Current Medicinal Chemistry - Online First

Cancer-associated fibroblasts (CAFs) play vital roles in HCC initiation and progression via multicellular, stromal-dependent processes. Despite their acknowledged significance, the comprehensive role of CAF-related gene signatures in HCC remains underexplored. Given the established role of CAFs in HCC progression and therapy resistance, we aimed to develop a CAF-derived gene signature for prognosis prediction.

This comprehensive analysis used RNA sequencing data from The Cancer Genome Atlas database and a validation cohort from the International Cancer Genome Consortium database. Differential gene expression analysis identified CAF-related genes associated with HCC prognosis. A gene signature was developed using the least absolute shrinkage and selection operator algorithm and Cox regression analysis, and its prognostic value was evaluated through Kaplan-Meier survival analysis and receiver operating characteristic curve (ROC) analysis. The signature’s associations with immune cell infiltration, chemotherapeutic response, and functional enrichment were investigated to further evaluate the prognostic value of CAF-related genes.

In total, 256 differentially expressed CAF-related genes were identified between samples with high and low CAF infiltration. After systematic analysis, a prognostic signature, including 23 genes, was constructed. Kaplan-Meier and ROC analyses demonstrated the robust predictive potential of our risk model for patients with HCC. Univariate/multivariate Cox regression analyses further confirmed that the risk model was an independent prognostic factor for HCC in both the testing and validation cohorts. The signature stratified patients into high- and low-risk groups with distinct survival (log-rank p < 0.001), achieving areas under the curve of 0.848 (1 year), 0.795 (3 years), and 0.781 (5 years). Patients in the high-risk group were more responsive to vinblastine, docetaxel, and navitoclax. Patients in the low-risk group had greater chemosensitivity to olaparib. Moreover, the stromal score was significantly higher in the high-risk group. Finally, the signaling pathways enriched in the high-risk group were mainly associated with HCC progression.

We established a CAF-related gene signature model as an independent prognostic predictor for HCC. This model may also guide adjuvant chemotherapy and targeted therapy, though further validation across diverse cohorts is needed to confirm its clinical utility.

The CAF-related gene signature exhibited good predictive potential concerning the prognosis of patients with HCC.

Esophageal cancer (EC) is a significant clinical challenge due to its aggressiveness and poor prognosis. CD47, a transmembrane protein, inhibits macrophage phagocytosis and is linked to tumor advancement and poor outcomes. The interaction between curcumin (CUR) and CD47 and its effects on EC needs further studies.

This study identified common target genes of CUR and EC through network pharmacology, and then found core genes via protein-protein interaction (PPI) analysis. In vitro experiments were conducted to investigate the effects of CUR on cell proliferation, apoptosis, and migration, and to explore the underlying mechanisms. in vivo xenograft experiments were also carried out to evaluate the effects and mechanisms of CUR on tumor growth.

CD47 was highly expressed in EC, and CUR shared ten common target genes with EC. Enrichment analysis and PPI network supported PTGS2 and BAX as core genes. in vitro, CUR could inhibit the proliferation and migration of CD47-overexpressing EC cells and induce apoptosis. In the xenograft model, CUR could inhibit tumor growth (p = 0.0144). The mechanism of CUR may be related to multiple components of the MAPK signaling pathway, especially ERK1/2 and its phosphorylation. Additionally, CUR treatment reduced the COX-2 expression level. Immunohistochemistry showed that both BAX and Bcl-2 proteins were upregulated, but the upregulation of BAX protein was significantly more pronounced than that of Bcl-2.

Our study has confirmed that CUR inhibits CD47-overexpressing esophageal cancer cells. This mechanism may be achieved by blocking ERK1/2 and its phosphorylation, reducing COX2 levels, and enhancing BAX protein expression.

This study highlights CUR's potential in treating EC, particularly in CD47 overexpression cases. These results clarify the molecular interactions and provide a basis for future research on CUR-based therapies targeting EC progression pathways.

Prostate cancer is the fourth most commonly diagnosed cancer worldwide and the eighth leading cause of cancer-related mortality, primarily affecting elderly males. Conventional therapeutic approaches, while effective in some cases, often come with substantial side effects, posing particular challenges for older patients. As a result, the exploration of natural compounds from traditional Chinese medicine (TCM) as potential anticancer agents has gained increasing attention. Sesamin, a dietary lignan found in sesame seeds and frequently used in TCM, has shown promise in preliminary studies for its antioxidant, anti-inflammatory, and potential anticancer properties. However, its specific effects and underlying mechanisms against prostate cancer cells remain inadequately characterized.

