Integrated Experimental and In-Silico Analysis Indicates Melittin as a Modulator of IL-37a-Associated Networks in...

Neuroinflammation is a key process that shapes tumor progression and cellular stress responses. While pro-inflammatory signaling components amplify these responses, IL-37a functions as an endogenous suppressor that limits inflammation. Melittin is a bioactive peptide with cytotoxic and immunomodulatory properties; however, its effects on IL-37a-centered immune regulation in neuroblastoma cells remain unclear. SH-SY5Y neuroblastoma cells were treated in vitro with melittin at concentrations of 1-32 µM for 24 and 48 h. Cell viability was assessed using the MTT assay. Expression levels of selected genes related to inflammation and extracellular matrix were analyzed by qRT-PCR. Targeted gene expression data were further used for protein-protein interaction network analysis, pathway enrichment analyses, and multivariate statistical approaches. In addition, potential interactions between melittin and STAT3 or IL-1R8 were evaluated by molecular docking, and ADMET properties were predicted. Melittin induced dose- and time-dependent cytotoxicity in SH-SY5Y cells, with an IC₅₀ value of 16 µM at 24 h. Melittin treatment led to a significant increase the expression of IL-37a, IL-18R1, and IL-1R8, while suppressing NF-κB, STAT3, MyD88, and Smad3. Caspase-1 expression was elevated, suggesting modulation of inflammation-associated cell death pathways. Extracellular matrix remodeling was differentially regulated, with increased MMP-2 and decreased MMP-9 expression. Multivariate analyses revealed a treatment-specific gene expression pattern. Molecular docking analyses suggested potential interactions between melittin and STAT3 or IL-1R8, while ADMET analysis indicated limited permeability and certain safety constraints. Melittin may emerge as a molecule that modulates inflammation-related gene expression in neuroblastoma cells and may be associated with IL-37a-related regulatory responses. These findings suggest that melittin could act as a potential modulator of inflammation-associated signaling pathways.