Pleiotropic effects of GDF-15 to regulate nutritional status: perspectives from body composition to nutrition-related...

Growth differentiation factor 15 (GDF-15), a stressful cytokine of the transforming growth factor-β (TGF-β) superfamily, plays pivotal roles in diverse physiological and pathological processes. Most recently, its pleiotropic effects regarding energy metabolism and nutritional modulation are of intense scrutiny. Its physiological functions involve signaling pathways such as GDF-15/glial cell-derived neurotrophic factor family receptor α-like protein (GFRAL)/rearranged during transfection (RET), phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (Akt)/mammalian target of rapamycin (mTOR), nuclear factor kappa B (NF-κB), and reactive oxygen species (ROS). The mechanism of action involves regulation of energy metabolism, inflammation, oxidative stress, and muscle-fat-bone metabolism, and it holds important prognostic value and potential therapeutic significance. Mounting evidence has suggested that GDF-15 levels are significantly increased in the context of cancer cachexia, metabolic syndrome (MetS), and amongst older patients, paralleling multiple indicators of nutrition. Notably, this association appears to be gender- and age-specific, therefore serving as a good biomarker alongside a therapeutic target to mitigate or even reverse disease-related nutritional deficiency and aggravation. However, the precise contribution of GDF-15 to evaluate nutritional status and its mechanistic basis across varying disorders is not fully elucidated. In light of these knowledge gaps, we sought to delve into basic research, clinical information and translational evidence, aiming to analyze the molecular regulatory network of GDF-15 and clarify its clinical implications as a novel diagnostic tool and assessment metric, and in turn provide a theoretical basis for early intervention and personalized treatment. Future research should focus on elucidating GDF-15's neuroanatomical basis and signaling pathways, validating gender-disparity mechanisms, establishing clinical diagnostic thresholds, optimizing targeted therapeutic strategies, and developing dynamic monitoring approaches, so as to bridge the gap from biomarker discovery to precision intervention.