Estrogen signaling and ferroptosis in intervertebral disc degeneration: A proposed mechanistic framework and its evidence gaps.

Intervertebral disc degeneration (IVDD) is a leading contributor to low back pain and disability, characterized by progressive cell loss, extracellular matrix (ECM) degradation, and structural failure. Emerging evidence identifies ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, as a critical mechanism underlying disc cell dysfunction and degeneration. In parallel, estrogen signaling has been increasingly recognized as a key modulator of disc homeostasis, particularly in the context of sex differences and postmenopausal disease acceleration. This review examines whether estrogen signaling and ferroptosis intersect in IVDD, and finds that the question has not been tested. Three separate bodies of evidence bear on the question. First, 17β-estradiol (E2) inhibits ferroptosis in other tissues, through multiple mechanisms in acute kidney injury, through G protein-coupled estrogen receptor (GPER)-dependent lipogenic signaling in tumour cells, and through dihydroorotate dehydrogenase upregulation in hippocampus. Second, ferroptosis is well characterised in disc cells, with established roles for iron dysregulation, the Nrf2/SLC7A11/GPX4 axis, and ACSL4-dependent lipid remodelling. Third, E2 is cytoprotective in nucleus pulposus and annulus fibrosus cells, reducing reactive oxygen species, suppressing NF-κB signaling, and preserving ECM. These bodies of evidence have not been joined: to our knowledge no published study has measured a ferroptosis endpoint in estrogen-treated intervertebral disc tissue, no ovariectomy study has assessed disc iron content or ferroptotic markers, and estrogen-dependent regulation of GPX4, SLC7A11, ACSL4 or iron-handling proteins has not been examined in any disc compartment. Estrogen replacement and the selective estrogen receptor modulator raloxifene preserve disc structure in ovariectomized and aging rodent models, and ferrostatin-1 and iron chelation are independently protective in disc models; no study has combined the two approaches, and receptor selection remains unsettled, since the one directly demonstrated estrogen-ferroptosis mechanism operates through GPER rather than the nuclear receptors targeted by available modulators. This review therefore presents the estrogen-ferroptosis intersection as a biologically coherent hypothesis rather than an established mechanism, specifies the minimum experiment that would test it, and identifies the evidence gaps that currently prevent its translation.