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Integrative Proteogenomics and Single-Cell Transcriptomics Prioritize Candidate Causal Proteins and Therapeutic Targets in Age-Related Macular Degeneration.
Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment, yet identifying effector proteins and tissue-specific mechanisms underlying genome-wide association study (GWAS) loci remains challenging. This study aimed to systematically prioritize candidate causal circulating proteins and delineate their cellular and transcriptional dynamics in AMD. We integrated plasma protein quantitative trait loci (pQTL) summary statistics from the UK Biobank Pharma Proteomics Project (UKB-PPP; N=53,022) with FinnGen AMD GWAS data using proteome-wide association studies (PWAS), summary-data-based Mendelian randomization (SMR) with the HEIDI test, and Bayesian colocalization analysis. Prioritized candidates were mapped across human and murine retinal single-cell/single-nucleus RNA sequencing atlases. Transcriptional responsiveness was validated in an independent clinical microarray dataset (GSE103060) and in human retinal pigment epithelial cells (ARPE-19) via in vitro inflammatory stimulation and RT-qPCR. Target tractability was assessed using pharmacological databases. Multi-stage genetic screening prioritized five candidate proteins stratified into two confidence tiers: three Tier 1 causal drivers supported by colocalization (PP4 > 0.80)-including risk factors CSF2, IL20RB, and WARS1 (also known as WARS)-alongside two Tier 2 candidates supported by SMR and HEIDI, comprising risk factor PILRA and inversely associated metabolic factor ACADSB. Retinal transcriptomic mapping localized PILRA specifically to microglia, ACADSB to inner retinal neurons, and WARS1 to photoreceptors, RPE, and vascular compartments, while IL20RB and CSF2 exhibited low baseline expression. In independent validation cohorts, IL20RB and WARS1 were significantly up-regulated in choroidal neovascularization (CNV) membrane-derived RPE from patients with AMD (p<0.01). Exposure of ARPE-19 cells to TNF-α markedly induced mRNA levels of IL20RB (P=0.0025) and WARS1 (p<0.0001). Dual normalization against ACTB as a secondary internal reference yielded consistent significant induction. Pathway enrichment highlighted cytokine-driven receptor cascades (JAK-STAT signaling) and mitochondrial substrate catabolism (branched-chain amino acid and fatty acid metabolism). Drug-target profiling identified small molecules and nutraceuticals interacting with ACADSB, CSF2, and WARS1. By combining large-scale plasma proteomic genetics with single-cell mapping and experimental validation, this study identifies a prioritized set of candidate causal proteins linking neuroimmune activation, vascular remodeling, and mitochondrial bioenergetics in AMD, providing candidate entry points for mechanistic and therapeutic exploration.
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Investigating the prognostic role of citrullination-related genes in breast cancer by combining transcriptomics, single-cell analysis and verification.
Citrullination, a process linked to autoimmune diseases, has been implicated in cancer, but its role in breast cancer (BRCA) remains unclear. This study aimed to identify citrullination-related genes (CRGs) associated with prognosis in BRCA. We utilized datasets from The Cancer Genome Atlas (TCGA-BRCA) and Gene Expression Omnibus (GEO), pinpointing candidate genes by intersecting differentially expressed genes (DEGs) from TCGA-BRCA with known CRGs. Prognostic CRGs were selected using univariate Cox regression and Lasso regression analyses, and a predictive nomogram was created based on independent prognostic factors identified through multivariate Cox regression. Our findings revealed that SEZ6, S100B, SPIB, and TFF1 were key CRGs used to construct a risk model. High-risk BRCA patients exhibited immune-suppressive tumor microenvironments (TMEs) with low CD8+ T cell mutation and enrichment in C1/C4 immune subtypes. In contrast, low-risk patients displayed high immune infiltration and enrichment in C2/C3/C6 subtypes. High expression of S100B, SPIB, and TFF1 was associated with increased immune infiltration by NK cells and T cells, while high SEZ6 expression was linked to neutrophil mutations, PD-L1 upregulation, and low CD8+ T cell infiltration. Molecular docking studies explored the interactions of these CRGs with entinostat. In conclusion, SEZ6, S100B, SPIB, and TFF1 were identified as significant prognostic genes in BRCA, providing insights into BRCA pathogenesis and potential personalized treatment strategies.
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MFAP5 Activates ITGA5 to Drive Tooth Germ Mineralization Through the MAPK/ERK Pathway: Insights from Single-Cell Transcriptomics.
