Advances in adropin-mediated signaling pathways and molecular mechanisms: Receptor controversies, tissue-specific evidence, and emerging physiological roles.

BACKGROUND: Adropin, a 76-amino-acid peptide encoded by ENHO, is involved in metabolic balance, endothelial function, and inflammatory regulation. It has been linked to PI3K/Akt, MAPK/ERK1/2, AMPK, Notch, and redox/inflammatory pathways, although the identity of a dedicated receptor and the extent to which these mechanisms are conserved across tissues remain unresolved. OBJECTIVES: This review summarizes adropin signaling insights, critically evaluates the strength and limitations of the available evidence, and examines emerging endocrine and reproductive roles. METHODS: We reviewed primary in vitro, ex vivo, animal, and human studies, with particular attention to species/cell model, pathway-specific perturbation, direct biochemical readouts, conflicting findings, and human validation. RESULTS: Adropin activates VEGFR2-dependent Akt/ERK/eNOS signaling in endothelial cells and enhances insulin-stimulated Akt signaling and cell-surface GLUT4 in skeletal muscle. In the liver, PP2A/AMPK signaling provides strong mechanistic support for suppression of hepatic glucose production. NB-3/Notch signaling is best supported in neural models, whereas GPR19 remains a putative, disputed receptor candidate. Importantly, skeletal-muscle AMPK activation is not universal, direct adipose AMPK activation remains unproven, and pancreatic and reproductive effects are context dependent. CONCLUSIONS: Adropin is a versatile regulator connecting energy metabolism, vascular biology, neural function, redox homeostasis, and emerging endocrine/reproductive processes. Current evidence supports a tissue- and model-dependent signaling network rather than a single universal receptor-pathway cascade.