The lack of a sufficient number of validated miRNA targets severely hampers the understanding of their biological function. Even for the well-studied miR-155-5p, there are only 239 experimentally validated targets out of 42,554 predicted targets. For a more complete assessment of the immune-related miR-155 targetome, we used an inverse correlation of time-resolved mRNA profiles and miR-155-5p expression of early CD4+ T cell activation to predict immune-related target genes. Using a high-throughput miRNA interaction reporter (HiTmIR) assay we examined 90 target genes and confirmed 80 genes as direct targets of miR-155-5p. Our study increases the current number of verified miR-155-5p targets approximately threefold and exemplifies a method for verifying miRNA targetomes as a prerequisite for the analysis of miRNA-regulated cellular networks.

Multiple myeloma (MM) is a hematological malignancy with the proliferation of malignant plasma cells. Numerous studies have highlighted the critical role of ferroptosis in MM. However, how to use ferroptosis-related genes (FRGs) for prognostic prediction and treatment guidance in MM remains unknown.

By analysis of GEO databases, the prognostic gene was identified and a therapeutic strategy for MM patients based on FRGs was explored. A total of 12 FRGs were identified, utilizing the STRING database and Cytoscape software, and the PPI networks were constructed to identify hub genes and further functional enrichment analyses. Based on the aforementioned data, this study analyzed the expression of RUVBL2 in MM patients by qRT-PCR and Western blotting. To validate the functional role of RUVBL2 in the MM cells, cellular experiments were ultimately conducted.

The analysis highlighted six hub genes, including TP53, MCM5, TLR4, RUVBL2, GCLM and ITGA6, and functional enrichment analyses indicating enrichment in DNA replication, regulation of apoptotic signaling pathway and PI3K/AKT signaling pathway. Prognostic analysis indicated that TP53, RUVBL2, and MCM5 are associated with MM prognosis, with RUVBL2 displaying a notable area under the curve (AUC) of 0.823 in ROC analysis. The study first determined that RUVBL2 is highly expressed in MM, siRUVBL2-mediated deletion of RUVBL2 inhibited proliferation, promoted apoptosis and increased the sensitivity of BTZ in MM cells, and also overcame BTZ resistance in CD138+ primary cells from MM patients.

Our study first suggested that RUVBL2 may be regarded as potential therapeutic targets and prognostic value in MM.

The gut microbiota is a crucial link between diet and cardiovascular disease (CVD). Using fecal metaproteomics, a method that concurrently captures human gut and microbiome proteins, we determined the crosstalk between gut microbiome, diet, gut health, and CVD. Traditional CVD risk factors (age, BMI, sex, blood pressure) explained < 10% of the proteome variance. However, unsupervised human protein-based clustering analysis revealed two distinct CVD risk clusters (low-risk and high-risk) with different blood pressure (by 9 mmHg) and sex-dependent dietary potassium and fiber intake. In the human proteome, the low-risk group had lower angiotensin-converting enzymes, inflammatory proteins associated with neutrophil extracellular trap formation and auto-immune diseases. In the microbial proteome, the low-risk group had higher expression of phosphate acetyltransferase that produces SCFAs, particularly in fiber-fermenting bacteria. This model identified severity across phenotypes in heart failure patients and long-term risk of cardiovascular events in a large population-based cohort. These findings underscore multifactorial gut-to-host mechanisms that may underlie risk factors for CVD.

The Coronavirus Disease 2019 (COVID-19) pandemic has led to numerous cases of co-infection with SARS-CoV-2 and other viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), worldwide. This co-infection has increased patient mortality due to the lack of efficient bi-targeted drugs. Cambogin, a bioactive natural product, has been shown to effectively induce regression of KSHV-latently infected tumours in xenograft mice models; however, its impact on SARS-CoV-2 infection remains unclear. Here, we report that Cambogin targets 46 host genes commonly affected by both SARS-CoV-2 and KSHV infections, as identified through bioinformatics analysis. These genes are related with 14 key upstream signalling pathways, particularly those involved in inflammation regulation, protein phosphorylation, metabolic processes, and cellular stress response. Within the transcriptional factor (TF)-miRNA co-regulatory network, ten out of 46 hub-target genes are closely linked to Cambogin and KSHV/SARS-CoV-2. Importantly, Cambogin not only efficiently blocks the replication and virion production of SARS-CoV-2 in vitro and in vivo by reducing the expression of EGFR and Cyclin A2, but also simultaneously inhibits both SARS-CoV-2 infection and the growth of KSHV-induced tumours in vivo using a murine xenograft model. These findings provide an alternative strategy for the potential use of Cambogin in the treatment of SARS-CoV-2 patients, particularly those with KSHV co-infection.

Skin hyperpigmentation is a type of difficult-to-treat disease that frequently results from the improper metabolism of facial pigment. The herb Forsythiae Fructus (FF) possesses whitening and freckle-removal properties. Its probable active components and anti-hyperpigmentation mechanism, however, are still unknown. In the current investigation, the active components were initially identified and screened by UHPLC-Q-Orbitrap HRMS/MS employing B16 cell-specific extraction and plasma pharmaceutical chemistry, respectively. Subsequently, the component-target-disease network and protein-protein interaction (PPI) network of FF were built by using a network pharmacology approach. The probable targets and pathways were found using gene ontology (GO) and KEGG enrichment analysis. The essential elements and core genes causing illnesses were identified through molecular docking. Lastly, based on network analysis, cell experiments were carried out to further explore the efficacy of the main active ingredients in the treatment of abnormal melanosis. As a result, 37 ingredients were identified in FF extract, 22 compounds in the decoction had a specific affinity with B16 mouse melanoma cells, and a total of 10 prototype compounds and 11 metabolites were detected in rat plasma. Through in vitro and in vivo screening methods, 16 potential active ingredients were obtained, and 229 biological targets and 1515 disease-related targets were predicted by network pharmacology. In addition, in vitro cell experiments revealed that kaempferol, luteolin, and wogonin all exhibited inhibition of melanin production and tyrosinase activity. The proposed combination method of rapid screening of active ingredients in vivo and integrated network pharmacology in vitro could explore the therapeutic mechanism of FF against hyper-pigmentation, and provide a theoretical evidence for the development and utilization of FF.