This study investigated the anticancer effects of sesamin on human prostate cancer DU145 cells. Cell viability was evaluated using MTT assays. Apoptosis induction and cell cycle distribution were assessed by flow cytometry. Protein expression levels of PPAR-γ, p21, and p53 were measured using Western blotting. Additionally, in silico molecular docking was performed using the LibDock algorithm to evaluate sesamin’s binding affinity with the target proteins PPAR-γ and p21.

Sesamin treatment significantly reduced the viability of DU145 cells in a dose-dependent manner. Flow cytometry revealed increased apoptosis and cell cycle arrest at the G1 phase. Western blot analysis showed upregulated expression of PPAR-γ and p21, while p53 expression remained largely unchanged. Molecular docking analysis demonstrated strong binding affinity of sesamin to PPAR-γ (LibDock score: 125.03) and p21 (LibDock score: 105.45), supporting its involvement in a p53-independent apoptotic mechanism.

The study demonstrates that sesamin exerts significant anticancer effects on prostate cancer DU145 cells by inhibiting cell viability, inducing apoptosis, and causing G1 phase cell cycle arrest. The upregulation of PPAR-γ and p21, coupled with unchanged p53 expression, suggests that sesamin may activate a p53-independent pathway, a valuable feature in treating prostate cancers with defective p53 signaling. Molecular docking results corroborate these findings, indicating direct interactions between sesamin and its molecular targets.

Sesamin exhibits promising antiproliferative and pro-apoptotic activities against DU145 prostate cancer cells. Its potential to act as a G1-phase-specific chemotherapeutic agent via a p53-independent mechanism warrants further investigation and development as a natural candidate for prostate cancer therapy.

Observational studies have suggested associations between circulating metabolites and breast cancer (BC) risk, but the direction and causality of these relationships remain unclear due to confounding and reverse causation. Therefore, we aimed to evaluate the potential causal effects of 1,400 circulating metabolites on BC subtypes using Mendelian randomization (MR) based on GWAS data from European-ancestry populations.

Two-sample and reverse MR analyses were performed to explore potential causal links between metabolites and BC from the FinnGen and Breast Cancer Association Consortium (BCAC) cohorts. The inverse-variance weighted (IVW) approach served as the main analytical method to evaluate these associations. To further ensure the robustness and credibility of the MR findings, sensitivity analyses were conducted, incorporating leave-one-out procedures, the Cochran's Q test, and the MR-Egger intercept test.

Following correction using the False Discovery Rate (FDR) method at a significance level of 0.10, we identified 5alpha-pregnan-3beta,20alpha-diol monosulfate levels (p = 6.7714*10-5, PFDR = 0.0798) and Myristoleate (14:1n5) levels (p =0.0002, PFDR = 0.0798) were associated with an increased risk of ER+ BC. Conversely, the Caffeine to paraxanthine ratio (p =0.0001, PFDR = 0.0798) was associated with a reduced risk. In the reverse MR analysis, interactions were observed between Eicosanedioate (C20-DC) levels, Piperine levels, Caffeine to theobromine ratio, Indolepropionate levels, 1-oleoyl-GPC (18:1) levels, and Oleoylcarnitine levels with BC. Notably, the p-values of intercept terms in MR-Egger regression all exceeded 0.05, suggesting an absence of potential horizontal pleiotropy.

These findings suggested that hormone-related, lipid-related, and diet-derived metabolites might play subtype-specific roles in breast cancer development. The identified metabolites provided mechanistic insights and highlighted potential biological pathways that warrant further functional validation. They may also serve as preliminary biomarkers for future metabolomic and translational research.

Our MR study identified several metabolites that may be causally associated with BC risk. These findings offer potential candidates for further mechanistic investigation and highlight the importance of subtype-specific approaches in metabolomics research.

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis and a high fatality rate. To predict the prognosis of HNSCC, this study developed a prognostic model based on nitrogen metabolism (NM)-related genes.

This study utilized transcriptomic data and clinical information from HNSCC obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify differentially expressed NM-related genes. Subsequently, an NM-related prognostic risk model was established by integrating univariate Cox regression, LASSO regression, and multivariate Cox regression. Its predictive value was validated using Kaplan-Meier and ROC curves. Further analysis using GSVA and CIBERSORT examined the relationship between the risk model and the tumor microenvironment immune status, while also evaluating chemotherapy drug sensitivity across different risk groups. Finally, protein-protein interaction (PPI) networks and key gene screening were employed, and the functional validation of the core genes was conducted through in vitro experiments.

