Growth differentiation factor 15 (GDF15) in health and disease: a translational journey from metabolic stress to oncology and paediatric pathophysiology

Growth Differentiation Factor 15 (GDF15) is a stress-responsive cytokine linking metabolism, inflammation and disease pathophysiology. In this review, we provide a comprehensive overview of its physiological and pathological functions, emphasising its relevance in various clinical contexts. We discuss the molecular mechanisms that regulate its expression and signalling, its role as a systemic biomarker of cellular and mitochondrial stress, and its function in maintaining metabolic homeostasis and in obesity-related disorders. In oncology, this cytokine plays a pivotal role by displaying context-dependent functions as a mediator of tumour progression, immune modulation and cancer-associated cachexia, making it both a biomarker and a therapeutic target. In paediatric medicine, GDF15 indicates treatment-related toxicity and systemic stress. Taken together, these findings establish the cytokine as a distinctive endocrine mediator that links stress sensing, metabolism, and disease adaptation across different developmental and clinical stages. Despite the growing body of evidence supporting its diagnostic and therapeutic potential, further research is needed to clarify its context-dependent biological actions and facilitate the successful clinical translation of GDF15-targeted strategies in the treatment of metabolic, oncological, and paediatric disorders.