Prediction of primary human targets and toxicity mechanisms of imidacloprid using integrative

Imidacloprid is frequently detected as a residue in food commodities, raising concerns about potential human health risks. Previous findings remain fragmented, and no study has systematically elucidated the primary human target organs and underlying mechanisms using an integrative systems toxicology framework. We applied a human-specific network toxicology approach to characterize imidacloprid-induced toxicity comprehensively. By integrating target prediction and ADME/toxicity models (ADMETlab 3.0, admetSAR 3.0, and ProTox 3.0), the study identified three primary human-relevant toxicity endpoints (respiratory toxicity, liver injury, and genotoxicity/carcinogenicity). Protein-protein interaction, GO, and KEGG pathway analyses revealed that MAPK, NF-κB, JAK-STAT, UPR-ER stress, and Wnt signaling networks may be key pathways involved in oxidative stress, inflammatory signaling, cell-cycle dysregulation, and apoptosis. Molecular docking analysis further supported relatively stronger predicted binding of imidacloprid to several upstream regulatory proteins, including PTGS2 (COX-2), NOS3 (eNOS), APC, CDH1 (cadherin-1 or E-cadherin), AR, HSPA5 (GRP78 or BiP), HSP90AA1 (HSP90α), JAK2, and RELA (p65), whereas downstream signaling proteins such as MAPK14 (p38α), MAPK1 (ERK2), MAPK3 (ERK1), NFKB1 (p50/p105), WNT3A (Wnt), TNF (TNF-α), ESR1 (ERα), and BCL2 exhibited moderate predicted binding. Although these findings are derived from computational analyses and do not establish functional disruption, the coordinated involvement of upstream and downstream signaling hubs suggests possible mechanisms through which imidacloprid exposure may influence multiple organ systems. Taken together, this study provides a systems-level, hypothesis-generating framework to support future experimental validation and human health risk assessment.