We identified 10 key NM-related genes (GLS, ASNS, EXT2, HPRT1, SLC7A5, SMS, B3GNT8, GATM, NAGK, and SULT1B1) to construct a prognostic risk model. The GSVA analysis revealed that the low-risk group was enriched in immune-related pathways, while the high-risk group favored metabolic pathways. Additionally, the low-risk group exhibited higher levels of immune cell infiltration. We discovered that gefitinib, belinostat, erlotinib, and phenformin were more effective against cancer cells with lower risk scores. The PPI network screening identified key hub genes, including LORICRIN. Experimental validation demonstrated that LORICRIN overexpression significantly suppressed migration and invasion in HNSCC cells, suggesting its potential tumor-suppressive role in carcinogenesis and progression.

This study emphasizes the links between NM signatures, immune regulation, and signaling pathways, underscoring their potential in the HNSCC mechanism research.

Our study established a NM-related gene signature closely linked to immune microenvironment and drug sensitivity, highlighting potential biomarkers and therapeutic targets for prognosis and personalized therapy in HNSCC.

Osteosarcoma is a highly aggressive cancer with a notably low five-year survival rate. Although aspirin has demonstrated potential in inhibiting the malignant progression of osteosarcoma, the underlying mechanisms remain unclear.

In this study, RNA sequencing (RNA-seq) was employed to identify the downstream targets of aspirin in osteosarcoma cells. Then, we examined the expression and clinical significance of PDE4D using osteosarcoma patient samples, tissue microarrays, and data from the TARGET and GTEx databases. The effects of PDE4D on cell growth and mobility were assessed by CCK-8, colony formation, transwell, and wound-healing assays. To explore how aspirin influenced the NF-κB/p65/PDE4D axis, we performed qRT-PCR, Western blotting, luciferase reporter assays, etc. Additionally, mouse models with subcutaneous tumors were used to confirm the roles of aspirin and PDE4D.

Our results showed that aspirin significantly impeded the proliferation, migration, and invasion of osteosarcoma cells by various functional assays. RNA-seq identified PDE4D as a key target modulated by aspirin treatment in osteosarcoma. Clinically, PDE4D was highly expressed in osteosarcoma cells and tissues, and higher levels of PDE4D were linked to poorer patient outcomes. Functionally, PDE4D served as an oncogene that promoted the malignant traits of osteosarcoma both in vitro and in vivo. Mechanistically, our findings revealed that NF-κB/p65 directly interacted with the core region of the PDE4D promoter, increasing its expression.

The findings of this study reveal a novel mechanism whereby aspirin exerts its anti-tumor effects by inhibiting the NF-κB/p65/PDE4D axis, providing a mechanistic basis for its therapeutic potential. Further validation in different animal models of osteosarcoma is warranted.

Aspirin suppressed the malignant progression of osteosarcoma by targeting the NF-κB/p65/PDE4D axis, positioning PDE4D as a potential therapeutic target for aspirin-based treatment strategies.

Radiotherapy remains a cornerstone of treatment for non-small cell lung cancer (NSCLC). Despite its critical role, the emergence of radiation resistance remains a significant hurdle, often leading to therapeutic failure and disease progression. This research aimed to investigate the expression of Pellino E3 ubiquitin protein ligase family member 3 (PELI3) in NSCLC and examine its involvement in modulating the tumor's response to radiation.

To quantify PELI3 levels in NSCLC tissues, real-time PCR and Western blotting techniques were employed. The effects of silencing PELI3 on cancer cell proliferation were evaluated using CCK-8 and colony formation assays. Furthermore, an in vivo mouse xenograft model was used to corroborate the in vitro results.

PELI3 expression was markedly elevated in NSCLC tumor samples relative to normal tissues and showed a strong association with clinical features, such as tumor volume, lymph node involvement, and radiotherapy responsiveness. Further analysis revealed that PELI3 promoted epithelial-to-mesenchymal transition (EMT) following radiation exposure. Suppressing PELI3 expression mitigated radiation-induced EMT in both cellular and animal models.

Elevated PELI3 promotes radiation-induced EMT and radioresistance in NSCLC. Suppressing PELI3 reverses EMT features and enhances radiosensitivity in vitro and in vivo, highlighting PELI3 as a potential biomarker and therapeutic target to improve radiotherapy outcomes.

