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Investigating the prognostic value of constructing disulfidptosis-related gene models for lung adenocarcinoma patients.
OBJECTIVE: Disulfidptosis is a novel mode of cell death, a programmed mode of intracellular disulfide accumulation due to solute carrier family 7 member 11 (SLC7A11)-mediated abnormalities in the cell membrane cystine transport system. Numerous studies have confirmed the prominent role played by SLC7A11 in tumors, but the involvement of SLC7A11 as an important mediator of disulfidptosis in the death process of lung adenocarcinoma cells remains unclear. MATERIALS AND METHODS: We obtained 4,107 SLC7A11-related genes and analyzed them using a total of 1,040 lung adenocarcinoma transcriptome sequencing data from The Cancer Genome Atlas (TCGA) cohort and GEO (Gene Expression Omnibus) cohort and 991 relevant clinical data. First, we screened for differential genes and identified molecular subtypes for assessing characteristic differences between lung adenocarcinoma subtypes under the influence of SLC7A11-associated genes. Then, risk score models were constructed to assess the prognosis, immune infiltration, tumor microenvironment, and drug treatment effects in lung adenocarcinoma patients. Finally, we also analyzed the distribution of cell types and expression of characteristic genes within the tumor using a single-cell database. In addition, relevant drug sensitivities were predicted. RESULTS: We screened 956 genes with significant differences and identified 2 molecular subtypes and found significant differences in their prognosis and that subtype B had a significantly better survival prognosis than subtype A. In addition, we found that pathways associated with cell proliferation division and DNA repair were enriched in the high-risk type A samples. Finally, we constructed a robust risk-scoring system, and our risk analysis revealed a general reduction of various immune cell components and tumor stromal components in the immune microenvironment of high-risk lung adenocarcinoma and a distinct immune infiltration pattern of immune cells, which was associated with a lower survival rate. CONCLUSIONS: Our comprehensive analysis of SLC7A11-related genes suggests that disulfidptosis has a potential value in the tumor microenvironment, immunity, clinical outcome, and prognosis of lung adenocarcinoma. These findings may increase our understanding of disulfidptosis as a novel cell death paradigm and provide ideas for assessing the prognosis of lung adenocarcinoma and developing new diagnostic and therapeutic strategies.
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Single-cell atlas of hepatic cellular plasticity and immune niche reprogramming in liver cirrhosis.
BACKGROUND: Cirrhosis is a severe liver disease characterized by inflammation, fibrosis, and immune dysregulation. This study exploits publicly available single-cell sequencing datasets to decipher disease-relevant specific immune cell subtypes, their gene expression profiles and altered transcription factor activity in cirrhosis, aiming to understand their roles in disease onset and progression. METHODS: To investigate the dynamic changes and underlying mechanisms of immune cells in cirrhosis, we employed a comprehensive bioinformatics approach integrating several advanced tools and analytical methods. Single-cell RNA sequencing data were processed and analyzed using Seurat for cell clustering and annotation. Monocle was used for pseudotime trajectory analysis to explore cellular differentiation pathways. CellChat enabled the assessment of cell‒cell communication networks among immune populations. Additionally, we conducted single-cell regulatory network inference to identify key transcriptional regulators. Immune response enrichment analysis (IREA) was performed to evaluate immune-related functional pathways, providing deeper insights into the immune landscape and disease progression in cirrhosis. RESULTS: We analyzed 35,017 cells, identifying 21 clusters and 12 major immune cell types. Macrophages, CD4+ T cells, and NK cells showed notable shifts in proportion in cirrhosis, suggesting key roles in disease progression. Pseudotime analysis revealed core macrophage and CD4+ T-cell subpopulations linked to cirrhosis. Functional analysis showed enrichment of IFN-α, IFN-β, and IL-1β in cirrhotic immune cells, primarily regulated by ETS2 and THRA. Fibroblast-mediated intercellular communication was enhanced, especially via increased macrophage migration inhibitory factor (MIF) signaling with B cells, indicating potential therapeutic targets in cytokine pathways and transcriptional regulation. CONCLUSION: The analysis revealed three key axes influencing disease-related immune regulation: TNF-α/ETS2-driven polarization of macrophages toward a Mac-d phenotype, IL-1α/β/THRA-associated polarization of CD4+ T cells toward a T4-c phenotype, and enhancement of the fibroblast-to-B-cell MIF signaling axis. This network offers valuable insights and potential therapeutic targets for advancing cirrhosis research and clinical treatment.
