SREBPs in Metabolic Reprogramming and Disease: Mechanisms and Therapeutic Potential

Sterol regulatory element-binding proteins (SREBPs) are key transcription factors belonging to the basic helix-loop-helix leucine zipper (bHLH-Zip) family. They play central roles in coordinating cellular lipid metabolic signaling and maintaining metabolic homeostasis. This review systematically summarizes the origin, classification, structural characteristics, and activation mechanisms of SREBPs mediated by the INSIG-SCAP-SREBP complex. Building on this, we further outline the lipid metabolic programs regulated by SREBPs, with a focus on their roles in de novo lipogenesis, triglyceride accumulation, cholesterol metabolism, and membrane remodeling. In addition, we provide a cross-disease overview of SREBP-driven metabolic reprogramming, highlighting its involvement in inflammation amplification, immune metabolic imbalance, disruption of cellular homeostasis, and malignant progression. Based on current advances, we also summarize emerging small-molecule modulators targeting SREBP signaling and their potential therapeutic value. Furthermore, we discuss key challenges in current research, including functional heterogeneity, context-dependent regulation, organismal and cell-type specificity, as well as barriers to clinical translation. Overall, SREBPs are not only central regulators of lipid metabolism but also pivotal hubs linking metabolic remodeling to disease progression. A deeper understanding of their mechanisms and targeted interventions is expected to provide new insights for therapeutic strategies against metabolic diseases.