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PubMed2026

Diosmetin Inhibits Bladder Cancer through Suppression of the PI3K-AKT Signaling Pathway and Activation of the p53 Signal Pathway Revealed by Network Pharmacology and In Vitro Experimental Verification.

INTRODUCTION: Diosmetin, a naturally occurring flavonoid abundant in plants such as chrysanthemums, lemons, and oranges, has been reported to exhibit diverse antitumor properties. However, its potential efficacy against bladder cancer remains unexplored. This study aims to investigate the anti-bladder cancer effects of Diosmetin and elucidate the underlying mechanisms using network pharmacology combined with in vitro experiments. METHODS: Public databases were employed to identify shared targets between Diosmetin and bladder cancer. A Protein-Protein Interaction (PPI) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to predict core targets and signaling pathways. The predicted mechanisms were subsequently validated through in vitro assays. RESULTS: A total of 48 common targets were identified. PPI network analysis revealed 22 hub genes, including AKT1 and MDM2. GO analysis indicated enrichment in 208 biological processes, 23 cellular components, and 38 molecular functions. KEGG analysis suggested that Diosmetin exerts anti-bladder cancer effects primarily through pathways such as Pathways in cancer, PI3K-AKT signaling, and Proteoglycans in cancer. Notably, the PI3K-AKT pathway showed the highest gene enrichment, indicating its potential prominence. In vitro experiments demonstrated that Diosmetin suppresses bladder cancer cell proliferation and induces apoptosis. Additionally, Diosmetin reduced the expression of p-PI3K, p-AKT, and MDM2, while upregulating p53 expression, suggesting involvement of both the PI3K-AKT and p53 pathways. DISCUSSION: These findings align with network pharmacology predictions and highlight the potential of Diosmetin as a multi-target agent against bladder cancer, warranting further in vivo investigation. CONCLUSION: Diosmetin inhibits bladder cancer cell proliferation and promotes apoptosis by suppressing the PI3K-AKT pathway and activating the p53 pathway.

Diosmetin↗

PubMed2026

Transcriptomic characterization of the intestine in Stichopus monotuberculatus under gradient temperature stress and HSP gene family-mediated molecular adaptation.

The increasing frequency of extreme temperature events under climate change poses a growing threat to the stability of tropical sea cucumber aquaculture. To characterize the molecular responses of the tropical sea cucumber Stichopus monotuberculatus to acute temperature stress, juveniles were exposed for 96 h to 15 °C, 20 °C, 25 °C, 30 °C, and 35 °C, followed by transcriptomic profiling of the intestine. By transcriptomic analysis, 2258, 634, 1618, and 2980 differentially expressed genes (DEGs) were identified at 15, 20, 30, and 35 °C compared to control, respectively. More DEGs were generally detected at temperatures further from 25 °C, with the 35 °C group showing the largest transcriptional response. Although cold and heat stress both affected metabolism and protein homeostasis, their enrichment profiles differed. At 15 °C, DEGs were mainly enriched in the spliceosome and p53 signaling pathways, highlighting RNA processing and p53 signaling as prominent features of the cold-stress response. At 35 °C, DEGs were mainly enriched in the PI3K-Akt signaling pathway, ubiquitin-mediated proteolysis, and mitophagy, indicating enhanced regulation of cell survival, protein turnover, and mitochondrial quality control. HSP genes also responded differently to cold and heat stress. Most HSP70 and HSP90 family members were downregulated at low temperatures, whereas HSP70 genes and small heat shock proteins were markedly upregulated at high temperatures. Overall, the intestinal transcriptome showed distinct responses to cold and heat stress. These results identify pathways and HSP genes potentially involved in the temperature response of S. monotuberculatus and provide useful information for evaluating temperature tolerance and defining suitable temperatures for its aquaculture.

Heat shock protein↗

PubMed2026

SLC25A45 as a prognostic biomarker promotes malignant progression via mutant p53 in hepatocellular carcinoma.

