Gnetol targeting of TNFAIP3 promotes SLC7A11 ubiquitination and ferroptosis in osteoclasts to ameliorate osteoporosis.

Osteoporosis, a disorder characterized by excessive bone resorption due to hyperactive osteoclasts outpacing bone formation, remains a significant clinical challenge. Emerging evidence suggests that selectively inducing ferroptosis in osteoclasts represents a promising therapeutic strategy. In this study, we identified Gnetol (GT), a naturally occurring stilbene compound, as a potent inducer of ferroptotic cell death in osteoclasts. GT treatment markedly impaired osteoclast differentiation and viability by promoting lipid peroxidation, depleting intracellular glutathione, and increasing labile iron levels. These effects were mechanistically linked to suppression of the cystine/glutamate antiporter SLC7A11. We further demonstrated that GT directly interacted with the E3 ubiquitin-editing enzyme A20 (TNFAIP3) at the Asp70 residue, thereby enhancing K48-linked ubiquitination and proteasomal degradation of SLC7A11, which triggered ferroptosis in osteoclasts. In vivo, GT administration improved trabecular bone architecture and suppressed osteoclast activity in an ovariectomy-induced osteoporosis mouse model, effects that were abolished in mice lacking TNFAIP3 in myeloid cells. Metabolomic profiling of bone tissue further revealed a ferroptosis-associated metabolic signature following GT treatment, which was reversed by pharmacological inhibition of ferroptosis. Collectively, our findings delineate a previously unrecognized TNFAIP3-SLC7A11 regulatory axis governing osteoclast ferroptosis and identify GT as a promising therapeutic candidate for osteoporosis through targeted induction of ferroptotic cell death. These results underscore the therapeutic potential of modulating ubiquitin-mediated ferroptosis pathways in osteolytic disorders.