The S100 family of calcium-binding proteins (S100s) had been tightly related to the biological processes of various cardiovascular diseases. This study aims to investigate the expression of S100s in Atherosclerosis (AS) and explore their potential as diagnostic biomarkers and therapeutic targets.

We analyzed multiple sequencing datasets from the GEO database to compare the expression profiles of S100s in AS tissues versus normal samples. Employing unsupervised clustering techniques, AS subtypes were discerned based on the intricate variations in S100-related gene expression profiles. Subsequent analyses delved into immune cell infiltration and GSVA pathway enrichment, shedding light on the nuanced immune landscape characterizing diverse AS subtypes. Machine learning techniques were employed to develop a diagnostic model for AS. Single-cell RNA analysis was utilized to investigate the cellular distribution of S100 hub genes in AS.

Unsupervised clustering analysis identified two distinct AS subtypes (C1 and C2), characterized by specific S100 gene expression patterns. The RF-based diagnostic model exhibited the highest efficacy (AUC=0.881), and the top five genes (S100A4, S100A10, S100A11, S100A13, S100Z) were used to construct a diagnostic nomogram.

This study systematically elucidates the roles of S100s in AS, offering insights into molecular subtyping, immune characteristics, and diagnostic model construction. The findings provide valuable implications for the precise treatment and prognosis assessment of AS and pave the way for further research into related mechanisms.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social communication, restricted interests, repetitive behavior and irritability. Exposure to valproic acid (VPA) during pregnancy has been shown to increase the risk of autism in children and has led to the development of the in-utero VPA rat model that elicits neurodevelopmental autistic-like features. Offspring exhibit behavioral and neurobiological alterations modelling ASD symptoms. We performed a behavioral and molecular assessment in a rat in-utero VPA model treated with a novel botanical cannabinoid, JZP541. Male offspring from dams treated with VPA were tested acutely and sub-chronically with JZP541 (10, 30, or 100 mg/kg, intraperitoneally). A behavioral testing battery was performed, and brain frontal cortex and hippocampus used for RNA sequencing. In utero exposure to VPA resulted in progeny showing behavioral phenotypes characteristic of ASD. JZP541 attenuated these deficits in social, stereotypic, hyperactivity and irritability behavior in a dose-dependent fashion. VPA exposure was associated with a substantial transcriptional dysregulation impacting multiple key biological processes in a tissue-dependent manner. The expression profiles were integrated with publicly available datasets of autism-associated genes to support the validity of the model used and to focus on the effects of treatment on known autism-relevant transcriptional targets. This approach indicated a strong and dose-dependent reduction of the autism-associated gene expression signature in brain samples from animals dosed with JZP541. Our findings demonstrate JZP541 was able to ameliorate ASD associated behavioral deficits, and this was supported by improvements in putative transcriptional biomarkers of ASD.

Our study shows that Bifidobacterium spp. supplementation reduces lung damage in acute lung injury by enhancing immune cell activity and restoring thrombospondin-1 levels, offering a promising therapeutic approach for the treatment of ALI/ARDS.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions characterized by severe lung inflammation and damage, often exacerbated by mechanical ventilation. Probiotics, particularly those containing Bifidobacterium spp. (Bifidus) have shown promise in modulating immune responses and reducing inflammation.

In this study, we investigated the effects of Bifidus supplementation in a mouse model of lipopolysaccharide induced ALI and ventilator-induced lung injury.

Our results demonstrate that Bifidus significantly ameliorates lung injury by enhancing efferocytosis and reducing pro-inflammatory cytokine levels. Single-cell RNA sequencing revealed significant changes in lung immune cell populations, particularly macrophages and monocytes, which showed increased efferocytosis activity and modulation of key signaling pathways such as TNF, MAPK and TLR. Notably, Bifidus feeding restored thrombospondin-1 levels in lung tissue, facilitating clearance of apoptotic cells and promoting resolution of inflammation.

Overall, our study highlights the potential of Bifidus as a therapeutic strategy to mitigate lung injury in ALI/ARDS.

Although a wide variety of medicinal interventions and lifestyles have been endeavored so far for the treatment of diabetes mellitus, it is still intractable. The current study aimed to examine the effect of mesenchymal stem cells (MSCs) and/or placental extract (PE) on streptozotocin (STZ) induced diabetic rats.

Fifty male albino rats were used. Ten of them as negative control (group I) and the remaining forty rats were subjected to diabetes induction using 50 mg/kg STZ then divided into; group II (positive controls), group III (MSCs treated), group IV (PE treated), and group V (MSCs/PE combination treated). After 4 weeks of treatment, animals were sacrificed; blood samples were collected for determination of glycated hemoglobin by HPLC, and serum was separated for determination of glucose spectrophotometrically and insulin by ELISA. Pancreatic tissues were harvested for histopathological examination and pancreatic duodenal homeobox 1 (Pdx1) gene expression by PCR.

The three treated groups showed significant enhancement in glycemic parameters and Pdx1 gene expression compared with positive control group (P < 0.05). Histopathological examination revealed great improvement in the three treated groups where group V showed the best picture and the best glycemic control.

This study points to the possible role of PE in DM treatment. The MSCs/PE combination had the ability to return all parameters and Pdx1 gene expression to their normal levels. This action could be attributed to MSCs homing into the pancreas and the pancreatic rejuvenation provided by PE contents of growth factors; EGF, HGF, IGF-1 and IGF-II.