BACKGROUND: SLC25A45 belongs to the mitochondrial trimethyllysine carrier protein family. To date, its role in tumor development has not been fully elucidated. Previous studies have demonstrated its pro-tumor function in ovarian cancer; however, research on the expression characteristics, biological roles and underlying regulatory pathways of SLC25A45 in hepatocellular carcinoma (HCC) is limited. This study aims to explore the expression, functional roles, and regulatory pathways of SLC25A45 in HCC. METHODS: This study examined SLC25A45 expression and clinical relevance in HCC using publicly available transcriptomic data. SLC25A45 knockdown cell lines were constructed using PLC/PRF/5, Huh7, and Huh1 cells. Functional assays, including cell proliferation and colony formation assays, were then conducted. To investigate the effects of SLC25A45 knockdown on the malignant phenotypes of HCC cells in vitro, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analyses were performed to identify potential underlying mechanisms, which were subsequently validated by experimental assays. RESULTS: SLC25A45 was elevated in clinical HCC specimens, and high SLC25A45 expression was correlated with disease progression and poor overall survival (OS). In vitro functional assays demonstrated that SLC25A45 silencing reduced HCC cell proliferation and colony formation. Mechanistically, GSEA indicated that high SLC25A45 expression was significantly enriched in the p53 signaling pathways. SLC25A45 knockdown in HCC cells led to a significant increase in wild-type p53 protein expression, but a substantial decrease in mutant p53 expression. CONCLUSIONS: SLC25A45 is a potential prognostic indicator and may drive HCC tumorigenesis and progression through the differential modulation of the p53 signaling pathways.

SLC25A45↗

PubMed2026

Interaction analysis of miRNA and mRNA reveals the regulatory mechanism of immune response in golden pompano (Trachinotus ovatus) spleen to Streptococcus iniae infection.

Streptococcus iniae is a major warm-water pathogen that cause high mortality and severe economic losses in golden pompano industry. In the present study, we performed the mRNA-miRNA integrated transcriptomic analysis of spleen of golden pompano challenged with S. iniae to explore the possible regulatory mechanism to bacterial infection. In total, we excavated 5072 DEGs, of which 2765 up-regulated and 2307 down-regulated genes. KEGG enrichment analysis indicated that the DEGs were primarily enriched in immune-related pathways, such as proteasome, cytokine-cytokine receptor interaction, p53 signaling pathway, lysosome, phagosome, Herpes simplex virus 1 infection. Additionally, a protein-protein interaction (PPI) network was constructed to extract hub genes. And the result showed that 4 hub genes, comprising cd4, il10, tnfsf2, myd88, may play vital roles in response to S. iniae infection. Furthermore, a total of 46 differentially expressed miRNAs (DEMs) were identified, containing 23 known and 23 novel DEMs. By integrating mRNA and miRNA joint analysis, we established a miRNA-mRNA regulatory network, including 12 miRNAs and 14 genes. Among them, novel-miR-357 were identified as a multi-target hub miRNA. These results provide important insights into the molecular regulatory mechanisms of immune response and inflammation processes in the defense of golden pompano against S. iniae infection.

Integrative interaction↗

PubMed2024

Transcriptome-wide N6-methyladenosine modification profiling of long non-coding RNAs in patients with recurrent implantation failure.

N6-methyladenosine (m6A) is involved in most biological processes and actively participates in the regulation of reproduction. According to recent research, long non-coding RNAs (lncRNAs) and their m6A modifications are involved in reproductive diseases. In the present study, using m6A-modified RNA immunoprecipitation sequencing (m6A-seq), we established the m6A methylation transcription profiles in patients with recurrent implantation failure (RIF) for the first time. There were 1443 significantly upregulated m6A peaks and 425 significantly downregulated m6A peaks in RIF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that genes associated with differentially methylated lncRNAs are involved in the p53 signalling pathway and amino acid metabolism. The competing endogenous RNA network revealed a regulatory relationship between lncRNAs, microRNAs and messenger RNAs. We verified the m6A methylation abundances of lncRNAs by using m6A-RNA immunoprecipitation (MeRIP)-real-time polymerase chain reaction. This study lays a foundation for further exploration of the potential role of m6A modification in the pathogenesis of RIF.

Humans↗

PubMed2026

Identification of putative causal associations between MicroRNAs and breast cancer via Mendelian randomization and bioinformatic analysis.

