Drosophila melanogaster Models for Natural Product Discovery: Cross-Disease Conserved Signaling Networks and a Generalizable Translational Pipeline

Abstract

Simple Summary Natural products from plants and traditional medicines are rich sources of potential new drugs, but finding them is often slow, expensive, and plagued by uncertainty about which ingredients are active and how they work. This review tackles these problems using Drosophila melanogaster—a rapid, low-cost animal model that shares most human disease genes. We systematically compare fly models of six major diseases (diabetes, kidney stones, inflammatory bowel disease, cancer, and Alzheimer’s/Parkinson’s) and make two key highlights. First, effective natural products—ranging from polyphenols and terpenoids to alkaloids and bioactive peptides—are used across these distinct etiologies, yet they consistently act on five evolutionarily conserved cell-signaling pathways—IIS/PI3K/Akt/FOXO, JNK/JAK/STAT, Nrf2/Keap1, mTOR/TORC1, and IMD/Toll immune signaling. This explains why a single herbal medicine can treat multiple conditions. Second, we propose a practical step by step pipeline: screen crude extracts in flies, isolate pure active compounds, dissect their genetic targets using fly tools, and finally validate in human cells and mice. This workflow, which is exemplified by representative nephrolithiasis studies, directly solves the major bottlenecks of unclear active ingredients and vague mechanisms. Together, this framework provides a practical roadmap for accelerating natural product discovery while reducing costs and reliance on mammalian models.