JOURNAL/nrgr/04.03/01300535-202508000-00026/figure1/v/2024-09-30T120553Z/r/image-tiff Interferon regulatory factor 7 plays a crucial role in the innate immune response. However, whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown. Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells. Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype. In addition, siRNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase, tumor necrosis factor α, CD16, CD32, and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1. Taken together, our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

In this study, using RNA-Seq gene expression data and advanced machine learning techniques, we identified distinct gene expression profiles between male and female pancreatic ductal adenocarcinoma (PDAC) patients. Building on this insight, we developed sex-specific 3-year survival predictive models alongside a single comprehensive model. Despite smaller sample sizes, the sex-specific models outperformed the general model. We further refined our models by selecting the most important features from the initial models. The refined sex-specific predictive models achieved higher accuracy and consistently outperformed the refined comprehensive model, highlighting the value of sex-specific analysis. To ensure robustness, all refined sex-specific models were calibrated and then evaluated using an independent dataset. Random Forest models emerged as the most effective predictors, achieving accuracies of 90.33 % for males and 90.40 % for females on the training dataset, and 81.25 % for males and 89.47 % for females on the independent test dataset. These top-performing models were integrated into Gap-App, a web application that leverages individual gene expression profiles and sex information for personalized survival predictions. As the first online tool bridging complex genomic data with clinical application, Gap-App facilitates more precise, individualized cancer care, marking a significant step in personalized prognosis prediction. This study underscores the importance of incorporating sex differences in predictive modeling and sets the stage for the shift from traditional one-size-fits-all to more personalized and targeted medicine. The Gap-App service is freely available for patients and clinicians at www.gap-app.org.

In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow-derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8+ T cells prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of Spg15-driven neuropathology.

Chemotherapy-related cognitive impairment (CRCI), is a well-recognized phenomenon in cancer patients who have undergone chemotherapy but the exact molecular mechanisms underpinning CRCI remain elusive. Symptoms reported by people with CRCI resemble those experienced by people with age-related neurodegenerative disorders (ARNDDs), yet no clear connection between CRCI and ARNDDs has been reported to date. The existence of shared mechanisms between these conditions offers opportunities for repurposing drugs already approved for the treatment of ARNDDs to improve symptoms of CRCI. Given that there is no available microarray or RNA-Seq data from the brains of people who have experienced CRCI, we investigated to what extent brain gene expression perturbations from validated rodent models of CRCI induced by chemotherapy compared with validated rodent models of Alzheimer's disease and Parkinson's disease. We utilized multiple bioinformatic analyses, including functional enrichment, protein-protein interaction network analyses, gene ontology analyses and identification of hub genes to reveal connections between comparable gene expression perturbations observed in these conditions. Collectively 165 genes overlapped between CRCI and Parkinson's disease and/or Alzheimer's disease, and 15 overlapped between all three conditions. The joint genes between Alzheimer's disease, Parkinson's disease and CRCI demonstrate an average of 83.65% nucleotide sequence similarity to human orthologues. Gene ontology and pathway enrichment analyses suggest mechanisms involved in neural activity and inflammatory response as the key components of the studied neuropathological conditions. Accordingly, genes in which expression was comparably affected in all three condition models could be attributed to neuroinflammation, cell cycle arrest, and changes in physiological neural activity.

JOURNAL/nrgr/04.03/01300535-202507000-00024/figure1/v/2024-09-09T124005Z/r/image-tiff Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination. Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage. Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation, and plays an important role in the pathological process of ischemic stroke. However, there are few studies on oligodendrocyte progenitor cell ferroptosis. We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia. Bioinformatics analysis suggested that perilipin-2 (PLIN2) was involved in oligodendrocyte progenitor cell ferroptosis. PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation. For further investigation, we established a mouse model of cerebral ischemia/reperfusion. We found significant myelin damage after cerebral ischemia, as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area. The ferroptosis inhibitor, ferrostatin-1, rescued oligodendrocyte progenitor cell death and subsequent myelin injury. We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells. Plin2 knockdown rescued demyelination and improved neurological deficits. Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.

Anoectochilus roxburghii (Wall.) Lindl. (A. roxburghii) is an increasingly popular medicinal herb. Arbuscular mycorrhiza (AM) fungi, known for their symbiotic relationships with plant roots, enhance nutrient uptake and disease resistance in host plants. However, their specific regulatory mechanisms in A. roxburghii are not fully understood. In this study, Fujian A. roxburghii was inoculated with the AM fungus Glomus intraradices, and successful root colonization was observed. Following AM fungal colonization, there was a significant upregulation of photosynthesis-related genes in the stems, accompanied by improved canopy phenotypes and root architecture. Consequently, AM-inoculated plants exhibited increased fresh and dry biomass, as well as elevated levels of polysaccharides and flavonoids. Additionally, the incidence of Fusarium oxysporum-induced stalk rot was reduced in AM-inoculated plants. Analysis of defense-related enzymes indicated that AM-inoculated plants exhibited a rapid and robust response to pathogen infection, mitigating oxidative stress. Transcriptomic analysis revealed significant upregulation of genes associated "Fatty acid degradation", "MAPK signaling pathway-plant", and "Plant-pathogen interaction", suggesting their involvement in enhanced disease resistance. A regulatory network centered on ACX1 and calmodulin, involving multiple transcription factors such as WRKY, bHLH, ERF, NAC, and HSF, was implicated in defense responses. These findings demonstrated the beneficial effects of AM fungi on yield, quality, and disease resistance in A. roxburghii, providing a theoretical foundation for its cultivation and genetic improvement.

Glioblastoma multiforme (GBM) is the most frequent type of primary malignant brain tumor. This study utilized Mendelian randomization (MR) analysis to explore the causal link between proteins in plasma and cerebrospinal fluid and GBM.

This study aimed to identify proteins in both plasma and cerebrospinal fluid (CSF) that could serve as potential therapeutic targets for GBM.

We employed previously published protein quantitative trait loci (pQTL) data from CSF and plasma as the exposure data, alongside aggregated Genome-Wide Association Study (GWAS) data on GBM for our MR analysis. Furthermore, we conducted Bayesian co-localization analysis and examined the protein-protein interaction (PPI) networks of CSF and plasma proteins related to GBM risk.

MR identified three key proteins linked to GBM risk: ribophorin I (RPN1) in plasma, von Willebrand factor (vWF) and macrophage-stimulating protein (MSP). in CSF. Elevated RPN1 and MSP were associated with decreased GBM risk, while increased vWF was linked to higher risk. External validation confirmed that RPN1 served as a key protein in GBM development. Bayesian co-localization showed a 10.35 % probability of a shared causal variant between RPN1 and GBM. Protein-protein interaction analysis further highlighted related proteins for RPN1.

