Ferroptosis in osteocytes is a key mechanism underlying postmenopausal osteoporosis (PMOP). Estrogen withdrawal disrupts iron metabolism, leading to iron accumulation in bone tissues and osteocyte ferroptosis, which reduces bone mineral density. This process is associated with increased osteoclastogenesis, as shown in a direct osteocyte/osteoclast coculture system and in GPX4 knockout ovariectomized mice. The Nrf2 signaling pathway is crucial for regulating osteocyte ferroptosis. Nrf2 suppresses ferroptosis by regulating DNA methylation of the RANKL promoter via DNA methyltransferase 3a (Dnmt3a), thereby controlling osteoclast activation. Inhibition of Nrf2 leads to increased RANKL expression, promoting osteoclastogenesis and bone loss. Targeting Nrf2 could be a therapeutic strategy to prevent PMOP by inhibiting osteocyte ferroptosis and regulating osteocyte-osteoclast interactions. Iron overload in osteocytes, driven by estrogen deficiency, exacerbates ferroptosis, leading to bone loss. Nrf2 activation reduces ferroptosis and RANKL expression, improving bone health. These findings highlight the role of osteocyte ferroptosis in PMOP and suggest that targeting Nrf2 could be a promising approach for treating this condition.Ferroptosis in osteocytes is a key mechanism underlying postmenopausal osteoporosis (PMOP). Estrogen withdrawal disrupts iron metabolism, leading to iron accumulation in bone tissues and osteocyte ferroptosis, which reduces bone mineral density. This process is associated with increased osteoclastogenesis, as shown in a direct osteocyte/osteoclast coculture system and in GPX4 knockout ovariectomized mice. The Nrf2 signaling pathway is crucial for regulating osteocyte ferroptosis. Nrf2 suppresses ferroptosis by regulating DNA methylation of the RANKL promoter via DNA methyltransferase 3a (Dnmt3a), thereby controlling osteoclast activation. Inhibition of Nrf2 leads to increased RANKL expression, promoting osteoclastogenesis and bone loss. Targeting Nrf2 could be a therapeutic strategy to prevent PMOP by inhibiting osteocyte ferroptosis and regulating osteocyte-osteoclast interactions. Iron overload in osteocytes, driven by estrogen deficiency, exacerbates ferroptosis, leading to bone loss. Nrf2 activation reduces ferroptosis and RANKL expression, improving bone health. These findings highlight the role of osteocyte ferroptosis in PMOP and suggest that targeting Nrf2 could be a promising approach for treating this condition.