An Integrative Strategy Delineates Modular Metabolic Remodeling and Potential Therapeutic Targets Across Metabolic Diseases

ABSTRACT Metabolic diseases are a substantial global health burden. However, how different metabolic pathways are connected to the clinical relevance in metabolic diseases remains unclear. Here, by integrating previously published single‐cell RNA sequencing datasets, a single‐cell metabolic atlas including 562 699 cells from 86 patients across seven major metabolic diseases is compiled. An advanced integrative analytical strategy to assess the activity of 227 metabolic pathways is developed. It is identified 89 disease‐enriched pathways. These pathways are further organized into 15 cooperative metabolic modules, revealing metabolic module remodeling associated with coordinated pathway activities and underlying regulatory mechanisms. By linking module activities to transcription factor dynamics and ligand–receptor signaling, cross‐cell‐type regulatory circuits underlying module‐specific remodeling and the identification of 63 potential therapeutic targets are delineated. Furthermore, an open‐access resource is developed to enable in‐depth exploration of the results in this study. In summary, this study illustrates conserved principles of modular metabolic remodeling across metabolic diseases and sheds light on therapeutic target discovery.