GDF15 as a sentinel of metabolic integrity: a narrative review of stress signaling, multisystem pathophysiology, and therapeutic potential.

Growth differentiation factor 15 (GDF15) is a stress responsive cytokine belonging to the transforming growth factor-β (TGF-β) superfamily, serving as a sentinel of metabolic integrity. Its expression is induced by multiple convergent stress pathways, including the integrated stress response (ISR), endoplasmic reticulum (ER) stress, oxidative stress, inflammation, and hypoxia. GDF15 is secreted by a wide range of organs, such as adipose tissue, skeletal muscle, liver, heart, kidney, immune cells, and the central nervous system, with the relative contribution of each tissue varying across different physiological and pathological states. Through the hindbrain GFRAL-RET axis, GDF15 suppresses appetite and regulates energy balance, while also exerting peripheral effects on mitochondrial function, insulin sensitivity, and inflammatory responses. Transient GDF15 elevation in response to acute stressors supports adaptive metabolic resilience and tissue protection. In contrast, chronic and sustained elevation signals progressive metabolic dysfunction, organ impairment, and poor prognosis in conditions including obesity, metabolic dysfunction associated steatotic liver disease (MASLD), diabetes, and cardiovascular disease. Importantly, the biological impact of GDF15 is modified by factors such as age and metabolic context, which may shift the balance between adaptive and maladaptive outcomes and account for much of the predictive signal in clinical studies. Although GDF15 holds promise as a prognostic biomarker and a therapeutic target, its clinical translation is hindered by two major challenges: its dual protective and pathological roles, and an incomplete understanding of non-GFRAL signaling pathways. This narrative review summarizes the regulatory networks, tissue sources, and context-dependent functions of GDF15, with an emphasis on its roles in cardiometabolic homeostasis and the potential for future precision therapeutic strategies. We present the sentinel model as a working hypothesis that generates testable predictions, rather than as a proven biological mechanism. The acute-adaptive versus chronic-maladaptive distinction, while conceptually useful, requires validation through measurable parameters including concentration thresholds, temporal dynamics, and tissue specific contributions.