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Prognosis of colorectal cancer, prognostic index of immunogenic cell death associated genes in response to immunotherapy, and potential therapeutic effects of ferroptosis inducers.
INTRODUCTION: This study leverages bioinformatics and medical big data to integrate datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), providing a comprehensive overview of immunogenic cell death (ICD)-related gene expression in colorectal cancer (CRC). The research aims to elucidate the molecular pathways and gene networks associated with ICD in CRC, with a focus on the therapeutic potential of cell death inducers, including ferroptosis agents, and their implications for precision medicine. METHODS: We conducted differential expression analysis and utilized advanced bioinformatic techniques to analyze ICD-related gene expression in CRC tissues. Unsupervised consensus clustering was applied to categorize CRC patients into distinct ICD-associated subtypes, followed by an in-depth immune microenvironment analysis and single-cell RNA sequencing to investigate immune responses and cell infiltration patterns. Experimental validation was performed to assess the impact of cell death inducers on ICD gene expression and their interaction with ferroptosis inducers in combination with other clinical drugs. RESULTS: Distinct ICD gene expression profiles were identified in CRC tissues, revealing molecular pathways and intricate gene networks. Unsupervised consensus clustering refined the CRC cohort into unique ICD-associated subtypes, each characterized by distinct clinical and immunological features. Immune microenvironment analysis and single-cell RNA sequencing revealed significant variations in immune responses and cell infiltration patterns across these subtypes. Experimental validation confirmed that cell death inducers directly affect ICD gene expression, highlighting their therapeutic potential. Additionally, combinatorial therapies with ferroptosis inducers and clinical drugs were shown to influence drug sensitivity and resistance in CRC. DISCUSSION: Our findings underscore the importance of ICD-related genes in CRC prognosis and therapeutic targeting. The study provides actionable insights into the efficacy of cell death-inducing therapies, particularly ferroptosis inducers, and their regulatory mechanisms in CRC. These discoveries support the development of precision medicine strategies targeting ICD genes and offer valuable guidance for translating these therapies into clinical practice, with the potential to enhance CRC treatment outcomes and patient survival.
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Unveiling B7/CD28 family proteins in hepatocellular carcinoma: insights into communication and prognostic significance.
BACKGROUND: Immunotherapy has made remarkable achievements in cancer treatment, but it still faces the challenge of limited response rates in liver cancer therapy. Although there has been extensive research on the role of programmed cell death-ligand 1 (PD-L1) in hepatocellular carcinoma (HCC), our understanding of the effects of other inhibitory B7/CD28 family members is still limited despite advancements in prognostic tools, more specific, accurate, and robust biomarkers are required to improve HCC patient prognoses. METHODS: We acquired the single-cell sequencing data from relevant literature and selected 42 liver tissue samples, including 89,246 cells from HCC patients, to investigate the expression, localization, and intercellular communications of the B7/CD28 family in HCC. Within the Cancer Genome Atlas dataset, we utilized Lasso and Cox regression analyses to develop a risk model for identifying the most pertinent B7/CD28 family proteins associated with prognosis. Subsequently, we conducted a retrospective analysis of 94 HCC patients who underwent hepatectomy at our institution and determined the prognostic significance of this malignancy. RESULTS: Based on the single-cell RNA sequencing data, we have delineated various members of the B7/CD28 family and their corresponding receptors. We have elucidated their distribution on tumor cells and immune cells, revealing active intercellular communications among tumor cells, fibroblasts, and epithelial cells. Through the implementation of Lasso, we have pinpointed a significant correlation between the B7H3 molecule and prognosis. Leveraging multiplex immunofluorescence, we were able to discern three distinct patterns of B7H3 expression-tumor-associated, stroma-associated, and a hybrid form encompassing both. Notably, the presence of B7H3 in the stroma exhibited the most robust correlation with prognosis. Furthermore, the efficacy of our prognostic signature was validated through clinicopathological analyses conducted at our institution. CONCLUSIONS: In conclusion, the B7/CD28 family plays an active role in the tumor immune microenvironment and cellular communication. B7H3 could serve as an indicator for predicting the outcome of HCC. Additional investigation is required to validate these discoveries in future groups of individuals and assess their viability as therapies guided by biomarkers.