MicroRNAs (miRNAs) are implicated in breast cancer progression and prognosis. This study employed a Mendelian randomization (MR) framework to investigate causal relationships between plasma circulating miRNAs and breast cancer. miRNA expression quantitative trait loci were extracted from 2 independent cohorts. High-confidence miRNAs and their associated single-nucleotide polymorphisms were selected for 2-sample MR analyses using inverse-variance weighted and MR-Egger methods. Differential expression analysis and univariate Cox regression identified survival-associated genes in breast cancer, while enrichment analyses revealed pathways and biological processes linked to candidate targets. Pan-cancer analyses of miRNAs and targets were conducted via the ENCORI platform. Initial MR analyses in the discovery phase identified hsa-miR-100-5p, hsa-miR-125b-5p, and hsa-miR-339-5p as significantly associated with reduced breast cancer risk (P < .05), suggesting potential protective roles. A total of 1291 survival-associated differentially expressed genes were identified, with 39 overlapping targets implicated in miRNA-mediated breast cancer intervention. Enrichment analyses highlighted their involvement in cell cycle regulation and p53 signaling pathway. In the validation cohort, only hsa-miR-339-5p confirmed a protective effect on breast cancer risk, while hsa-miR-100-5p and hsa-miR-125b-5p did not reach significance. Pan-cancer profiling demonstrated aberrant miRNA expression across malignancies, prognostic relevance in multiple cancers, and significant negative correlations between miRNAs and target genes in breast tumors. Our findings provide novel insights into the causal roles of miRNAs in breast cancer pathogenesis and underscore their potential as noninvasive biomarkers and therapeutic targets. Future studies should prioritize functional validation and clinical translation of these miRNAs.

Humans↗

PubMed2026

Prognostic model based on calcium-related genes predicts prognosis and reveals the immune landscape of acute myeloid leukemia.

Acute myeloid leukemia (AML) exhibits heterogeneous outcomes and lacks reliable prognostic markers. As a critical regulator of cell fate, the prognostic value of calcium signaling in AML requires investigation. This study aimed to construct a calcium-related gene (CRG)-based prognostic model for AML. Differential analysis on RNA-seq data was conducted for AML from The Cancer Genome Atlas and Gene Expression Omnibus (GEO). Intersecting differentially expressed genes and CRGs yielded AML-associated differentially expressed CRGs (DECRGs). A prognostic model was developed using univariate/multivariate Cox regression and least absolute shrinkage and selection operator (LASSO) and validated in a GEO dataset. Bioinformatics analyses explored the links between risk groups and immune characteristics, genomic mutations, and drug sensitivity. Key genes' effects on cell proliferation, apoptosis, and differentiation were verified in vitro using CCK-8 assay, colony formation assay, and flow cytometry. The 13-DECRG-based model distinguished high- and low-risk patients in both training and validation cohorts, with high-risk patients showing a worse prognosis. The risk score was an independent prognostic factor. Immune analysis revealed a unique immune microenvironment for the high-risk group. CAMK2A overexpression inhibited cell proliferation and colony-forming ability, promoted cell apoptosis, and induced an increased proportion of CD11b- and CD14-positive cells. In vitro experiments indicated CAMK2A-induced suppression of AML cells' malignant phenotype by activating the P53 signaling pathway. An AML CRG-based model with favorable risk stratification performance was constructed. In vitro experiments revealed CAMK2A-induced inhibition of the malignant phenotype via suppressing proliferation, promoting apoptosis, and facilitating myeloid differentiation in AML cells. This study provides novel evidence for understanding CRGs in AML as well as the potential functions of CAMK2A.

Journal Article↗

PubMed2026

Systematic discovery of pathogen effector functions across human pathogens and pathways.

Pathogens deploy effector proteins to exploit host cell biology, and most effector open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the effector ORFeome (eORFeome), a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across nuclear factor κB (NF-κB), apoptosis, p53, cGAS-STING, and major histocompatibility complex class I (MHC class I) pathways revealed novel pathway-modulating functions for hundreds of uncharacterized eORFs, unexpected activities of known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of this approach, we identified HHV6A U14 as a p53 antagonist, HHV7 U21 as a dual-function STING antagonist and MHC-I antigen display inhibitor, and adenoviral 13.6K/i-leader protein as a de novo-evolved TAP inhibitor that suppresses MHC-I display. These results establish a general framework for systematic effector annotation, uncover new mechanisms of host-pathogen interaction across kingdoms, and highlight pathogen effectors as a versatile toolkit for rewiring and probing human cellular pathways.

Humans↗

PubMed2025

CCT8 drives colorectal cancer progression via the RPL4-MDM2-p53 axis and immune modulation.

