Ononin Mitigates Estrogen Deficiency‐Induced Osteoporosis Through Activation of ALDH2 in Mice

ABSTRACT Postmenopausal osteoporosis (PMOP) results from estrogen deficiency, oxidative stress, and impaired bone formation, yet effective treatments remain limited. In this study, we identify the natural isoflavone ononin as a potent antiosteoporotic compound and uncover its mechanism through activation of aldehyde dehydrogenase 2 (ALDH2). Using an ovariectomized (OVX) mouse model and bone marrow‐derived mesenchymal stem cells (BMSCs), we evaluated the in vivo and in vitro effects of ononin. An integrated approach combining network pharmacology, molecular docking, enzymatic assays, and ALDH2 knockout ( Aldh2 −/− ) models was employed to verify its molecular target. Ononin significantly alleviated OVX‐induced trabecular bone loss and promoted osteogenic differentiation of BMSCs in a dose‐dependent manner. Mechanistically, network pharmacology and docking analyses identified ALDH2 as the primary target. Enzymatic assays confirmed that ononin robustly enhances ALDH2 activity, reduces reactive oxygen species, lowers 4‐hydroxynonenal and malondialdehyde levels, and maintains mitochondrial integrity. These beneficial effects were largely abolished in Aldh2 −/− mice, confirming the dependence on ALDH2 activation. Collectively, these findings demonstrate that ononin protects against PMOP by promoting ALDH2‐mediated osteogenesis and restoring redox balance, highlighting its potential as a natural therapeutic agent for postmenopausal osteoporosis.