In summary, the plasma protein RPN1 and the CSF proteins vWF and MSP are causally associated with the risk of GBM. Further research is needed to clarify the roles of these candidate proteins in GBM. Notably, RPN1 may serve as a potential therapeutic target for GBM. Future clinical studies on GBM treatment could explore drugs targeting RPN1.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) have similar clinical characteristics in the brain and islet, as well as an increased incidence with ageing and familial susceptibility. Therefore, in recent years there has been a great desire for research that elucidates how anti-diabetic drugs affect AD. This work attempts to first elucidate the possible mechanism of action of DPP-IV inhibitors in the treatment of AD by employing techniques from network pharmacology, molecular docking, molecular dynamic simulation, principal component analysis, and MM/PBSA. A total of 463 targets were identified from the SwissTargetPrediction and 784 targets were identified from the SuperPred databases. 79 common targets were screened using the PPI network. The GO and KEGG analyses indicated that the activity of DPP-IV against AD potentially involves the hsa04080 neuroactive ligand-receptor interaction signalling pathway, which contains 17 proteins, including CHRM2, CHRM3, CHRNB1, CHRNB4, CHRM1, PTGER2, CHRM4, CHRM5, TACR2, HTR2C, TACR1, F2, GABRG2, MC4R, HTR7, CHRNG, and DRD3. Molecular docking demonstrated that sitagliptin had the greatest binding affinity of -10.7 kcal/mol and established hydrogen bonds with the Asp103, Ser107, and Asn404 residues in the active site of the CHRM2 protein. Molecular dynamic simulation, PCA, and MM/PBSA were performed for the complex of sitagliptin with the above-mentioned proteins, which revealed a stable complex throughout the simulation. The work identifies the active component and possible molecular mechanism of sitagliptin in the treatment of AD and provides a theoretical foundation for future fundamental research and practical implementation.

Intense physical activity in endurance horses triggers complex immune and inflammatory responses, yet the molecular mechanisms underlying these adaptations remain unclear. This study investigated immune-related transcriptomic changes following a 160 km endurance ride, focusing on sex-based differences. Using a bioinformatics approach, differentially expressed genes (DEGs), pathways, microRNAs (miRNAs), and transcription factors (TFs) were analyzed before (T0) and after (T1) the ride. A protein-protein interaction (PPI) analysis was conducted to identify key regulatory genes. Pathway enrichment analysis revealed significant activation of immune-regulatory and ribosomal pathways. Notably, TLR4, CXCL8, and CCL5 were identified as key hub genes involved in immune modulation post-exercise. Comparisons between female (FT1 vs FT0) and gelding (GT1 vs GT0) horses revealed distinct molecular responses. Female horses exhibited upregulation of ribosomal protein genes, suggesting enhanced protein synthesis and muscle recovery. In contrast, geldings showed increased expression of inflammatory and stress-related genes, indicating a heightened immune response. Notably, sex-based differences were observed, with FT1 vs FT0 and GT1 vs GT0 comparisons revealing distinct KEGG pathway enrichments. Additionally, miRNA and TF analyses revealed regulatory elements influencing endurance-related immune responses. Our findings demonstrated sex-specific molecular mechanisms underlying endurance exercise adaptation, with females prioritizing protein synthesis and recovery, while geldings exhibit stronger inflammatory responses and stress-related pathways. This study provides critical insights into how sex influences exercise physiology at the transcriptomic level, with potential applications in training and recovery strategies for endurance horses.

Neuroinflammation is a key pathological factor of PD, and T cells play a central role in neuroinflammatory progression. However, the causal effect of T cell-related genes on the risk of PD is still unclear. We explored single-cell RNA sequencing (scRNA-Seq) datasets of the peripheral blood T cells of PD patients and healthy controls, and screened the differentially expressed genes (DEGs) in the cytotoxic CD4 + T cells relative to the other T cell subsets. Pseudo-time series analysis, cell-cell communication analysis, and metabolic pathway analysis was performed for the cytotoxic CD4 + T cells. The DEGs were also functionally annotated through GO and KEGG pathway enrichment analyses. The MR approach was used to establish causal effects of the DEGs (exposure) on PD risk (outcome), and explore new drug targets for PD. The findings of MR analysis were further validated by Steiger filtering, bidirectional MR, Bayesian colocalization analysis, and phenotype scanning, and the GWAS data from an independent PD case-control cohort was used for external validation of the results. Finally, differences in gene expression between PD patients and healthy controls were further validated in scRNA-Seq and bulk transcriptome sequencing data. We found that increased expression of IL-32, GNLY, MT2A, and ARPC2 was significantly associated with a higher risk of PD. In contrast, the increase in ARRB2 was closely related to a lower risk of PD. IL32, GNLY, MT2A, ARRB2, and ARPC2 are the causal genes and potential drug targets of PD. Cytotoxic CD4 + T cells are likely the key effectors of PD-related neuroinflammation. These findings provide new insights into the pathogenesis and treatment options for PD, and further research and clinical trials based on the five potential drug targets and neuroinflammation are necessary.

Liver Hepatocellular Carcinoma (LIHC) and Kidney Renal Clear Cell Carcinoma (KIRC) are leading causes of cancer death worldwide, but their early detections remain hindered by a lack of genetic markers. Our study aims to find prospective biomarkers that could serve as prognostic indicators for efficient drug candidates for KIRC and LIHC treatment.

To detect differentially expressed genes (DEGs), four datasets were used: GSE66271 and GSE213324 for KIRC, and GSE135631 and GSE202853 for LIHC. Visualization of DEGs was done using heatmaps, volcano plots, and Venn diagrams. Hub genes were identified via PPI analysis and the cytoHubba plugin in Cytoscape. Their expression was evaluated using box plots, stage plots, and survival plots for prognostic assessment via GEPIA2. Molecular docking with PyRx's AutoDock Vina identified optimal binding interactions between compounds and proteins. Pharmacokinetic and toxicity analyses reinforced the drug-likeness and safety of these compounds.