PURPOSE: Colorectal cancer (CRC) ranks high in global mortality, emphasizing the need for effective interventions. The aim of the research is to elucidate the oncogenic role of CCT8 in CRC and its interaction with RPL4 in the RPL4-MDM2-p53 axis. METHODS: TIMER 2.0, TCGA, and GTEx databases were used to analyze CCT8 expression patterns in CRC. Immunohistochemistry was performed to examine CCT8 distribution in CRC tissues and adjacent non-tumor tissues. Functional assays, including CCK-8, transwell, wound-healing, and flow cytometry, were conducted using DLD-1 and HCT116 cell lines to assess the effects of CCT8 on cell proliferation, migration, invasion, and apoptosis. Gene set enrichment analysis, protein-protein interaction network analysis, and co-immunoprecipitation were performed to explore the interaction between CCT8 and RPL4 and their role in the RPL4-MDM2-p53 pathway. Additionally, gene set variation analysis was applied to investigate the relationship between CCT8/RPL4 expression and immune infiltration patterns in CRC. RESULTS: CCT8 was significantly upregulated in CRC and associated with tumor progression. Mechanistically, CCT8 potentially synergizes with RPL4 concluded from their positive correlation and similar immune infiltration patterns, influencing the RPL4-MDM2-p53 axis and contributing to p53 ubiquitination and degradation. CONCLUSION: These findings underscore the oncogenic significance of CCT8 in CRC and shed light on its molecular mechanisms, paving the way for potential therapeutic applications.

Humans↗

PubMed2025

Comprehensive evaluation of differential expression of piRNAs in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a prevalent and fatal cardiovascular condition characterized by a high incidence rate and nonspecific clinical manifestations, with no effective preventive or therapeutic measures currently available. Piwi-interacting RNAs (piRNAs) have been identified as significant biomarkers for disease diagnosis due to their essential functions in transposon suppression, maintenance of genomic stability, immune response, and epigenetic modulation. The piRNA is intimately associated with various diseases such as cardiac hypertrophy, tumors, and neurodegeneration, yet its role in AAA is unclear. In this study, we employed gene sequencing to analyze the piRNA expression profiles in AAA vascular tissues and predicted variations in their target genes. Our findings revealed a total of 1368 piRNAs with abnormal expression in the AAA group relative to the control group, including 1240 up-regulated and 128 down-regulated piRNAs (|log2(fold change)| ≥ 1.0), with 82 demonstrating significant differences (P < 0.05). Through bioinformatics analysis, it was determined that the Wnt signaling pathway, calcium signaling, TNF-α and the p53 pathway are crucial mechanisms by which piRNAs contribute to the development of AAA. RT-qPCR confirmed that hsa_piR_011324 was the most significantly up-regulated piRNA in AAA (P < 0.0001), corroborating RNA sequencing results. Further results indicate that hsa_piR_011324 promotes phenotypic transformation of human aortic vascular smooth muscle cells (HAVSMCs), enhances the activity of matrix metalloproteinases (MMPs), increased up-regulation of inflammation-related markers IL-1β and TNF-α, and induces apoptotic processes. In conclusion, the present study emphasizes the important regulatory role of hsa_piR_011324 in AAA, suggesting that it holds promise as a prospective target for diagnostic and therapeutic intervention.

Aortic Aneurysm, Abdominal↗

PubMed2026

POU2F3 expression in lung squamous cell carcinoma: transcriptomic and immunohistochemical profiling with prognosis.

BACKGROUND: Lung squamous cell carcinoma (LUSC) lacks well-defined molecular targets. This study investigated the clinical and biological relevance of POU class 2 homeobox 3 (POU2F3), a tuft cell-associated transcription factor, in LUSC. METHODS: RNA sequencing data of patients with LUSC from The Cancer Genome Atlas (TCGA cohort, n = 190) was analysed and compared to a cohort of surgically resected cases analyzed via immunohistochemistry (IHC cohort, n = 137). Prognostic impact was assessed via survival analyses. Transcriptomic features, pathway enrichment, and immune profiles were evaluated via differentially expressed gene analysis, Gene Set Enrichment Analysis, and CIBERSORTx. RESULTS: High POU2F3 expression independently predicted poor overall survival in the TCGA cohort (HR = 2.06, 95% CI: 1.04-4.08, P = 0.039). In contrast, POU2F3 expression was not prognostic in the IHC cohort (P = 0.995). Morphologically, POU2F3-positive tumours were enriched for non-keratinizing and poorly differentiated subtypes. Transcriptomic analysis showed suppression of proliferation and immune-related pathways (FDR < 0.001), with suggestive enrichment of the TGF-β (FDR = 0.143) and p53 (FDR = 0.229) signaling pathways. On immune deconvolution, POU2F3-high tumours showed a nominal increase in activated dendritic cells, which did not withstand multiple testing correction. POU2F3 protein was detected in 12.4% of tumours and was significantly associated with p53 or RB1 abnormalities (single or double) (P = 0.028). CONCLUSIONS: POU2F3 marks a transcriptionally distinct, early-stage subtype of LUSC with keratinization-related features. Its prognostic relevance appears context-dependent and requires prospective validation in uniformly treated cohorts.

