The estrogen-ferroptosis axis in postmenopausal osteoporosis, osteoarthritis, and intervertebral disc degeneration:...

Estrogen deficiency is a major risk factor for degenerative disorders of the musculoskeletal system in postmenopausal women, while ferroptosis, an iron-dependent form of programmed cell death, has been implicated in the pathogenesis of various osteoarticular diseases. Recent studies indicate an interplay between estrogen signaling and ferroptosis, with evidence relatively well supported in postmenopausal osteoporosis (PMOP), emerging in osteoarthritis (OA), and still limited in intervertebral disc degeneration (IVDD). Estrogen deficiency may disrupt iron homeostasis, lipid metabolism, and antioxidant defense systems, thereby increasing ferroptosis susceptibility across musculoskeletal tissues. This review summarizes the roles of estrogen and recent research progress in these three common degenerative diseases from the perspective of ferroptosis-related mechanisms. Particular emphasis is placed on the shared mechanisms and tissue-specific manifestations of this regulatory axis across these diseases. Finally, we highlight therapeutic opportunities and translational challenges associated with targeting this axis, including estrogen receptor subtype modulation, ferroptosis inhibition, and local delivery strategies. Overall, the estrogen-ferroptosis axis may provide a mechanistic framework for understanding postmenopausal musculoskeletal comorbidity and developing targeted interventions for degenerative musculoskeletal disorders.