In vivo and in silico analyses reveal hub genes drive Bisphenol A-induced metabolic dysfunction in male Drosophila melanogaster.

Metabolic dysfunction that results from complex interactions between genetics, metabolism, and environmental factors has emerged as a major global health concern. Endocrine-disrupting chemicals (EDCs), known for their ability to interfere with hormones and signalling cascades, are increasingly recognized for their role in promoting metabolic dysfunction. Bisphenol A (BPA), a widely used EDC, exhibits systemic toxicity, disrupting endocrine regulation while interfering with metabolism and energy homeostasis. However, the molecular mechanisms underlying BPA-induced metabolic dysfunction remain poorly understood, highlighting the need for robust in vivo models with measurable endpoints to evaluate its effects. Here, we developed a functional disease model using Drosophila melanogaster to investigate metabolic disruption following developmental exposure to BPA. Male flies exposed to BPA exhibited key metabolic dysfunction phenotypes, including reduced satiety (hyperphagia), elevated triacylglyceride (TAG) levels, impaired TAG mobilization under nutrient stress, and hypertrophy of lipid droplets. Protein-protein interaction (PPI) network analysis identified overlapping genes between obesity-associated and BPA-responsive datasets. Candidate genes- AKH, AKHR, Foxo, Akt, Hnf4, FASN1, Upd2, Lsd, adp, and ERR showed significant misregulation at transcript and protein levels, supporting in silico predictions. Our findings establish Drosophila as a promising model for xenobiotic-induced metabolic dysfunction and a translational platform for mechanistic studies and future applications.