Humans↗

PubMed2024

Knockdown Proteomics Reveals USP7 as a Regulator of Cell-Cell Adhesion in Colorectal Cancer via AJUBA.

Ubiquitin-specific protease 7 (USP7) is implicated in many cancers including colorectal cancer in which it regulates cellular pathways such as Wnt signaling and the P53-MDM2 pathway. With the discovery of small-molecule inhibitors, USP7 has also become a promising target for cancer therapy and therefore systematically identifying USP7 deubiquitinase interaction partners and substrates has become an important goal. In this study, we selected a colorectal cancer cell model that is highly dependent on USP7 and in which USP7 knockdown significantly inhibited colorectal cancer cell viability, colony formation, and cell-cell adhesion. We then used inducible knockdown of USP7 followed by LC-MS/MS to quantify USP7-dependent proteins. We identified the Ajuba LIM domain protein as an interacting partner of USP7 through co-IP, its substantially reduced protein levels in response to USP7 knockdown, and its sensitivity to the specific USP7 inhibitor FT671. The Ajuba protein has been shown to have oncogenic functions in colorectal and other tumors, including regulation of cell-cell adhesion. We show that both knockdown of USP7 or Ajuba results in a substantial reduction of cell-cell adhesion, with concomitant effects on other proteins associated with adherens junctions. Our findings underlie the role of USP7 in colorectal cancer through its protein interaction networks and show that the Ajuba protein is a component of USP7 protein networks present in colorectal cancer.

Ubiquitin-Specific Peptidase 7↗

PubMed2024

Molecular Signatures of Neurodegenerative Diseases Identified by Proteomic and Phosphoproteomic Analyses in Aging Mouse Brain.

A central hallmark of neurodegenerative diseases is the irreversible accumulation of misfolded proteins in the brain by aberrant phosphorylation. Understanding the mechanisms underlying protein phosphorylation and its role in pathological protein aggregation within the context of aging is crucial for developing therapeutic strategies aimed at preventing or reversing such diseases. Here, we applied multi-protease digestion and quantitative mass spectrometry to compare and characterize dysregulated proteins and phosphosites in the mouse brain proteome using three different age groups: young-adult (3-4 months), middle-age (10 months), and old mice (19-21 months). Proteins associated with senescence, neurodegeneration, inflammation, cell cycle regulation, the p53 hallmark pathway, and cytokine signaling showed significant age-dependent changes in abundances and level of phosphorylation. Several proteins implicated in Alzheimer's disease (AD) and Parkinson's disease (PD) including tau (Mapt), Nefh, and Dpysl2 (also known as Crmp2) were hyperphosphorylated in old mice brain suggesting their susceptibility to the diseases. Cdk5 and Gsk3b, which are known to phosphorylate Dpysl2 at multiple specific sites, had also increased phosphorylation levels in old mice suggesting a potential crosstalk between them to contribute to AD. Hapln2, which promotes α-synuclein aggregation in patients with PD, was one of the proteins with highest abundance in old mice. CD9, which regulates senescence through the PI3K-AKT-mTOR-p53 signaling was upregulated in old mice and its regulation was correlated with the activation of phosphorylated AKT1. Overall, the findings identify a significant association between aging and the dysregulation of proteins involved in various pathways linked to neurodegenerative diseases with potential therapeutic implications.

