From stress cytokine to drug target: The translational landscape of growth differentiation factor 15.

Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that translates cellular injury, metabolic imbalance, and disease burden into systemic physiological responses. Discovery of its hindbrain-restricted receptor, glial cell line-derived neurotrophic factor family receptor α-like (GFRAL) and cosignaling partner rearranged during transfection (RET), established a dedicated neuroendocrine axis (GDF15-GFRAL-RET) linking stress to appetite suppression, nausea, and autonomic effects on energy expenditure. Initially regarded as a passive disease biomarker, GDF15 is now recognized as an active mediator in cancer-related anorexia-cachexia syndrome, chemotherapy-induced nausea and vomiting, obesity, aging, cardiovascular disease, hepatic, renal, gastrointestinal diseases, neurodegeneration, eating disorders, and hyperemesis gravidarum. This expanding biology has driven parallel development of GFRAL agonists and antagonists, as well as approaches to bind and eliminate circulating GDF15 in the treatment of illness behaviors associated with these numerous disease states. Here we review GDF15 biology and signaling from a medicinal chemistry perspective, examining reported structure-activity relationship-guided drug discovery across biologics and small molecules, including patents and ongoing clinical trials targeting the GDF15-GFRAL-RET axis. SIGNIFICANCE STATEMENT: Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that signals through the hindbrain-restricted GFRAL-RET receptor complex to regulate appetite, nausea, and energy balance. This review highlights advances in understanding GDF15 biology, its role in disease, and synthesizes medicinal chemistry efforts targeting this pathway. By integrating structure-activity relationships, biologics, and small molecule approaches, this study outlines therapeutic strategies and translational challenges in modulating the GDF15-GFRAL-RET axis.