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Integration of Multi-Omics and Machine Learning Identifies TGFB1 and SERPINE1 as Biomarkers of Vascular Smooth Muscle Cell Senescence in Intracranial Aneurysms.
Intracranial aneurysms (IAs) are severe cerebrovascular disorders lacking effective gene therapy or pharmacological interventions. Vascular smooth muscle cell (VSMC) senescence has been associated with various cardiovascular and cerebrovascular diseases; however, its role in IA pathogenesis remains unexplored, and the key regulatory genes remain unidentified. By integrating multi-omics data, machine learning, and experimental validation, we identified two senescence-associated genes (SAGs) that may serve as VSMC senescence biomarkers in IAs. We integrated single-cell RNA sequencing data from a mouse elastase-induced IA model (GSE193533) with human bulk RNA sequencing and microarray datasets to investigate VSMC senescence in IA. Our analyses included cell clustering, cell-cell communication, differential expression, functional enrichment, pseudotime trajectory inference, and high-dimensional weighted gene co-expression network analysis (hdWGCNA). Machine learning identified candidate SAGs, which were validated using external datasets and immunohistochemical analysis of human IA tissues. Single-cell analysis of the mouse IA model revealed 26 clusters across 10 cell types, with IA samples showing VSMC depletion, immune cell enrichment, and fibroblast expansion. VSMCs were categorized into five subsets (VSMC1-5), with the extracellular matrix remodeling and synthetic-inflammatory subtype (VSMC1) significantly increased. Differential expression analysis of VSMCs intersecting with senescence-associated genes from the Aging Atlas database identified 159 SAGs enriched in inflammatory and apoptotic pathways. Integrating hdWGCNA and bulk transcriptomics identified 45 key SAGs. TGFB1 and SERPINE1 emerged as robust biomarkers of senescence-associated VSMCs, showing high diagnostic accuracy (AUC > 0.75) and upregulation in IA tissues. Our study provides new insights into the pathological mechanisms of intracranial aneurysms. VSMC senescence may contribute to IA progression. TGFB1 and SERPINE1 may serve as biomarkers and promising therapeutic targets for VSMC senescence in IA. However, their specific mechanisms require further investigation and validation.
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Increased Smoothened signaling promotes kidney fibrosis through inhibiting autophagy in fibroblasts.
INTRODUCTION: Kidney fibrosis progressively induces kidney function loss, leading to kidney failure. Myofibroblast transition from fibroblast is significantly involved in the development of kidney fibrosis. Previous studies revealed that sonic hedgehog (Shh), the upstream ligand of Smoothened (Smo) receptor signaling, contributes to kidney fibrosis. However, the role of Smo in fibroblast activation remains unclear. METHODS: Here, fibroblast-specific Smo and β-catenin knockout mice were generated, primary kidney fibroblasts were isolated and cultured. Single-nucleus (snRNA-seq) plus bulk RNA sequencing were performed. Autophagy capacities, including autophagy flux, autophagy vacuoles, and autophagy-related gene expression, were assessed. RESULTS: From snRNA-seq data of the human atlas combined with bulk RNA sequencing of primary mouse kidney fibroblasts, we discovered Smo was upregulated in kidney fibroblasts in chronic kidney disease (ureteral obstruction, ischemia/reperfusion, Adriamycin nephrosis and 5/6th nephrectomy models). This was accompanied by substantially diminished autophagic capacity. Shh stimulation or ectopic Smo deactivated autophagy, exaggerated myofibroblast proliferation and activation in the fibroblasts. These effects were further enhanced in autophagosome protein ATG5 knockout fibroblasts. Moreover, Smo, through the β-arrestin 1/Src/β-catenin pathway, induced the transcription of mammalian target of rapamycin. This mediated autophagy suppression in fibroblasts, leading to myofibroblast activation and kidney fibrosis. Fibroblast-specific knockout of Smo or β-catenin greatly preserves autophagy capacity and ameliorates kidney fibrosis. Notably, NVP-LDE225, a specific Smo antagonist, effectively restored fibroblast autophagy and retarded kidney fibrotic lesion formation. CONCLUSIONS: Our study defines a prominent mechanism of myofibroblast activation and supplies a potential avenue for targeting fibroblast Smo to treat chronic kidney disease.