In this study, 47 DEGs were identified, with the top 10 hub genes being TOP2A, BUB1, PTTG1, CCNB2, NUSAP1, KIF20A, BIRC5, RRM2, NDC80 and CDC45, chosen for their high MCC scores. Data mining revealed a correlation between TOP2A expression and clinical survival outcomes in KIRC and LIHC patients. Docking studies of the TOP2A structure identified a promising compound from Andrographis paniculata with high binding energy and interactions with TOP2A. Pharmacokinetic and toxicity assessments support its potential as a drug candidate.

Our study emphasizes TOP2A's prognostic significance in KIRC and LIHC and recognizes Andrographis paniculata compound as potential therapeutics, offering prospective for enhanced treatment and patient outcomes in these cancers.

The escalating prevalence of Type-2 diabetes mellitus (T2DM) poses a significant global health challenge. Utilizing integrative proteomic analysis, this study aimed to identify a panel of potential protein markers for T2DM, enhancing diagnostic accuracy and paving the way for personalized treatment strategies.

Proteome profiles from two independent cohorts were integrated: cohort 1 composed of 10 T2DM patients and 10 healthy controls (HC), and cohort 2 comprising 87 T2DM patients and 60 healthy controls. Differential expression analysis, functional enrichment analysis, receiver operating characteristic (ROC) analysis, and classification error matrix analysis were employed.

Comparative proteomic analysis identified the differential expressed proteins (DEPs) and changes in biological pathways associated with T2DM. Further combined analysis refined a group of protein panel (including CA1, S100A6, and DDT), which were significantly increased in T2DM in both two cohorts. ROC analysis revealed the area under curve (AUC) values of 0.94 for CA1, 0.87 for S100A6, and 0.97 for DDT; the combined model achieved an AUC reaching 1. Classification error matrix analysis demonstrated the combined model could reach an accuracy of 1 and 0.875 in the 60% training set and 40% testing set.

This study incorporates different cohorts of T2DM, and refines the potential markers for T2DM with high accuracy, offering more reliable markers for clinical translation.

The online version contains supplementary material available at 10.1007/s40200-025-01562-3.

Aquaporins (AQPs) are specialized membrane proteins that create selective water channels, facilitating the transport of water across cell membranes and playing a vital role in maintaining water balance and regulating osmotic pressure in aquatic animals. This study identified 9 aquaporin genes from the genome of R. philippinarum, and a comprehensive analysis was conducted on their gene structure, phylogenetic relationships, protein structure, and chromosome localization. RNA-seq data analysis revealed that aquaporin genes were differentially expressed at different developmental stages, in tissue distribution, and in response to salinity stress. In addition, qPCR results revealed that the expression levels of aquaporin genes (AQP1, AQP4d, and AQP3) were significantly elevated in response to both acute low and high salinity stress, suggesting their important role in osmotic pressure regulation in R. philippinarum. This study's results offer an important reference for further investigations into the regulation of osmotic pressure and salinity adaptation of aquaporin in R. philippinarum.

As an important member of global aquaculture, oysters (Crassostrea gigas) have significant economic value. With the development of commercial aquaculture, the frequent occurrence of diseases caused by Vibrio alginolyticus has become a hindrance to high-density aquaculture. Gill tissue, as an important component of immune system of the oysters, plays the key point in the face of invasion by foreign substances. Compared to the diploid oyster, the triploid oyster presents a higher growth rate and lower growth investment, making it a more ideal model for studying oyster immune defense. In this study, triploid oysters were as the research subject, and gill tissues attacked by V. alginolyticus were sequenced. By analyzing samples from different time points, 1746 DEGs were obtained. The KEGG and GO functional enrichment analysis showed that gill tissues mainly participate in immune function through the PIK3-Akt signaling pathway and the MAPK signaling pathway. The protein interaction network revealed three genes (CASP8, CASP9 and PIK3CA) that play core roles in immune defense by analyzing the interaction relationship between genes. Finally, qRT-PCR verified the expression of key genes. This study provides a more effective scientific basis for disease prevention and control of oysters and other bivalve shellfish, and helps to promote the sustainable development of aquaculture.

ObjectiveAlthough knee osteoarthritis (KOA) is a common disease, there is a lack of specific prevention and early treatment methods. Hence, this study aimed to examine the molecular changes occurring at different stages of KOA to elucidate the dynamic nature of the disease.DesignUsing a low-force compression model and analyzing RNA sequencing data, we identified molecular changes in the transcriptome of knee joint cartilage, including gene expression and molecular pathways, between the cellular changes and structural damage stages of KOA progression. In addition, we validated hub genes using an external dataset.ResultsGene set enrichment analysis (GSEA) identified the following pathways to be associated with KOA: "B-cell receptor signaling pathway," "cytokine-cytokine receptor interaction," and "hematopoietic cell lineage." Expression analysis revealed 585 differentially expressed genes, with 579 downregulated and 6 upregulated genes. Enrichment and clustering analyses revealed that the main molecular clusters were involved in cell cycle regulation and immune responses. Furthermore, the hub genes Csf1r, Cxcr4, Cxcl12, and Ptprc were related to immune responses.ConclusionsOur study provides insights into the dynamic nature of early-stage KOA and offers valuable information to support the development of effective intervention strategies to prevent the irreversible damage associated with KOA, thereby addressing a major clinical challenge.

Intact insulin signaling and glucose transport in adipocytes are crucial to maintaining whole-body energy metabolism. Focal adhesion kinase stands as a central intracellular protein facilitating signaling between the extracellular matrix and the cytoplasm, thereby regulating cellular metabolism. Here, we have investigated the role of focal adhesion kinase in adipocyte glucose transport using an array of methods, including affinity purification combined with quantitative mass spectrometry, glucose tracer assays, western blotting, and confocal imaging. Pharmacological inhibition (PF-573228) of focal adhesion kinase suppressed the interaction of focal adhesion kinase with numerous actin-associated proteins, reduced Rac1 activity, as well as phosphorylation of the Rac1 downstream target PAK1/2, and further led to impaired GLUT4 translocation and glucose uptake. In summary, we demonstrate that focal adhesion kinase plays a key role in controlling actin remodeling, subsequent GLUT4 translocation, and ultimately glucose transport in adipocytes.

