Ferroptosis, a form of iron-dependent regulatory cell death, is induced by estrogen withdrawal, leading to iron accumulation and ferroptosis in osteocytes, which reduces bone mineral density (BMD). The study demonstrates that ferroptosis of osteocytes facilitates osteoclastogenesis, contributing to postmenopausal osteoporosis. The Nrf2 signaling pathway is identified as a crucial regulator of osteocytic ferroptosis, regulating the expression of RANKL through DNA methylation of its promoter by Dnmt3a. Inhibition of Nrf2 results in increased RANKL expression and osteoclast activation, exacerbating bone loss. Targeting the Nrf2 pathway, either through iron chelation, Nrf2 activation, or anti-lipid peroxidation, effectively inhibits osteocyte ferroptosis and reduces bone loss, suggesting a potential therapeutic strategy for postmenopausal osteoporosis.Ferroptosis, a form of iron-dependent regulatory cell death, is induced by estrogen withdrawal, leading to iron accumulation and ferroptosis in osteocytes, which reduces bone mineral density (BMD). The study demonstrates that ferroptosis of osteocytes facilitates osteoclastogenesis, contributing to postmenopausal osteoporosis. The Nrf2 signaling pathway is identified as a crucial regulator of osteocytic ferroptosis, regulating the expression of RANKL through DNA methylation of its promoter by Dnmt3a. Inhibition of Nrf2 results in increased RANKL expression and osteoclast activation, exacerbating bone loss. Targeting the Nrf2 pathway, either through iron chelation, Nrf2 activation, or anti-lipid peroxidation, effectively inhibits osteocyte ferroptosis and reduces bone loss, suggesting a potential therapeutic strategy for postmenopausal osteoporosis.