These findings suggest that PELI3 could serve as a valuable prognostic marker in NSCLC and may represent a promising target to improve tumor sensitivity to radiotherapy.

This study investigates the therapeutic effects of Osthole and elucidates its mechanisms in oral squamous cell carcinoma (OSCC).

Differential expression analysis was performed, followed by nomogram construction, gene set enrichment analysis, and immune infiltration analysis. Molecular docking was conducted to evaluate binding interactions, and single-cell analysis was performed.

PTGS2 was identified as a key candidate capable of binding with Osthole. Immune infiltration analysis revealed elevated levels of activated inflammatory cells in OSCC. Single-cell analysis further showed high PTGS2 expression in macrophages and mast cells.

This study demonstrates PTGS2’s involvement in OSCC, highlighting its potential as both a biomarker and a therapeutic target.

Osthole can modulate OSCC by targeting PTGS2, providing a theoretical basis for OSCC management.

Centrosome Amplification (CA) is a state where malignant cells contain excessive centrosomes due to cell cycle dysregulation. Altered CA has been observed in Glioblastoma (GBM). This study developed a CA-related gene model to assess the Tumor Immune Microenvironment (TIME) and prognostic outcomes for patients with GBM.

TCGA-GBM and mRNAseq_325 cohorts were obtained from the Chinese Glioma Genome Atlas (CGGA) database. CA-relevant gene modules and feature genes were identified via WGCNA analysis. Key genes were selected to develop a risk model, followed by validation of the model’s performance. We further compared the gene mutation landscape, TIME characteristics, drug sensitivity, and enriched pathways between high- and low-risk patient groups.

The brown module, which showed the highest correlation with CA, was selected to identify CA-related key genes to develop a Riskscore model. The model can accurately categorize patients into high- and low-risk groups and predict their clinical outcomes with precision. Notably, high-risk GBM patients exhibited higher StromalScore and dendritic score, and the Riskscore was positively correlated with fibroblast infiltration. Moreover, patients with different risk levels displayed distinct enriched pathways and gene mutation landscapes. Further, the high-risk group showed an evidently higher CAF score, and the differential relation between drug sensitivity and the Riskscore was detected.

Though CA was altered in GBM, its prognostic utility remained to be explored. The current study addressed this gap by developing a 6-gene risk model capable of predicting the prognosis and TIME of GBM patients.

A CA-related model was constructed to assess the prognosis and TIME of GBM patients, contributing to the management of GBM in clinical practice.

Tic disorders are neuropsychiatric conditions characterized by involuntary motor or vocal tics; however, the mechanisms underlying these disorders and potential therapeutic targets remain unknown. Therefore, this study investigated the mechanisms underlying tic disorders, particularly focusing on the role of mitochondrial energy metabolism, and identified potential targets of traditional Chinese medicine for these disorders.

Mitochondrial energy metabolism-related genes were retrieved from GeneCards and relevant literature. Additionally, Wangwei powder components and their potential targets were obtained from the TCMSP, HERB, and PubChem databases. Bioinformatic analysis was employed to identify key genes and mechanisms involved in tic disorders.

Notably, 210 target genes of Wangwei powder, 365 mitochondrial energy metabolism-related genes, and 2020 differentially expressed genes in the tic disorder vs. control groups were identified. Based on the intersections of the differentially expressed genes, mitochondrial energy metabolism-related genes, and target genes, aldehyde dehydrogenase 2 (Aldh2), acetyl-CoA acetyltransferase 1 (Acat1), aldehyde dehydrogenase 1a1 (Aldh1a1), and adenylate kinase 2 (Ak2) were identified as key genes in tic disorder pathophysiology. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the key genes were mainly involved in liver development, cellular detoxification of aldehydes, pyruvate metabolism, and fatty acid degradation pathways. Additionally, immune infiltration analysis highlighted notable discrepancies in immune cell populations between the tic disorder and control groups.

Aldh2, Acat1, Aldh1a1, and Ak2 demonstrate potential as therapeutic targets for TD in WWS. The role of Acat1 in immune modulation and disease progression highlights its promise for immunotherapy. However, further experimental validation is needed to address study limitations.

The results indicate that the key genes (Aldh2, Acat1, Aldh1a1, and Ak2) play a crucial role in the pathogenesis of tic disorders through metabolic pathways and immune cell regulation.