Terpenoids modulation of the IFI16-AIM2 interaction for enhanced immune response in lung squamous cell carcinoma and AIM2-dysregulated diseases.

IFI16, a tumor suppressor gene, negatively regulates AIM2, a protein implicated in various cancers and kidney diseases. Disrupting the IFI16-AIM2 interaction could present a novel therapeutic strategy for enhancing immune responses. This study aims to identify terpenoids capable of disrupting the IFI16-AIM2 interaction, potentially activating AIM2 and boosting immune responses against cancers, particularly lung squamous cell carcinoma (LUSC), and other AIM2-dysregulated diseases. KEGG pathway analysis and protein-protein interaction (PPI) analysis with STRING were employed to understand the interaction network between IFI16 and AIM2. Transcription levels of the IFI16-AIM2 have been identified across various cancers. Furthermore, we evaluated the potential of terpenoids, known for their anti-inflammatory and anticancer properties, to modulate IFI16-AIM2 interaction using in silico docking computation. We performed docking studies of various terpenoids with the binding pocket of IFI16 to identify potential lead compounds with favorable binding affinities and postures. Subsequent analyses were conducted to evaluate the docked complexes' stability and intermolecular interactions. Molecular dynamics simulation was performed to evaluate the stability of the protein-ligand complex under physiological conditions. PPI analysis showed a strong co-expression score for IFI16 and AIM2 (0.929), highlighting a close functional link. Transcriptomic data revealed upregulation of both genes in bladder, renal, breast, testis, and lung cancers. Survival analysis indicated that high IFI16 expression was associated with significantly poorer overall survival (HR = 1.6, p < 0.001), while elevated AIM2 modestly increased mortality risk (HR = 1.1, p = 0.0034). Immune correlation analysis in LUSC showed IFI16 negatively associated with immune infiltration, whereas AIM2 positively correlated with CD8 + T cells, neutrophils, and dendritic cells. Docking identified terpenoid compound C10 as the top hit, with strong binding energies to IFI16 (- 9.2 kcal/mol) and AIM2 (- 9.5 kcal/mol), outperforming the standard drug (- 8.89 kcal/mol). Molecular dynamics simulations confirmed complex stability, with protein RMSD stabilizing within 1-2 Å, ligand RMSD remaining < 2 Å, and RMSF indicating limited flexibility outside terminal regions. Persistent hydrogen bonds with key residues (Arg-55, Arg-63 for C2_6MB2; Arg-55, Gln-60 for C3_6MB2) further supported stable binding. These findings provide a promising starting point for the development of terpenoids-based therapies targeting the IFI16-AIM2 interaction for the treatment of cancers and other AIM2-dysregulated diseases. Further in vitro and in vivo studies will be necessary to validate the identified terpenoids' effectiveness and safety for therapeutic applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00453-y.