Animals↗

PubMed2026

Histopathological evaluation of RPL5 expression in triple-negative breast cancer: an integrated immunohistochemical and transcriptomic study.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high invasiveness, limited therapeutic options, and unfavorable clinical outcomes. Ribosomal protein L5 (RPL5), a component of the large ribosomal subunit, has been implicated in ribosome biogenesis, translational regulation, and p53-associated cellular processes. This study investigated the immunohistochemical expression pattern of RPL5 in TNBC tissues and explored its potential biological significance through integrated transcriptomic analyses. Tumor tissues from 37 patients with TNBC and 7 adjacent non-tumorous breast tissues were collected from the Affiliated Tumor Hospital of Xinjiang Medical University between December 2017 and December 2023. RPL5 protein expression was evaluated by immunohistochemistry, and its association with clinicopathological characteristics was analyzed. Public transcriptomic datasets from TCGA-BRCA and GEO were further used to validate RPL5 expression patterns in TNBC. Co-expression analysis and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate potential biological functions and signaling pathways associated with RPL5. Immunohistochemical analysis demonstrated significantly lower RPL5 protein expression in TNBC tissues compared with adjacent normal breast tissues (p=0.001). In contrast, transcriptomic analyses revealed significantly higher RPL5 expression in TNBC compared with non-TNBC breast cancer subtypes (p<0.001). No significant associations were observed between RPL5 expression and clinicopathological parameters, including age, tumor size, menopausal status, TNM stage, histological grade, or lymph node metastasis (all p>0.05). Survival analysis showed no significant difference in overall survival between patients with high and low RPL5 expression. Functional enrichment analyses indicated that RPL5-related genes were predominantly involved in ribosome biogenesis, translational regulation, and p53-related signaling pathways. These findings suggest that abnormal RPL5 expression may be associated with TNBC biology through ribosome-related programs, although causal roles require functional validation. RPL5 may represent a potential histopathological and molecular indicator associated with TNBC biology, although its precise functional role requires further experimental validation.

Humans↗

PubMed2026

Exploring the mechanism of Acanthopanax in treating vertigo: A network pharmacology and molecular docking study.

Acanthopanax has therapeutic efficacy against vertigo; however, the underlying mechanism remains unclear. This study aimed to elucidate the mechanism by which Acanthopanax treats vertigo through integrated network pharmacology and molecular docking techniques, and retrieved all target genes of Acanthopanax for vertigo treatment from July to October 2025. Vertigo-related target genes were subsequently identified from public databases, including GeneCards and Online Mendelian Inheritance in Man. The intersection between Acanthopanax-derived targets and vertigo-related targets was analyzed to identify candidate target genes. Using the STRING platform, we constructed protein-protein interaction networks for the identified candidate targets and mined the core functional modules within these networks. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on candidate targets via the clusterProfiler package. A carp bile poisoning-liver injury target-pathway network was constructed via Cytoscape 3.8.2 software, network topology analysis was conducted, and the core components and targets were screened. The results found that A total of 295 candidate targets for the treatment of vertigo caused by Eleutherococcus senticosus were identified. Pathway enrichment analysis revealed that Eleutherococcus senticosus treatment for vertigo may be closely associated with pathways related to IL-17, TNF, phosphoinositide 3-kinase (PI3K)-Akt, p53, HIF-1, and Forkhead box O signaling. The core targets for the treatment of A. senticosus vertigo include TP53, AKT1, STAT3, TNF, and JUN. Network pharmacology and molecular docking studies suggest that A. senticosus may treat vertigo by regulating targets such as JUN, TNF, AKT1, STAT3, and STAT3 through pathways such as the IL-17, TNF, phosphoinositide 3-kinase-Akt, p53, HIF-1, and Forkhead box O signaling pathways. These mechanisms warrant further investigation in future o and in vitro studies.

Molecular Docking Simulation↗

PubMed2026

The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.

PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.

Humans↗

PubMed2026

The role of KIAA1467 in breast cancer: insights from pan-cancer and single-cell sequencing analysis.

