BDE47 exposure in lung adenocarcinoma: prognostic biomarkers, immune dysregulation, and mechanistic insights from toxicogenomic and docking studies

ADRB2 Modulates Asbestos-Induced Pleural Mesothelioma Progression by Influencing IL-17/NF-κB-Related Inflammatory Signalling: An Integrated Network Toxicology, Multi-Omics and Experimental Study.

Pleural mesothelioma (PM) is a highly aggressive asbestos-related malignancy with poor prognosis and limited early diagnostic options. In this study, network toxicology and integrated multi-omics analyses were used to investigate the molecular mechanisms by which chrysotile, crocidolite, and amosite may induce PM, and to identify diagnostic core genes. Asbestos-related targets from the Comparative Toxicogenomics Database (CTD) database were integrated with Gene Expression Omnibus (GEO) transcriptomic datasets, followed by differential expression analysis, weighted gene co-expression network analysis, protein-protein interaction analysis, functional enrichment, machine-learning screening, and SHAP interpretation. Candidate targets were mainly enriched in inflammation-related pathways, including cytokine regulation, complement and coagulation cascades, NF-κB, TNF, and IL-17 signalling. Adrenergic receptor beta 2 (ADRB2), LMO3, GPD1L, EDNRB, RNASE1, PDK4, CAT, and MAL showed strong diagnostic contributions, among which ADRB2 displayed particular mechanistic relevance. Immune-infiltration and single-cell RNA-sequencing analyses suggested that ADRB2 was associated with multiple immune-cell populations and was distributed across both malignant and immune-cell compartments within the PM microenvironment, while molecular docking indicated potential interactions between asbestos and multiple core proteins. LDH assays showed that 2.5 μg/cm2 represented a low-to-subtoxic exposure concentration in MeT-5A and MSTO-211H cells. At this concentration, all three asbestos types promoted proliferation, clonogenic growth, and invasion and up-regulated ADRB2, with crocidolite exerting the strongest effect. Mechanistically, ADRB2 knockdown attenuated crocidolite-induced IL-17/NF-κB-related signalling, reduced IL-6, CXCL1, and CXCL8 expression, and suppressed the malignant phenotype of MSTO-211H cells, whereas recombinant human IL-17A partially restored these effects. These findings identify ADRB2 as a potential diagnostic and mechanistic target in asbestos-related PM and suggest that ADRB2 may contribute to crocidolite-induced malignant progression by modulating cellular responses associated with IL-17/NF-κB-related inflammatory signalling.

Exploratory Toxicogenomic Profiling Identifies Candidate DINCH-Responsive Genes Relevant to Prostate Cancer

Diisononyl cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer adopted as a safer alternative for food-contact and medical-grade materials, is ubiquitously detected in human biomonitoring studies. Despite widespread exposure, its transcriptional effects in prostate cells and the potential prostate cancer relevance of DINCH-responsive genes remain unclear. We integrated transcriptomic profiling of DINCH-exposed human prostate epithelial cells with exploratory genetic association analyses in 630 patients with prostate cancer receiving androgen deprivation therapy (ADT). Haplotype-tagged single-nucleotide polymorphisms (SNPs) in candidate DINCH-responsive genes were evaluated for their association with overall survival (OS) and cancer-specific survival (CSS). The prostate cancer relevance of the prioritized genes was further validated using pooled multi-cohort bioinformatic analyses. DINCH exposure produced an exploratory molecular signature comprising 83 genes across all tested doses, broadly suppressing cell–matrix adhesion pathways and activating chromatin remodeling. Exploratory genetic screening identified nominal associations of LPP rs1040033 with OS (p = 0.0002, q = 0.131) and FAM111B rs7110278 with CSS (p = 0.0010, q = 0.575); neither association remained significant after multiple-testing correction. DINCH exposure significantly downregulated LPP and upregulated FAM111B expression in prostate epithelial cells. Independently, pooled analyses demonstrated reduced LPP and elevated FAM111B expression in prostate cancer tissues compared with normal prostate tissues. Higher LPP expression predicted a favorable prognosis, whereas elevated FAM111B predicted worse survival. Pathway analyses linked low LPP expression to impaired adhesion signaling and metabolic reprogramming, whereas high FAM111B expression was associated with mitotic and cell-cycle activation. DINCH exposure induced exploratory transcriptional alterations involving LPP-related adhesion pathways and FAM111B-related proliferative signaling. The genetic findings are exploratory and require independent validation. Although public datasets support the prognostic relevance of LPP and FAM111B in prostate cancer, they do not link these genes to DINCH exposure.

