A Computational and In Vivo Investigation into the Effects of Zeaxanthin-Lutein on the Responses of Drosophila melanogaster to Furan Toxicity

The toxic effects of environmental contaminants, such as furan, are a public health issue, prompting research into affordable, accessible treatments. Drosophila melanogaster is an arthropod that has been utilised as a model for human disease, as it harbours approximately 75% of human disease-related genes. Antioxidant-rich nutraceuticals may be beneficial. Lutein (L) and zeaxanthin (Z) are natural carotenoids with notable pharmacological and antioxidant effects. Network pharmacology (NP) analysis provides insight into the cellular and molecular mechanisms underlying biomolecular interactions in toxicity and chemoprevention, underscoring the importance of further in vivo studies. In silico NP exploration found 47 shared gene targets between lutein-zeaxanthin-induced protection and furan toxicity. Protein–protein interaction analysis identified ALB, APOE, IL-6, TNF, and IL-1 as central hub genes regulating gene expression and inflammation. Gene Ontology and KEGG pathway enrichment analyses revealed significant enrichment for pathways involved in cholesterol metabolism, inflammatory and immune responses, lipid transport, and protein binding. Additionally, we evaluated the protective effects of lutein-zeaxanthin (LZ) supplementation against furan-induced toxicity in Drosophila melanogaster in vivo by assessing oxidative imbalance in the flies' fat bodies (liver) and brains. D. melanogaster were exposed to Furan (100 µM) alone or supplemented with lutein-zeaxanthin combination (88µM + 18µM or 44µM + 9µM) via diet for seven consecutive days. Antioxidant enzyme activity, non-enzymatic antioxidant levels, and oxidative stress biomarkers were spectrophotometrically determined. LZ combined supplementation significantly ( p < 0.05 ) restored furan-induced oxidative stress by reversing the activity of antioxidant enzymes (glutathione- s -transferases) and non-enzymic antioxidants (non-protein thiols) and reducing other markers of oxidative stress (total hydroperoxide) in D. melanogaster. Additionally, supplementation with a lutein-zeaxanthin combination increases nitric oxide and total thiol levels. Furthermore, supplementation with the lutein-zeaxanthin combination ameliorated the histopathological alterations in the fat body (liver) and brain tissues of flies caused by furan exposure. This study indicates that lutein-zeaxanthin may help prevent furan- and related chemical-induced toxicity, acting as an antioxidant-rich nutraceutical with specific pathways identified by NP as therapeutic targets. Furthermore, molecular docking simulations indicated that lutein, particularly in combination with zeaxanthin, exhibits strong binding affinity (including binding scores) to target proteins, suggesting the potential to attenuate the toxic effects of furan.