The aim of this study is to employ network pharmacology to identify potential therapeutic targets for Ganoderma lucidum in the treatment of optic atrophy, and elucidate the underlying pharmacological mechanism.

This study is mainly divided into two parts. In the first part, the chemical composition and Target of Ganoderma lucidum compound were predicted by TCMSP and Swiss Target Prediction, and the crossover gene between OA and Ganoderma lucidum target gene was screened based on GeneCards and OMIM database. Then, the target genes were enriched and the main pathways of action were analyzed to discover the possible mechanism of action for the treatment of optic atrophy. Finally, the selected core compounds and core targets were interfaced to understand the main binding patterns and affinity. The second part mainly verifies whether Ganoderma lucidum polysaccharide has protective effect on RGC. Firstly, CCK8 method was used to detect the proliferation and virulence analysis of RGC-5 cells with different concentrations of Ganoderma lucidum polysaccharide, and then RGC-5 cells were cultured in subgroups for 12 h, and then put into anaerobic encapsulation to make molds. After 24 h of continuous culture, cells were removed and collected for subsequent RT-PCR and WB detection.

Through screening target genes of Ganoderma lucidum and OA, 85 potential therapeutic targets were obtained by intersection. Through PPI network analysis of 85 potential targets, it was found that the degree values of TP53, TNF, CASP3, IL6, EGFR, MTOR, ESR1 and other targets were higher. (+)-Ganoderic acid Mf, (+)-Methyl ganolucidate A, epoxyganoderiol A, Ergosta-4,7, 22-Trien-3, 6-Dione and other compounds play a key role in the whole network. It may be the key compound of ganoderma lucidum in treating OA. Through enrichment pathway analysis, it was found that the number of genes was enriched in AGE-RAGE signaling pathway, cAMP signaling pathway, inflammation and cancer pathways, and the structure of TP53, TNF, CASP3, and IL6 binding to the above compounds was stable and the binding activity was high.

The findings suggest that Ganoderma lucidum may exert its therapeutic effects on optic atrophy by targeting TP53, TNF, CASP3, and IL6. Additionally, it may also be involved in the AGE-RAGE signaling pathway and cAMP signaling pathway. These results provide reference for the clinical application of ganoderma lucidum in the treatment of OA.

Understanding how plants adapt their physiology to overcome severe and often multifactorial stress conditions in nature is vital in light of the climate crisis. This remains a challenge given the complex nature of the underlying molecular mechanisms. To provide a comprehensive picture of stress-mitigation mechanisms, an exhaustive analysis of publicly available stress-related transcriptomic data has been conducted. We combine a meta-analysis with an unsupervised machine-learning algorithm to identify a core of stress-related genes active at 1-6 h and 12-24 h of exposure in Arabidopsis thaliana shoots and roots. To ensure robustness and biological significance of the output, often lacking in meta-analyses, a triple validation is incorporated. We present a 'stress gene core': a set of key genes involved in plant tolerance to ten adverse environmental conditions and ethylene-precursor supplementation rather than individual conditions. Notably, ethylene plays a key regulatory role in this core, influencing gene expression and acting as a critical factor in stress tolerance. Additionally, the analysis provides insights into previously uncharacterized genes, key genes within large families, and gene expression dynamics, which are used to create biologically validated databases that can guide further abiotic stress research. These findings establish a strong framework for advancing multi-stress-resilient crops, paving the way for sustainable agriculture in the face of climate challenges.

Adolescent depression is increasingly recognized as a serious mental health disorder with distinct clinical and molecular features. Using single-nucleus RNA sequencing, we identified cell-specific transcriptomic changes in the nucleus accumbens (NAc), particularly in astrocytes, of adolescent macaques exhibiting depressive-like behaviors. The level of diacylglycerol kinase beta was significantly reduced in neurons and glial cells of depressed macaques, while FKBP5 levels increased in glial cells. Disruption of GABAergic synapses and disruption of D-glutamine and D-glutamate metabolism were linked to depressive phenotypes in medium spiny neurons (MSNs) and subtypes of astrocytes. Communication pathways between astrocytes and D1/D2-MSNs were also disrupted, involving factors like bone morphogenetic protein-6 and Erb-B2 receptor tyrosine kinase-4. Bulk transcriptomic and proteomic analyses corroborated these findings, and FKBP5 upregulation was confirmed by qRT-PCR, western blotting, and immunofluorescence in the NAc of rats and macaques with chronic unpredictable mild stress. Our results highlight the specific roles of different cell types in adolescent depression in the NAc, offering potential targets for new antidepressant therapies.

Lung cancer remains one of the leading causes of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for 85% of cases worldwide. NSCLC pathogenesis and progression are intricately linked to inflammatory stimuli, immune evasion, and metabolic reprogramming. In this study, the impact of inflammation, immunity, and metabolism on NSCLC was investigated by a Mendelian randomization analysis taking 91 inflammatory factors, 731 immune cells, and 1400 metabolites as exposures, and the FinnGen database NSCLC cohort (ncases = 5315, ncontrol = 314,193) was the outcome. A number of metabolites, inflammatory proteins, and immune cells were identified as potentially associated with NSCLC based on mendelian randomization analysis. Validation in the UK Biobank database lung cancer cohort (ncases = 2671, ncontrols = 372,016) further confirmed the inhibitory role of the metabolite N-acetyl-aspartyl-glutamate (NAAG) on lung cancer. Subsequently, single-cell and protein-protein interaction analyses identified inflammatory protein expression patterns in NSCLC, distribution ratios of immune cells in NSCLC. Subsequent multi-omics network analysis showed key interaction nodes between NAAG and inflammatory proteins. These findings enhance the understanding of the roles of inflammation, immunity, and metabolism in NSCLC occurrence and progression, offering potential targets and strategies for further research on its treatment and management.