Tooth germ development is a precisely orchestrated process dependent on integrated cellular interactions and molecular signals, yet its regulatory mechanisms remain incompletely defined. Here, we constructed a high-resolution cellular atlas of miniature pig tooth germs using 10× single-cell RNA sequencing to investigate the molecular mechanisms underlying tooth mineralization. By leveraging cellular heterogeneity and dynamic gene expression trajectories in epithelial and mesenchymal populations, we identified microfibril-associated protein 5 (MFAP5) as a previously unrecognized regulator of the odontogenic program. Functional assays demonstrate that MFAP5, an extracellular matrix component, is indispensable for mesenchymal differentiation and matrix mineralization in vitro. Mechanistically, MFAP5 engages Integrin alpha-5 (ITGA5) to activate Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase (ERK/MAPK) signaling in odontoblast-lineage cells, thereby promoting odontoblast differentiation and dentin deposition. Collectively, our single-cell-resolved analyses uncovered a MFAP5-ITGA5-ERK/MAPK signaling axis that operates in a cell-state-specific manner during tooth germ mineralization, providing new mechanistic insights into odontogenic differentiation and a potential molecular basis for dental tissue regeneration strategies.
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Single-Cell RNA Sequencing Combined with MEBOCOST Reveals Alveolar Macrophage-Mediated Immunometabolic Communication Mechanisms in Sepsis-Induced Acute Lung Injury.
Background: Sepsis-induced acute lung injury (SI-ALI) leads to high mortality in critically ill patients, and no specific targeted treatments are available. Current studies mainly characterize intercellular crosstalk via protein-ligand-receptor frameworks, while metabolite-derived immune signal transmission is largely unclarified. Alveolar macrophages are located at the alveolar barrier and may act as central metabolic coordinators to trigger neutrophil-mediated lung inflammation, yet the complete metabolite signaling network has not been systematically mapped. Methods: We integrated single-cell and bulk transcriptomic datasets from CLP-induced septic mouse lungs. CellChat and MEBOCOST were jointly used to reconstruct protein-metabolite dual communication networks. LASSO regression and random forest were combined to screen core metabolic hub genes, followed by single-cell expression mapping and in vivo histology & qPCR validation. Results: We identified a pivotal alveolar macrophage-neutrophil immunometabolic axis dominated by iron-Slc40a1 and LTB4-Ltb4r1 signaling. Three hub genes (Pmvk, Slc2a1, Slc7a11) coordinately regulate inflammatory pathways, among which myeloid-enriched Slc7a11 balances cellular redox and paracrine inflammatory responses. Conclusions: This study establishes the first dual-layer cell communication atlas for SI-ALI, proposes a macrophage-centered metabolic inflammatory regulatory model, and highlights Slc7a11 as a potential therapeutic target for septic lung injury.
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Mapping and engineering the human cell-cell interactome.
Efforts to systematically understand how cell interactions tune tissue-level function have motivated transformative advances in single-cell transcriptomics and spatial profiling. Although these technologies can measure molecular states in individual cells and their spatial mapping within tissues, they also reveal that there exists a fundamental knowledge gap of how cells influence each other in context. In this Perspective, we propose an initiative to map and engineer the human cell-cell interactome: a functional atlas of how all major human cell types communicate. We highlight how recent innovations can make this vision achievable. As a first moonshot, we propose the 'Billion Cell×Cell Project', which systematically characterizes the outcomes of defined cell-cell dyads across diverse cell types and conditions. We envision this multistage initiative will produce progressively deeper insights and unlock additional avenues for therapeutic discovery. We call on the scientific community to join us in building the tools, datasets and models that will decode and rewrite the language of life between cells.
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Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea.
Rosacea is a chronic inflammatory skin disorder, whose underlying cellular and molecular mechanisms remain obscure. Here, we generate a single-cell atlas of facial skin from female rosacea patients and healthy individuals. Among keratinocytes, a subpopulation characterized by IFNγ-mediated barrier function damage is found to be unique to rosacea lesions. Blocking IFNγ signaling alleviates rosacea-like phenotypes and skin barrier damage in mice. The papulopustular rosacea is featured by expansion of pro-inflammatory fibroblasts, Schwann, endothelial and macrophage/dendritic cells. The frequencies of type 1/17 and skin-resident memory T cells are increased, and vascular mural cells are characterized by activation of inflammatory pathways and impaired muscle contraction function in rosacea. Most importantly, fibroblasts are identified as the leading cell type producing pro-inflammatory and vasodilative signals in rosacea. Depletion of fibroblasts or knockdown of PTGDS, a gene specifically upregulated in fibroblasts, blocks rosacea development in mice. Our study provides a comprehensive understanding of the aberrant alterations of skin-resident cell populations and identifies fibroblasts as a key determinant in rosacea development.