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Cellular Characterization and Interspecies Evolution of the Tree Shrew Retina across Postnatal Lifespan.
Tree shrews (TSs) possess a highly developed visual system. Here, we establish an age-related single-cell RNA sequencing atlas of retina cells from 15 TSs, covering 6 major retina cell classes and 3 glial cell types. An age effect is observed on the cell subset composition and gene expression pattern. We then verify the cell subtypes and identify specific markers in the TS retina including CA10 for bipolar cells, MEGF11 for H1 horizontal cells, and SLIT2, RUNX1, FOXP2, and SPP1 for retinal ganglion cell subpopulations. The cross-species analysis elucidates the cell type-specific transcriptional programs, different cell compositions, and cell communications. The comparisons also reveal that TS cones and subclasses of bipolar and amacrine cells exhibit the closest relationship with humans and macaques. Our results suggests that TS could be used as a better disease model to understand age-dependent cellular and genetic mechanisms of the retina, particularly for the retinal diseases associated with cones.
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Mapk14 is a Prognostic Biomarker and Correlates with the Clinicopathological Features and Immune Infiltration of Colorectal Cancer.
Background: Colorectal cancer (CRC) is one of the most common gastrointestinal tumors, ranking in the top 5 of all common tumors in terms of incidence and mortality. However, the mechanisms driving the evolution of colorectal cancer remain unclear. Therefore, we investigated the association between Mapk14 expression and clinicopathological and tumor-infiltrating immune cells. Methods: In this study, we collected CRC patient data from The Cancer Genome Atlas (TCGA), compared the expression level in CRC and normal colorectal tissue using the Wilcoxon rank sum test and assessed the relationship between Mapk14 and clinicopathological features using the Welch one-way ANOVA test. Kaplan-Meier and timeROC GSE17537 datasets were obtained from the Gene Expression Omnibus (GEO) dataset to assess the prognostic impact of the Mapk14 gene on colorectal cancer. Second, we further explored the methylation level of Mapk14 and its influencing factors. Single-cell sequencing of Mapk14 in the tumor immune microenvironment (TIME) was analyzed using the GSE108989 dataset. Further analyses based on the TIMER method were performed to assess the correlation between Mapk14 and tumor immune infiltration, immune checkpoints, tumor mutational load and microsatellite instability. Finally, the results of the bioinformatics analysis were verified by an immunohistochemical analysis. Results: The results showed that the expression of Mapk14 was upregulated in CRC tumor tissues compared with normal colorectal tissues and the high expression of Mapk14 was associated with poor clinicopathological features and poor prognoses in the CRC array. In addition, cg05798012 and cg25375420 of Mapk14 are the main DNA methylation sites affecting OS. Single-cell sequencing of the tumor immune microenvironment showed that the abundance and cell state of dysfunctional T cells changed greatly. Importantly, the abnormal overexpression of Mapk14 in colorectal cancer is related to the level of immune infiltration of immune cells (including CD8+ T cells, neutrophils, dendritic cells, B cells, CD4+ T cells, and macrophages). The high expression of Mapk14 was significantly correlated with immune checkpoints (including SIGLEC15, TIGIT, LAG3, CTLA4 and PDCDILG2), while the high expression of Mapk14 was negatively correlated with TMB and MSI but mostly positively correlated with drug sensitivity. Finally, the immunohistochemical results confirmed that the clinical stage (Ⅰ, Ⅱ, Ⅲ and Ⅳ) and M stage (M0 and M1) affected the abnormally high expression of Mapk14. Conclusion: A comprehensive bioinformatics study and experimental validation revealed that Mapk14 could serve as a novel prognostic biomarker associated with immune infiltration and pharmacotherapy and may represent a potential therapeutic target for the treatment of CRC.