Toxicogenomic Characterization of Common Genes and Signaling Pathways Associated with Multiple Toxic Metal(loid)s in Lung Cancer: A Comparative Analysis of Small-Cell and Non-Small-Cell Lung Cancer

Simple Summary Exposure to toxic metals and metalloids has been associated with an increased risk of lung cancer, yet the underlying molecular mechanisms remain incompletely understood, particularly in the context of combined environmental exposure. In this study, we used publicly available toxicogenomic databases and bioinformatics tools to identify genes, interaction networks, and signaling pathways commonly associated with the investigated toxic metal(loid)s (lead, cadmium, methylmercury, arsenic, nickel, and hexavalent chromium) and lung carcinogenesis. We identified several genes and signaling pathways implicated in biological processes relevant to lung cancer, including cell survival, inflammation, oxidative stress, and angiogenesis. TP53 was consistently identified across all investigated lung cancer categories, suggesting its relevance as a common molecular link warranting further investigation. Predicted molecular interaction networks and enriched pathways differed between lung cancer subtypes, underscoring the biological heterogeneity of the disease. These findings generate hypotheses and identify candidate biomarkers for future experimental, epidemiological, and mechanistic studies of combined toxic metal(loid) exposure.

Chronic Monobutyl Phthalate Exposure Promotes Anaplastic Thyroid Cancer Progression Through Inflammatory Signaling Dysregulation: Integrated Transcriptomic and Network Toxicology Analyses

Background/Objectives: Chronic exposure to endocrine-disrupting chemicals has been increasingly recognized as a potential contributor to cancer progression. Monobutyl phthalate (MBP), a major metabolite of dibutyl phthalate, is widely detected in human biological samples, yet its long-term impact on anaplastic thyroid cancer (ATC) has not been systematically investigated. Methods: CAL-62 cells were continuously exposed to an environmentally relevant concentration of MBP (10 nM) over 3 months to establish a chronic exposure model that mimics long-term environmental exposure. Transcriptomic profiling was integrated with network toxicology to identify key molecular pathways and hub genes, followed by molecular docking and Western blot validation. Results: Chronic MBP exposure significantly enhanced cell viability, proliferation, colony formation, and tumorsphere formation, indicating promotion of malignant phenotypes. Transcriptomic profiling revealed extensive molecular remodeling characterized by activation of inflammation-associated pathways, including cytokine–cytokine receptor interaction, IL-17, TNF, and JAK–STAT signaling, accompanied by suppression of p53- and mTOR-related pathways. Integrated analysis identified 57 overlapping KEGG pathways, with IL6 and CSF2 emerging as central hub genes. Molecular docking demonstrated favorable binding affinities between MBP and representative target proteins, including IL6, TP53, CASP3, BCL2, and PPARG. Western blot analysis further confirmed increased IL6 and BCL2 expression together with decreased TP53, CASP3, and PPARG expression following chronic MBP exposure. Conclusions: Chronic environmentally relevant MBP exposure promotes ATC malignant progression through coordinated inflammation-associated molecular network remodeling accompanied by suppression of apoptosis-related signaling. Integrating network toxicology with transcriptomic profiling provides an effective systems-level strategy for identifying biologically relevant molecular networks underlying chronic environmental toxicant exposure.

Prognostic and immunological value of LINC01615-related genes in kidney clear cell carcinoma

LINC01615, a long noncoding RNA, plays a pivotal role in the progression of kidney renal clear cell carcinoma (KIRC). This study aimed to assess the prognostic value of LINC01615-associated genes in KIRC by developing a risk model. Differential expression analysis in the The Cancer Genome Atlas-KIRC dataset identified differentially expressed genes between high and low LINC01615 expression groups, as well as between KIRC and control groups. Signature genes were subsequently selected through protein-protein interaction (PPI) network analysis, while prognostic genes were identified via Cox regression. The risk model was then constructed and validated using the E-MTAB-1980 dataset. Furthermore, an independent prognostic analysis identified key risk factors, and a nomogram was created for clinical application. Additional analyses, including enrichment analysis, immune-related analysis, drug sensitivity evaluation, and regulatory network construction, were performed to explore the underlying mechanisms in high and low-risk groups. The GSE40435 dataset was employed for the validation of prognostic gene expression. Reverse transcription-quantitative PCR (RT-qPCR) was conducted to confirm the expression levels of prognostic genes and LINC01615 in clinical samples. LINC01615 expression was found to differ significantly between KIRC and control groups, with notable survival differences observed between high and low expression groups. A total of 757 candidate genes were identified. Among these, COL4A4, COL5A1, and COL15A1 were screened as prognostic genes, and a risk model with better accuracy was constructed. Age and risk score were recognized as independent risk factors, and the nomogram demonstrated enhanced predictive accuracy. Twelve drugs showed a significant negative correlation with risk scores. Additionally, the high-risk group exhibited an increased likelihood of immune escape. A regulatory relationship between hsa-miR-3163 and COL4A4/LINC01615 was identified. In both The Cancer Genome Atlas-KIRC and GSE40435 datasets, COL5A1 and COL15A1 were overexpressed in the KIRC group. RT-qPCR results for COL5A1 and COL4A4 were consistent with the above findings, while COL15A1 showed no significant differences in clinical samples, possibly due to the small sample size. COL4A4, COL5A1, and COL15A1 were identified as prognostic biomarkers through bioinformatics analysis. The developed risk model offers valuable insights for clinical prognostic prediction and immunotherapy in KIRC.

From Environmental Lead Exposure to Colorectal Cancer: Integrated Transcriptomic and Genetic Analyses Identify HMOX1 as a Prioritized Candidate.