Phloridzin Mitigates Gorham-Stout Disease by Dual Inhibition of Osteoclastogenesis Related to the Ca²⁺ Signaling Pathway and Vascular Proliferation

Phloridzin, a natural compound derived from <i>Malus doumeri</i>, exhibits a wide range of biological activities, making it a promising candidate for the development of functional foods aimed at promoting health and preventing disease. Gorham-Stout disease (GSD) is an orphan rare disorder defined by gradual bone resorption and vascular proliferation, with fewer than 400 cases documented, leading to severe pathological consequences. This study aims to examine the mechanisms underlying two key features of GSD, including progressive osteolysis, through osteoclastogenesis, and vascular proliferation, by examining endothelial and vascular cell proliferation. Additionally, the relationship between phloridzin and GSD was investigated. Our findings demonstrate that PHL suppresses RANKL-induced osteoclast differentiation, alleviates mitochondrial dysfunction, and inhibits osteoclast-specific transcription factors related to the calcium signaling pathway. In terms of vascular involvement, PHL also attenuates VEGF-A-induced endothelial cell proliferation, migration, development, and related inflammatory gene expression. Collectively, our data indicate that PHL is a promising food-derived compound for the formulation of functional foods targeting osteoporosis and potentially GSD-related complications.