High-salt diet modulates endocrine regulation between cortisol and FGF23

Abstract Excessive dietary salt intake is a global health concern, affecting cardiovascular, renal, and bone health. While the renin–angiotensin–aldosterone system (RAAS) is a known regulator of dietary salt-induced hormonal responses, the impact of adrenal cortisol remains unclear. Here, we performed a retrospective analysis in individuals ( n  = 321) consuming a random diet. Dietary salt intake positively correlated with urinary cortisol and inversely correlated with plasma fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D homeostasis. Controlled salt diets in healthy individuals confirmed a dose-dependent increase in urinary cortisol and suppression of plasma FGF23. In mice, oral corticosterone, a cortisol analogue, reduced circulating FGF23 levels. RNA-seq analysis of corticosterone-treated MC3T3 osteoblasts identified suppression of FGF23 via glucocorticoid receptor activation, anti-inflammatory pathways, and reduced osteoblast activity. Our findings provide evidence for an endocrine cascade in which high salt intake elevates cortisol signaling and suppresses FGF23.