Insulin-like growth factor receptor signaling in physiology and disease

The insulin-like growth factor (IGF) signaling pathway plays a pivotal role in regulating a myriad of cellular and physiological processes, including cell proliferation, differentiation, and the maintenance of redox homeostasis. This review provides a comprehensive overview of the IGF/IGF receptor (IGFR) signaling axis, outlining its historical milestones and delineating its evolution from foundational discoveries to contemporary advancements. We elucidate the structural components of pathway, including ligands, receptors, and IGF-binding proteins, and discuss how multilevel regulation integrates upstream signals with downstream effectors such as the PI3K-AKT and MAPK/ERK pathways. Particular emphasis is placed on the crosstalk between IGF signaling and other pathways, including insulin, EGFR, PDGFR, VEGF, Wnt/β-catenin, JAK-STAT, and TGF-β/BMP in homeostasis and pathophysiological processes. We further discuss the role of IGF signaling in pathological process, highlighting insights from animal models and its implication in a wide range of human diseases, including cancer, cardiovascular diseases, neurodegenerative conditions, metabolic syndromes, skeletal abnormalities, and autoimmune and rare genetic disorders. Finally, we examine the therapeutic potential of targeting the IGF/IGFR axis, current clinical research advancements, FDA-approved pharmacological agents, and ongoing clinical trials. By incorporating historical insights with up-to-date scientific breakthroughs, our review underscores the need for systems-level and context-specific approaches to better understand IGF signaling dynamics, thus paving the way for the development of precision and personalized therapeutic strategies.