Cigarette smoke-induced metabolic disorders potentially driven by inflammatory hub genes: Insights from network toxicology and molecular-docking.

Cigarette smoke is a major risk factor for metabolic disorders, notably atherosclerosis and type 2 diabetes mellitus(T2DM). However, the molecular mechanisms that link its constituent toxicants to metabolic pathophysiology remain poorly defined. This study aimed to elucidate these mechanisms by employing an integrated in silico framework that synergized network toxicology with molecular docking to delineate critical toxicant-protein interaction networks.Focusing on five prototypical toxicants (nicotine, carbonic oxide(CO), nitric oxide(NO), nitrogen dioxide(NO2), and benzene) and four prevalent metabolic conditions, we identified a core network of six proteins-including caspase 3 (CASP3), tumor necrosis factor(TNF), tumor protein 53(TP53), estrogen receptor 1 (ESR1), signal transducer and activator of transcription 3 (STAT3),and kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1)-that function as central hubs linking cigarette smoke exposure to metabolic disease. The profound biological importance of these hubs lies in their direct command over the core pathways of cell fate-specifically, the regulation of inflammation (TNF, NF-κB1), programmed cell death (CASP3, TP53), and metabolic homeostasis (ESR1, STAT3). Functional enrichment analysis confirmed this network's centrality, highlighting its roles in inflammatory signaling, apoptosis, and lipid metabolism-all fundamentally dysregulated in metabolic disorders. Importantly, molecular docking simulations predicted strong, stable binding between nicotine and these hub proteins, indicating that it acts as a primary driver of these pathological interactions. Gene expression data from public repositories further confirmed the dysregulation of these core genes in patients with metabolic disorders. This study provides a mechanistic framework elucidating how major cigarette smoke toxicants disrupt critical cellular pathways, thereby offering novel targets for therapeutic intervention and future toxicological research.