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Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.
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Tangential single-cell spatial transcriptomics resolves early ray lineage trajectory in poplar.
Vascular cambium drives secondary growth in woody plants, yet its closely related stem-cell populations-fusiform and ray initials-are difficult to distinguish, limiting resolution of early ray fate specification. In Populus tremula × Populus alba clone 717, we integrated a 2-yr biweekly field survey of xylem ray anatomy with time-series stem transcriptomes and single-cell-resolution tangential spatial transcriptomics to resolve early ray-lineage states in situ. Across 2 growing seasons, ray cell number and size/area traits showed reproducible dynamics and were most strongly associated with daylength, radiation and temperature averaged over the preceding 1 to 4 wks. Co-expression analysis identified gene modules that covary with ray traits and these environmental indices. By enhancing recovery of ray cambial cells through tangential sectioning, we generated a single-cell-resolution spatial transcriptomic atlas that distinguishes fusiform initial cells (FICs) and ray initial cells (RIC_1/2), and reconstructs a continuous early ray trajectory from FICs to RICs and xylem ray precursor cells (XRP_1-3), supported by RNA in situ hybridization. Integrating field-linked candidates, public single-cell RNA sequencing resources, and spatial markers, we identified 227 ray-lineage candidates, enriched for chromatin/nuclear functions and ribosome biogenesis, with relatively few transcription factors. These results provide stage-resolved markers and candidates for dissecting ray development and its seasonal environmental covariation.
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Single-cell transcriptomics uncovers endothelial progenitor-like remodelling driving human coronary atherosclerosis progression.
Coronary atherosclerosis underlies life-threatening conditions such as myocardial infarction and stroke, yet its cellular dynamics remain incompletely understood. Here, through single-cell RNA sequencing of 27,941 cells from 56 human coronary segments, we constructed a disease-stage-resolved cellular atlas, revealing pathological remodelling of endothelial cells (ECs) into a progenitor-like state (EC5SLCO4A1+) with low expression of canonical EC dysfunction signatures. EC5SLCO4A1+ abundance increased with atherosclerotic stage, and its emergence is driven by PRDM15 through direct transcriptional activation. Analysis of the EC5SLCO4A1+ interaction network revealed extensive crosstalk with immune cell types, the interaction between which contributed to atherosclerotic progression. Endothelial overexpression of Prdm15 in vivo exacerbated atherosclerosis, while its suppression ameliorated the disease phenotype, with diminished EC5SLCO4A1+-like cells and immune infiltration. Our findings underscore the central role of EC subtype remodelling in the progression of human coronary atherosclerosis and reveal tractable targets for therapeutic intervention.
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scDrugLink: Single-Cell Drug Repurposing for CNS Diseases via Computationally Linking Drug Targets and Perturbation Signatures.
Central nervous system (CNS) diseases such as glioblastoma (GBM), multiple sclerosis (MS), and Alzheimer's disease (AD) remain challenging due to their complexity and limited treatments. Conventional drug repurposing strategies often rely on bulk RNA sequencing data, which can overlook cellular heterogeneity and mask rare but critical cell populations. Here, we introduce scDrugLink, a computational method that integrates single-cell transcriptomic data with drug targets and perturbation signatures to improve repurposing. For each cell type, scDrugLink constructs a Drug2Cell matrix based on drug targets to estimate promotion/inhibition scores and derives sensitivity/resistance scores by reverse matching signatures and disease-associated genes. These scores are then "linked", yielding robust therapeutic rankings. In our study, we present a systematic evaluation of single-cell drug repurposing methods for CNS diseases. Applied to atlas data for GBM, MS, and AD, scDrugLink surpassed three state-of-the-art methods (ASGARD, DrugReSC, and scDrugPrio), achieving area under the receiver operating characteristic curve (AUC) ranges of 0.6286-0.7242 and area under the precision-recall curve (AUPRC) ranges of 0.3412-0.5484. It also ranked top when comparing AUC and AUPRC at the level of individual cell types. Moreover, applying the "linking" principle to baseline methods boosted their performance, on average improving AUC and AUPRC by 0.0160 and 0.0244, respectively. Despite the advancements, the complexity and heterogeneity of CNS diseases, along with incomplete drug data, indicate that further improvement is necessary. We discuss these challenges and suggest directions for enhancing single-cell drug repurposing in the future.