DPP4-Driven Ferroptosis Promotes Senescence: Galangin as a Therapeutic Agent for Age-Related Bone Loss.

Abstract

Senile osteoporosis is driven by bone marrow stromal cell (BMSC) senescence. Ferroptosis, an iron-dependent cell death pathway, is implicated in aging. The natural flavonoid galangin possesses anti-aging properties, yet its effects on ferroptosis and BMSC senescence are unknown. Natural aging and d-galactose-induced aging models were used, with galangin supplementation. Bone mass was assessed via micro-computed tomography and histomorphometry. Senescence markers (P21, SA-β-gal, NAD+) and ferroptosis regulators (GPX4, GSH/GSSG) were measured. BMSC senescence was induced by d-galactose or serial passaging. Effects of galangin on senescence, ferroptosis, osteogenic differentiation, and dipeptidyl peptidase-4 (DPP4) signaling were evaluated. Galangin significantly attenuated bone loss and reduced senescence markers in both aging mouse models. Ferroptosis was activated in senescent BMSC. Galangin suppressed ferroptosis, rescued senescence phenotypes, and restored osteogenic differentiation capacity. Mechanistically, galangin inhibited DPP4 nuclear translocation and disrupted its interaction with NADPH oxidase NOX1, thereby blocking reactive oxygen species-dependent ferroptosis signaling without altering total DPP4 expression. Galangin ameliorates Senile osteoporosis by specifically inhibiting DPP4 nuclear translocation and its interaction with NOX1, thereby suppressing ferroptosis, rescuing BMSC senescence, and restoring osteogenic function. This identifies galangin as a promising agent against skeletal aging.