remains unclear. AIMS: We aimed to delineate the shared genetic architecture across IA phenotypes and inflammatory biomarkers. MATERIALS AND METHODS: We applied genomic structural equation modelling (Genomic SEM) to GWAS summary statistics for RA, PsA, gout, CRP and IL-6, fitted a single common factor, and performed multivariate GWAS followed by fine-mapping, transcriptome-wide association, gene-based analysis, pathway enrichment, and cell-type and spatial mapping. RESULTS: A single common factor was fitted (CFI = 0.990, SRMR = 0.045). The multivariate GWAS identified 56 genome-wide significant SNPs across 10 independent lead loci, including one novel signal. Fine-mapping prioritized high-confidence variants near PTPN22, the CRP gene cluster and a urate-associated locus. Gene-level analyses converged on DCLRE1B, PTPN22, IL6R, NLRP3 and HNF1A, with pathway enrichment implicating inflammasome assembly and metabolic-inflammatory overlap. Cell-type enrichment highlighted myeloid populations, and spatial mapping localized signals to lung, kidney, mucosal epithelium and gastrointestinal tissues. DISCUSSION: These results delineate a shared inflammatory genetic dimension across IA phenotypes and biomarkers, anchored in immune, inflammasome, cytokine-receptor and metabolic pathways. CONCLUSION: Together, these findings provide a valuable framework for prioritizing candidate genes and cellular contexts for future investigation.

TWAS↗

PubMed2026

FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by profound immunosuppression that facilitates tumor progression and promotes therapeutic resistance. Fibroblast activation protein (FAP), a recognized theranostic target in multiple cancers, is upregulated in GBM and predominantly expressed by pericyte-like stromal cells. Here we identify a role for FAP⁺ pericyte-like cells in shaping the GBM immune microenvironment through monocyte recruitment and differentiation. Analysis of The Cancer Genome Atlas (TCGA) datasets, supported by reverse-transcription quantitative PCR and immunohistochemistry, revealed that elevated FAP expression-serving as a proxy for the abundance of FAP⁺ pericyte-like cells-is associated with an immune-enriched tumor microenvironment characterized by higher macrophage abundance and elevated expression of M2 polarization markers. Spatial analyses, including immunofluorescence and spatial transcriptomics, demonstrated that immunosuppressive macrophages preferentially localize in proximity to FAP⁺ pericytes. Single-cell RNA sequencing identified these FAP⁺ cells as a distinct perivascular stromal subset with a unique expression pattern of extracellular matrix components and cytokines, including CCL2 and CSF1, with corresponding receptors expressed on myeloid cells. Functional assays using patient-derived FAP⁺ pericyte-like cells confirmed their ability to attract monocytes via soluble mediators and to promote their differentiation and polarization into tumor-associated macrophages with immunoregulatory features, partly mediated by the CSF1-CSF1R axis. Orthotopic co-implantation experiments in mice further supported their capacity to enhance myeloid infiltration in vivo. Consistent with these biological effects, a transcriptional signature characteristic of FAP⁺ pericytes correlated with worse overall survival in patients with GBM. Together, these findings position FAP⁺ pericyte-like cells as modulators of the GBM immune landscape, fostering a tumor-permissive niche by promoting the differentiation of circulating monocytes into immunoregulatory macrophages. Targeting this stromal population may offer new therapeutic avenues to reprogram tumor-associated immune responses in GBM.

Journal Article↗