Melittin Modulates IL-37a-Associated Networks, Inducing Cytotoxicity in Neuroblastoma Cells

Neuroinflammation is a critical process influencing tumor progression and cellular stress responses. While pro-inflammatory signals often amplify these responses, IL-37a functions as an endogenous suppressor that limits inflammation. However, its precise role in neuroblastoma and how it can be therapeutically modulated remains unclear. Melittin, a bioactive peptide derived from bee venom, possesses known cytotoxic and immunomodulatory properties, making it a candidate for influencing these complex inflammatory networks. Current neuroblastoma treatments often face challenges with specificity and systemic side effects, underscoring the need for targeted approaches that can modulate the tumor microenvironment.

SH-SY5Y neuroblastoma cells were treated in vitro with melittin at concentrations ranging from 1-32 µM for 24 and 48 h. Cell viability was quantitatively assessed using the MTT assay. Expression levels of selected genes related to inflammation and extracellular matrix remodeling were analyzed by qRT-PCR. The targeted gene expression data were subsequently used for protein-protein interaction network analysis, pathway enrichment analyses, and multivariate statistical approaches. Additionally, potential interactions between melittin and STAT3 or IL-1R8 were evaluated via molecular docking, and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties were predicted.

Melittin induced dose- and time-dependent cytotoxicity in SH-SY5Y cells, demonstrating an IC50 value of 16 µM at 24 h. Melittin treatment led to a significant increase in the expression of anti-inflammatory IL-37a, along with IL-18R1 and IL-1R8. Conversely, it suppressed key pro-inflammatory and signaling molecules, including NF-κB, STAT3, MyD88, and Smad3. Caspase-1 expression was elevated, suggesting a modulation of inflammation-associated cell death pathways. Extracellular matrix remodeling was differentially regulated, with increased MMP-2 expression and decreased MMP-9 expression. Multivariate analyses revealed a distinct, treatment-specific gene expression pattern. Molecular docking analyses suggested potential direct interactions between melittin and STAT3 or IL-1R8.