GDF15 (Growth Differentiation Factor 15), a member of the TGF-β superfamily, is a stress-responsive cytokine implicated in diverse physiological and pathological processes. Initially identified as MAC-1 (Macrophage Inhibitory Cytokine-1) or PLAB (Placental Bone Morphogenetic Protein), it is secreted under cellular stress, inflammation, or metabolic disturbances. GDF15 binds to the GFRAL-RET receptor complex, primarily expressed in the brainstem, to regulate appetite, energy balance, and body weight. Elevated GDF15 levels are associated with conditions including cancer, cardiovascular diseases, obesity, diabetes, and pregnancy-related disorders like preeclampsia. In cancer, GDF15 promotes cachexia by suppressing hunger and altering metabolism, while in metabolic diseases, it may exert protective or detrimental effects depending on context.
GDF15-targeting antibodies have emerged as therapeutic tools. Neutralizing antibodies are explored to counteract cancer-associated cachexia or chemotherapy-induced anorexia by blocking GFRAL signaling. Conversely, agonist antibodies mimicking GDF15’s effects are investigated for obesity treatment due to their appetite-suppressing properties. Challenges include balancing systemic effects, optimizing receptor specificity, and managing potential off-target consequences. Preclinical studies show promise, with several candidates advancing to clinical trials. However, the dual role of GDF15 in disease progression and homeostasis necessitates precise therapeutic modulation. Ongoing research aims to unravel context-dependent mechanisms and refine antibody-based strategies for metabolic, oncologic, and inflammatory disorders.