Despite the diminishing global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus continues to circulate and undergo mutations, posing ongoing challenges for public health. A comprehensive understanding of virus entry mechanisms is crucial for managing new epidemic strains. However, the cellular processes post-endocytosis remain largely unexplored. This study employs proximity labeling to examine proteins near ACE2 post-viral infection and identified syntaxin-6 (STX6) as a factor that inhibits SARS-CoV-2 infection by impeding the endocytic release of the virus. SARS-CoV-2 infection enhances early endosome recruitment of STX6. STX6 appears to hinder the maturation of viral particles-laden early endosomes into late endosomes, from which the virus could escape. Instead, it promotes the trafficking of the virus toward the autophagy-lysosomal degradation pathway. STX6 exhibits a broad-spectrum effect against various SARS-CoV-2 variants and several other viruses that enter via endocytosis. We report for the first time the function of STX6 as a restrictive factor in viral infection.IMPORTANCEVirus entry is the first step of the virus life cycle, and the exploitation of the endo-lysosome pathway for cellular entry by viruses has been well documented. Meanwhile, the intrinsic defense present within cells interferes with virus entry. We identified STX6 as a host restriction factor for viral entry by facilitating the virus trafficking to the autophagy-lysosomal degradation pathway. Notably, STX6 exhibits broad-spectrum antiviral activity against diverse severe acute respiratory syndrome coronavirus 2 variants and other viruses employing endocytosis for entry.

Heart failure (HF) is a life-threatening condition that poses a significant challenge on public health, particularly among the elder populations. To develop new diagnostic and therapeutic strategies for HF, we analyzed large-scale transcriptome sequencing data from HF patients as an exploratory approach. We identified 18 HF-related genes and developed a robust scoring model for HF diagnosis, by applying two machine learning algorithms for data analysis. Meanwhile, we evaluated and compared the predictive abilities of three bioinformatics methods in identifying potential HF treatment drugs. Significantly, an unconventional network-based proximity analysis, integrating multidimensional drug target information, outperformed other methods in the assessment of predictive ability. To validate these findings, we tested several candidate drugs in a mouse model transitioning from acute myocardial infarction (MI) to chronic HF. Among the candidates, mirtazapine exhibited cardioprotective effects in both early (1-week) post-MI and chronic HF (4-week post-MI) settings, while cabergoline showed potential efficacy primarily in the early post-MI phase. Additionally, the screened triamterene, used as a positive control, exhibited protective effects in both early post-MI and chronic HF stages. Mechanistic studies revealed that growth factor receptor-bound protein 14 and Ras-related protein Rab-3 A were critical to the observed cardioprotection. These findings provide valuable evidence and insights for exploring potential therapeutic agents for HF treatment.

To investigate if FVIII-Fc Fusion protein (FcFVIII) may modulate inflammation and immune stimulation in hemophilic synovium via the Fc-portion of immunoglobulin used for half-life extension we performed gene expression profiling in FVIII-deficient mice. Hemarthrosis was induced by sub-patellar puncture in FVIII-KO mice, + /- periprocedural recombinant human (rh)FVIII,murine (m)FcFVIII, or mIgG2a. Synovium was harvested at baseline and on days (D) 3 and 14, followed by RNA extraction and sequencing, and histological analysis. RNASeq data were processed using standard protocols followed by differential gene expression (DGE) analysis. Functional enrichment analysis generated molecular pathways (KEGG and Reactome). To distinguish between on-target and off-target (related and unrelated to injury/bleed) effects the following groups were compared: i) Baseline vs. injured-saline, ii) injured-saline vs. injured-rhFVIII, iii) injured-saline vs. injured-mFcFVIII. Knee injury in FVIII-KO mice resulted in hemarthrosis, which was prevented by peri-procedural rhFVIII and mFcFVIII treatments. Only a small proportion of genes was affected by FVIII treatment, exhibiting overlap but also distinct differences between both FVIII-preparations. Acutely (D3), mFcFVIII had unique on-target effects related to immune and inflammatory regulation, whereas rhFVIII mostly affected mRNA and protein processing. On day 14, macrophage profiling indicated a transition from M1 to M2, and only mFcFVIII uniquely influenced pathways and genes associated with tissue remodeling and repair. Some mFcFVIII DGE patterns resembled mIgG2a patterns. Synovial vascular remodeling and cartilage health were better with mFcFVIII than rhFVIII. Interestingly, both FVIII-preparations exerted off-target effects on immune system pathways, albeit with temporal differences. These observations provide proof-of-principle that the type of FVIII preparation can influence synovial processes beyond acute hemostasis control, deserving exploration in the setting of joint bleed control in hemophilia.

Pediatric neurological disorders are a diverse group of conditions affecting the nervous system in children, often challenging to diagnose due to their nonspecific and overlapping clinical features. Advances in molecular diagnostics, particularly whole exome sequencing (WES), have significantly improved the identification of genetic causes, enabling precise diagnoses and personalized treatments. This study explores the application of WES in diagnosing pediatric neurological disorders within Moroccan childrens with undiagnosed or challenging pediatric neurological conditions to uncover genetic causes of complex pediatric neurological conditions unresolvable by traditional diagnostic methods. The study included 188 pediatric patients with complex neurological conditions from the Children's Hospital of Rabat who underwent exome sequencing to investigate suspected genetic causes. WES revealed a diagnostic yield of 45%, identifying conditions such as intellectual disabilities, hereditary metabolic disorders and epilepsies. It also uncovered neurodevelopmental and neurodegenerative disorders, neuromuscular diseases, and genetic syndromes. A total of 157 variants were detected: 34% were classified as pathogenic, 28.5% as likely pathogenic, and 37.5% as variants of uncertain significance (VUS). These findings underscore the utility of WES as a robust diagnostic tool, providing insights into genetic causes and enabling tailored treatment strategies. They also highlight the importance of expanding genetic research to improve diagnostic accuracy and clinical management of pediatric neurological disorders.