BACKGROUND: Improving the response rate of single-agent immune checkpoint blockade (ICB) urgently requires the discovery of new therapeutic targets for combinatorial regimens. Analyses of tumor microenvironment (TME)-associated biomarkers have verified that KIAA1467 drives the formation of an immune-excluded, non-inflamed TME in breast cancer (BRCA). This study systematically explores the expression pattern, prognostic value, immune regulatory function, biological effects, and drug resistance relevance of FAM234B (also known as KIAA1467) in BRCA. METHODS: We performed pan-cancer survival analysis using The Cancer Genome Atlas (TCGA) datasets. Multi-omics bioinformatics analyses were conducted to evaluate KIAA1467 expression across malignancies. Single-cell RNA sequencing (scRNA-seq) data from GSE176078 was utilized to localize KIAA1467 expression at the cellular level. Immunohistochemistry and western blot assays validated KIAA1467 expression in BRCA clinical specimens. Correlation analyses were implemented to assess relationships between KIAA1467 expression, clinicopathological features, immune modulators, tumor-infiltrating immune cells, and p53 mutation status. Functional enrichment analysis uncovered relevant signaling pathways. Bioinformatic half maximal inhibitory concentration (IC50) prediction and in vitro cellular experiments were applied to evaluate associations between KIAA1467 and chemotherapeutic drug sensitivity. RESULTS: TCGA pan-cancer survival analysis demonstrated that elevated KIAA1467 expression significantly predicted shortened overall survival in BRCA and multiple other tumor types. KIAA1467 displayed distinct expression patterns across cancers, with prominent upregulation in BRCA. scRNA-seq confirmed enriched KIAA1467 expression within BRCA cells, and its upregulation in BRCA tissues was further verified by immunohistochemistry and western blot. High KIAA1467 expression was positively correlated with advanced tumor grade and lymphatic metastasis. KIAA1467 showed negative correlations with most immune modulators and core immune checkpoint molecules, as well as tumor-infiltrating immune cells in the TME, implying its potential function in tumor immune evasion. Low KIAA1467 expression was tightly linked to p53 mutations. Enrichment analysis indicated participation of KIAA1467 in epithelial-mesenchymal transition, apoptosis and cell cycle arrest. Furthermore, high KIAA1467 expression corresponded to higher estimated IC50 values of cisplatin, gefitinib, paclitaxel and gemcitabine, consistent with reduced chemosensitivity observed in vitro. CONCLUSIONS: This study reveals the multifaceted oncogenic role of KIAA1467 in BRCA. KIAA1467 participates in remodeling an immunosuppressive TME, correlates with malignant progression and chemoresistance, and may serve as a promising candidate target to optimize ICB-based combination therapy for BRCA. These findings offer new perspectives for the clinical treatment and comprehensive management of BRCA.

KIAA1467↗

PubMed2022

Krüppel-like factor 5 promotes the progression of oral squamous cell carcinoma via the baculoviral IAP repeat containing 5 gene.

BACKGROUND: Krüppel-like factor 5 (KLF5) is highly expressed in a variety of tumors, and our study aimed to investigate the role of KLF5 in oral squamous cell carcinoma (OSCC). METHODS: To explore the differential expression of KLF5, next-generation sequencing (NGS) and further analyses were conducted in paired premalignant and tumor tissues and adjacent normal mucosa. We then analyzed the mRNA expression data from The Cancer Genome Atlas (TCGA) and performed gene set enrichment analysis (GSEA) to predict the function of KLF5. Small interfering RNA (siRNA) targeting KLF5 was used to knock down its expression in cells and further evaluate the changes in cell apoptosis, proliferation, and migration. We predicted whether baculoviral inhibitor of apoptosis protein (IAP) repeat containing 5 (BIRC5) was the potential target gene of KLF5 via the NCBI and JASPAR databases. Furthermore, we analyzed BIRC5 expression after KLF5 knockdown and explored its function in athymic BALB/c nude mice. RESULTS: KLF5 expression in clinical samples gradually increased from normal mucosa tissues to premalignant and then to OSCC tissues. Analysis of TCGA data and GSEA also suggested that KLF5 was expressed at higher levels in OSCC and involved apoptosis and the protein 53 (P53), transforming growth factor-β (TGF-β), and wingless/integrated (Wnt) signaling pathways. Cell apoptosis was promoted, whereas proliferation and migration were inhibited after KLF5 knockdown. Furthermore, we found KLF5 transcription binding sites on the BIRC5 promoter and BIRC5 expression was inhibited after suppressing KLF5 in vitro and in vivo. CONCLUSIONS: Our findings indicate that KLF5 promotes the development of OSCC via BIRC5, and could be a potential diagnostic and therapeutic target for OSCC.

Krüppel-like factor 5 (KLF5)↗