Air pollution and hepatocellular carcinoma: Integrated network toxicology, machine learning, molecular docking and...

Air pollution is closely related to the incidence and prognosis of hepatocellular carcinoma (HCC); however, the mechanisms remain elusive. Therefore, using network toxicology and molecular docking analysis, the present study aimed to identify candidate molecular pathways potentially linking 10 air pollutants (APs) and HCC through machine learning and multi-omics analyses. Using weighted gene co-expression network analysis, differential gene expression analysis and multiple online databases, AP-related and HCC-related genes (AP-HCC-Gs) were obtained for functional and pathway enrichment analyses. A total of 101 combinations of 10 machine learning algorithms were applied to construct an AP-related and HCC-related prognostic signature (AP-HCC-PS), and three machine learning algorithms were used to screen AP-related and HCC-related diagnostic markers (AP-HCC-DMs). Based on the AP-HCC-PS and AP-HCC-DMs, molecular docking and nomogram analyses were conducted. The AP-HCC-PS and AP-HCC-DMs were intersected, and single-cell RNA, reverse transcription-quantitative PCR, small interfering RNA, wound healing and immune cell infiltration analyses were performed. A total of 43 AP-HCC-Gs were identified, which were mainly involved in cell proliferation, oxidative stress and the immune response. The AP-HCC-PS (seven AP-HCC-Gs) and two AP-HCC-DMs showed good prognostic and diagnostic value. Molecular docking analysis suggested the potential binding affinity between these targets and APs. The hub gene proteasome 20S subunit β5 (PSMB5) was highly expressed in regulatory T cells (Tregs) and positively associated with Treg infiltration. AP exposure may be associated with HCC incidence through two AP-HCC-DMs and with prognosis through seven AP-HCC-Gs, with PSMB5 potentially representing an important candidate gene in HCC progression. The present study provided a multi-dimensional analytical framework for identifying candidate genes and pathways potentially linking APs to HCC, thereby advancing hypotheses regarding environmental carcinogenesis.