From Stress Cytokine to Drug Target: The Translational Landscape of GDF15

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, GDNF family receptor alpha-like (GFRAL) and co-signaling partner 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 (CACS), chemotherapy-induced nausea and vomiting (CINV), 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 (SAR)-guided drug discovery across biologics and small molecules, including patents and ongoing clinical trials targeting the GDF15–GFRAL–RET axis.