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Development of a prognostic RiskScore model using efferocytosis-related signature genes for lung adenocarcinoma.
BACKGROUND: Lung adenocarcinoma (LUAD) has high incidence and mortality rates. Efferocytosis is involved in the progression of various cancers. The current work set out to develop a prognosis signature using efferocytosis-related genes (ERGs) for LUAD. METHODS: Public databases were accessed to obtain bulk and single-cell data of LUAD. Molecular subtyping of LUAD was performed using ConsensusClusterPlus, and efferocytosis-related candidate genes were screened by weighted gene co-expression network analysis (WGCNA) in combination with differential analysis. Subsequently, Least Absolute Shrinkage and Selection Operator (LASSO) regression was applied to construct a prognostic RiskScore model, followed by evaluating the relationship between the RiskScore, immune infiltration, and drug sensitivity. Single-cell transcriptomic profiling of LUAD was performed with the Seurat package to elucidate the cellular origins of the key genes. The expression and potential function of the representative genes were verified by reverse transcriptional quantitative polymerase chain reaction (qPCR) (RT-qPCR), Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays. RESULTS: Two molecular subtypes of LUAD with different outcomes and clinical features were identified. Candidate ERGs were mainly enriched in inflammatory and immune-related pathways. Subsequently, seven key genes (CD200R1, BTN2A2, STAP1, DNASE2B, SAMD9, SEMA7A, BIRC3) associated with efferocytosis in LUAD were identified to establish a RiskScore model, which exhibited high robustness in predicting patient prognosis. Notably, high-risk group had lower immune scores and more unfavorable prognosis than low-risk group. Moreover, eight drugs were closely linked to the RiskScore, and low-risk group was more sensitive to Doramapimod_1042. Single-cell atlas of LUAD showed that the prognostic ERGs were mainly expressed in mast cells. In vitro experiments revealed that most of the seven ERGs were overexpressed in LUAD cells, and that SEMA7A knockdown could suppress LUAD cell proliferation, migration and invasion. CONCLUSIONS: Our results provided novel insights for the prognosis prediction and personalized treatment of LUAD.
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Dynamic transcriptomic and regulatory networks underpinning the transition from fetal primordial germ cells to spermatogonia in mice.
The transition from fetal primordial germ cells (PGCs) to spermatogonia (SPG) is critical for male germ cell development; however, the detailed transcriptomic dynamics and regulation underlying this transition remain poorly understood. Here by interrogating the comprehensive transcriptome atlas dataset of mouse male germ cells and gonadal cells development, we elucidated the regulatory networks underlying this transition. Our single-cell transcriptome analysis revealed that the transition from PGCs to SPG was characterized by global hypertranscription. A total of 315 highly active regulators were identified to be potentially involved in this transition, among which a non-transcription factor (TF) regulator TAGLN2 was validated to be essential for spermatogonial stem cells (SSCs) maintenance and differentiation. Metabolism profiling analysis also revealed dynamic changes in metabolism-related gene expression during PGC to SPG transition. Furthermore, we uncovered that intricate cell-cell communication exerted potential functions in the regulation of hypertranscription in germ cells by collaborating with stage-specific active regulators. Collectively, our work extends the understanding of molecular mechanisms underlying male germ cell development, offering insights into the recapitulation of germ cell generation in vitro.