Decoding Metabolic Rewiring: A Systems-Level Perspective

A groundbreaking study applies Worm Perturb-Seq (WPS) to uncover the transcriptional regulation of metabolism in Caenorhabditis elegans, revealing fundamental design principles of metabolic rewiring. By perturbing ~900 metabolic genes and mapping over 110,000 interactions, researchers constructed a metabolic gene regulatory network (mGRN), which displays a highly modular structure with 22 perturbation clusters and 44 gene expression programs. The study identifies multiple transcriptional rewiring strategies, from simple pathway compensation to complex network coordination. A newly proposed compensation–repression (CR) model explains how organisms balance metabolic gene activation and suppression to maintain core functions related to energy and biomass. Preliminary evidence suggests that the CR model may also govern metabolic adaptation in human cells, offering new insights into metabolic disorders and therapeutic strategies.