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.
TL;DR
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.
Abstract
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.