Modulation Sterol Regulatory Element-Binding Protein Signaling: Mechanisms, Probes, and Roles in Disease

Maintenance of lipid homeostasis requires cells to coordinate lipid synthesis precisely. Sterol regulatory element-binding proteins (SREBPs) represent one of the central mechanisms by which cells sense lipid availability and adjust the biosynthesis of fatty acids, cholesterol, and phospholipids in response to metabolic and other changes. Dysregulation of SREBP signaling has been implicated in a broad spectrum of diseases, where altered lipid metabolism reshapes membrane organization, cellular signaling, and stress adaptation. In this review, we summarize the molecular mechanisms governing SREBP activation and systems-level regulation. Particular emphasis is placed on the approaches that have enabled interrogation of SREBP signaling. We discuss imaging-based assays, perturbation strategies, pharmacological inhibitors, lipidomics, and other approaches that collectively allow SREBP activity to be interrogated across spatial, biochemical, and metabolic scales. Finally, we highlight how integration of systems-level approaches can refine our understanding of membrane homeostasis and reveal new opportunities for therapeutic intervention in diseases driven by altered SREBP metabolism.