Acmella paniculata has been traditionally used in folklore medicine to alleviate pain and manage articular rheumatism. This study explores its potential anti-inflammatory and antiarthritic effects through in silico and in vivo approaches. A. paniculata bioactives' antiarthritic mechanisms were elucidated using computational techniques, namely, gene set enrichment analysis, network pharmacology, molecular docking, and molecular dynamics (MD) simulations using KEGG pathway analysis, PyRx, Discovery Studio, and GROMACS tools. A. paniculata hydroalcoholic extract (APE) and the ethyl acetate fraction (APF) were analyzed via LC‒MS for phytochemical profiling. In vivo studies assessed anti-inflammatory and antiarthritic potential in carrageenan-induced paw edema and complete Freund's adjuvant (CFA)-induced arthritis models in Wistar rats. Ferulic acid, isoferulic acid, and acetyl aleuritolic acid were identified as bioactives that targeted RELA, a key NF-κB component. Stable interactions were confirmed through docking and MD simulations. LC‒MS verified these compounds in APE and APF. In vivo study revealed significant reductions in paw volume, arthritis scores, and inflammatory markers (CRP, RF, IL-6, and TNF-α) and improved histopathological outcomes in the APE and APF-treated groups compared to the CFA. These findings highlight the anti-inflammatory and antiarthritic potential of A. paniculata via multi-protein modulation, particularly NF-κB signaling, and it can be utilized as a promising therapeutic for rheumatoid arthritis.

The diagnosis and treatment of chronic glomerulonephritis (CGN) during childhood pose distinct challenges. Acteoside (ACT) is the primary active ingredient extracted from the leaves of Rehmannia glutinosa by our research group, accounting for 2.15 %, which possess multiple biological activities, especially for nephropathy treatment. However, its mechanism intervention on CGN in children remains obscure. In this study, we established a model of purinomycin aminonucleoside (PAN)-induced CGN in childhood rats to assess the potential therapeutic effect and underlying mechanisms of ACT. Leveraging network pharmacology and multi-omics technology, we delved into the effects and mechanisms of ACT intervention on CGN. And these findings were further corroborated through qRT-PCR, western blot and targeted metabolomics. Our results demonstrated that ACT had significantly efficient in the treatment of CGN in childhood rats by improving the key indicators and pathological changes. Further, ACT could significantly regulate differences in endogenous small molecules and genes based on non-target metabolomics and transcriptomics. Meanwhile, target capture analysis found the crucial targets of ACT treatment in CGN. Integrated analysis of multi-omics study indicated that PI3K/Akt signaling pathway and its downstream amino acid metabolism were significantly enriched, hinting at the essential regulatory pathway for ACT in treating of CGN. Finally, through qRT-PCR, western blot and targeted metabolomics, it was verified that ACT could ameliorate CGN through Cxcr4-PI3K-Akt-eNOS signaling pathway, thereby regulating amino acid metabolism. The collective results were consistent with those of multi-omics analysis. Our study illuminated that ACT had notable curative effect on CGN rats, and preliminarily elucidated its mechanism of action. Our research will provide solid basis for the treatment of chronic glomerulonephritis in children with ACT and developing it into innovative traditional Chinese medicine.

Currently, the pathogenesis of Parkinson's disease (PD) remains enigmatic, primarily due to the scarcity of definitive diagnostic markers, thereby hampering both diagnosis and treatment. The urgent need for accessible plasma markers and targeted therapeutic agents has prompted us to employ various methodologies. We leveraged Mendelian randomization analysis, colocalization analysis, SMR analysis, and the HEIDI test to delve into the causal relationships between 2923 plasma proteins in the UK Biobank and PD. Our findings revealed that 21 plasma proteins, including CTF1 and STX4, may demonstrate causal relationships with PD. Further single-cell and bioinformatics analyses have shed light on the fact that 18 of these proteins exhibit differential expression across various brain cell types in patients with PD. These proteins are involved in crucial biological processes, including peptide binding, amide binding, amyloid-beta binding, endocytic vesicle formation, and the functioning of early endosomes. Notably, the PPI network exhibited interactions between ITGAM and HLA-DRA, as well as APOE, while APOE displayed interactions with APOA1, and SERPINE2 interacted with VNN2. Furthermore, our study demonstrates that plasma proteins, including CTF1, STX4, HPGDS, and APOA1, exhibit therapeutic potential for drug development based on gene-drug interaction predictions. While these findings provide a theoretical basis for the exploration of diagnostic markers and potential therapeutic targets for PD, extensive experimental validation is essential to confirm their potential in the future.

Caspases (CASPs) are attractive targets for cancer therapy. Many prognostic models based on gene signatures include genes from the CASPs family in diffuse glioma. CASP3, CASP4 and CASP6 in glioma have been studied individually. However, specialized comprehensive analysis of the roles of CASPs family in glioma is lacking. Therefore, this study utilized bioinformatics methods to investigate this issue. CASP1-10 expressionlevels were significantly up-regulated in LGG and GBM and glioma, and varied significantly across different clinical subgroups of glioma and LGG and various cell types, and most of CASP1-10 members showed significant differences in recurrence status of LGG. 10 signatures (CASP1-10) were associated with poor overall survival (OS) in glioma and LGG and GBM. However, pan-cancer survival analysis showed that CASP1-10 were associated with the prognosis of LGG, but not GBM. CASP1-10 were related to poor prognosis of glioma and LGG, except for CASP9, which was the opposite of a protective factor. CASP1-10 were independent prognostic factors for OS in glioma and LGG, except for CASP5, and also for recurrence-free survival (RFS) in LGG. Most of CASP1-10 were also independent prognostic factors for disease-specific survival (DSS) and progression-free interval (PFI) and had diagnostic value in glioma and LGG. Genetic alterations of CASP1-10 genes set were associated with poor prognosis in LGG. CASP1-10 were involved in immune infiltration and programmed cell death in glioma and LGG and GBM, and might promote the apoptosis of immune cells. Compared to GBM, CASP1-10 had a more significant impact on the prognosis, cancer-related pathways, and immune infiltration in LGG, indicating that CASP1-10 might play important roles in the recurrence and progression of LGG, and might be promising therapeutic targets for LGG. Therefore, it is speculated that natural caspase inhibitor p35 may be a promising drug for the treatment of glioma, especially for LGG.