Integrating phytometabolomics, Drosophila proteomics, and network pharmacology to evaluate the metabolic effects of Citrus maxima peel extract following bisphenol a and benzyl butyl phthalate exposure

Abstract

Bisphenol A (BPA) and benzyl butyl phthalate (BBP) are endocrine-disrupting chemicals (EDCs) with reported obesogenic activity, attracting interest in their potential contribution to obesity and metabolic dysfunction. This study investigated the effect of pomelo peel extract (PPE) on BPA- or BBP-associated metabolic alterations in 3T3-L1 adipocytes and Drosophila using an integrated multi-omics approach. HPLC-qTOF-MS profiling revealed prominent negative-ion signals tentatively annotated as naringin. BBP caused greater disruption of adipocytes than BPA, with ∼4-fold higher accumulation of lipid droplets. PPE did not significantly reduce total lipid-droplet area but altered lipid-droplet morphology. In Drosophila , BPA and BBP decreased survival, disturbed carbohydrate homeostasis, and impaired locomotion. PPE improved survival and metabolic homeostasis and were comparable to pioglitazone. Proteomics identified distinct sets of proteins with significant overall abundance differences among treatment groups in the BPA and BBP datasets, with mitochondrial pathways represented in both. Importantly, PPE co-treatment was associated with a distinct proteomic profile, suggestive of an adaptive and stress-responsive network remodeling, rather than complete restoration toward control. To summarize, PPE seems to have a potential effect against EDC-induced metabolic dysfunction and support sustainable pomelo peel valorization.