---
title: "Estrogen–Ferroptosis Axis in Postmenopausal Osteoporosis, Osteoarthritis, and Disc Degeneration"
id: "frontiers-in-immunology-2-the-estrogen-ferroptosis-axis-in-postmenopausal-osteoporosis-osteoarthritis-and"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-2-the-estrogen-ferroptosis-axis-in-postmenopausal-osteoporosis-osteoarthritis-and"
content_type: "clinical_feed_article"
specialty: "Rheumatology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1951300"
published_at: "2026-08-26T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Estrogen–Ferroptosis Axis in Postmenopausal Osteoporosis, Osteoarthritis, and Disc Degeneration
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-2-the-estrogen-ferroptosis-axis-in-postmenopausal-osteoporosis-osteoarthritis-and
- **Specialty:** [Rheumatology](https://medichelpline.com/clinical-feed/rheumatology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1951300)
- **Published At:** 2026-08-26T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The full article text and substantive content were not available in the provided source excerpt; only journal navigation and metadata were present. - The original article title indicates a focus on the **estrogen–ferroptosis axis** as it relates to three conditions: **postmenopausal osteoporosis**, **osteoarthritis**, and **intervertebral disc degeneration**. - Because the body text was missing, specific mechanisms, experimental data, study designs, outcomes, and authors' conclusions were not reported in the source and cannot be summarized or inferred. - Key terms signaled by the title that would be central to any review include **estrogen**, **ferroptosis**, and the three musculoskeletal conditions named above, but detailed interactions or evidence linking these concepts were not provided. - The absence of article content means clinical implications, therapeutic suggestions, and research gaps reported by the authors are not available from the provided source. - Any synthesis or recommendations beyond the title would require access to the full article; readers should consult the original Frontiers in Immunology article for complete data and conclusions.
## Clinical Analysis & Structured Key Points
Frontiers | The estrogen–ferroptosis axis in postmenopausal osteoporosis, osteoarthritis, and intervertebral disc degeneration: shared mechanisms and emerging evidence REVIEW article Front. Immunol. , 26 August 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1951300 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Editor & Reviewers Edited by K I Keiichi Ishihara Reviewed by C S Chao Song J Z Jian Zhang Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Molecular mechanisms linking estrogen signaling to ferroptosis regulation. View in article Table 2 Shared mechanisms and tissue-specific differences of the estrogen–ferroptosis axis in PMOP, OA, and IVDD. View in article Table 3 Therapeutic strategies, potential targets, applicable scenarios, and translational limitations for targeting the estrogen–ferroptosis axis. View in article REVIEW article Front. Immunol. , 26 August 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1951300 The estrogen–ferroptosis axis in postmenopausal osteoporosis, osteoarthritis, and intervertebral disc degeneration: shared mechanisms and emerging evidence K Z Kaiyuan Zheng 1,2 † P Z Peiyue Zhang 1,3 † S W Siyu Wang 1 † L W Li Wang 1 X Z Xiaoyan Zheng 1,2 N N Nik Nasihah Nik Ramli 2 * J T Juan Tan 1 * 1. Department of Rehabilitation Medicine, Department of Nursing, Intensive Care Unit, Department of Ultrasound Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China 2. School of Graduate Studies, Post Graduate Centre, Neuroscience & Mental Well-being Centre (NeuroMIND), International Medical School, Management & Science University, Shah Alam, Selangor, Malaysia 3. School of Nursing, North Sichuan Medical College, Nanchong, Sichuan, China See more Article metrics View details Abstract 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. 1 Introduction Estrogen plays a pivotal role in preserving the homeostasis of the skeletal and joint systems, and its decline is widely recognized as a major contributor to the initiation and progression of degenerative disorders such as postmenopausal osteoporosis (PMOP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD) ( 1 , 2 ). A substantial body of evidence has shown that estrogen exerts protective effects across multiple musculoskeletal tissues. In bone, it is essential for maintaining the balance of bone remodeling ( 3 ). In articular cartilage, estrogen attenuates cartilage degeneration by suppressing inflammatory responses and the expression of matrix-degrading enzymes ( 4 ). In the intervertebral disc, it is thought to preserve the functional stability of nucleus pulposus cells through the regulation of apoptosis, oxidative stress, and extracellular matrix metabolism ( 5 ). Notably, epidemiological and clinical observations suggest that although PMOP, OA, and IVDD arise in distinct anatomical structures and present with different clinical manifestations, they often coexist and tend to progress more rapidly under estrogen-deficient conditions ( 2 , 6 ). To date, studies on estrogen have mainly focused on inflammation, hormone signaling, and apoptosis. However, whether these disorders share additional cell-death mechanisms that are sensitive to estrogen deficiency remains incompletely understood ( 7 , 8 ). In recent years, ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has attracted increasing attention as a mechanistic link between metabolic imbalance, oxidative damage, and tissue degeneration ( 9 ). At its core, ferroptosis involves the disruption of several critical processes, including intracellular iron homeostasis, lipid redox balance, and the System Xc − /GSH/GPX4 antioxidant defense axis. Growing evidence indicates that ferroptosis is actively involved in the development and progression of multiple degenerative bone and joint disorders. In osteoporosis, factors such as hyperglycemia, aging, and oxidative stress can trigger ferroptosis in osteoblasts, often accompanied by impaired antioxidant capacity and mitochondrial dysfunction ( 10 , 11 ). In OA, inflammatory stimuli such as IL-1β promote the accumulation of reactive oxygen species and lipid peroxides while suppressing glutathione peroxidase 4 (GPX4) expression, thereby inducing chondrocyte ferroptosis and accelerating extracellular matrix degradation ( 12 ). In IVDD, ferroptosis in nucleus pulposus cells has been closely associated with heightened oxidative stress, impaired extracellular matrix synthesis, and progressive disc degeneration ( 13 ). Collectively, these findings suggest that ferroptosis may represent a key common execution pathway across degenerative disorders affecting distinct musculoskeletal tissues. Recent mechanistic studies have established estrogen as an important determinant of cellular ferroptosis susceptibility ( 14 ). Conversely, disruption of estrogen/ESR1 signaling or estrogen-deprived conditions can weaken anti-ferroptotic defenses and increase cellular susceptibility to ferroptosis ( 15 ). Beyond the classical estrogen receptor α/β (ERα/ERβ)-mediated pathways, emerging evidence suggests that the G protein-coupled estrogen receptor (GPER/GPR30) also participates in the regulation of ferroptosis, for example by modulating YAP1 phosphorylation and ferritin heavy chain 1 (FTH1) expression ( 16 ). At the mechanistic level, estrogen may regulate ferroptosis through several interconnected processes, including activation of Nrf2-dependent antioxidant defenses ( 17 ), maintenance of the SLC7A11/GSH/GPX4 axis ( 18 ), regulation of intracellular iron homeostasis through proteins such as FTH1 ( 16 ), and modulation of lipid metabolism and lipid peroxidation ( 14 , 15 ). Collectively, these findings support a direct regulatory relationship between estrogen signaling and ferroptosis and provide a mechanistic basis for the potential involvement of this axis in degenerative musculoskeletal diseases. Although current studies have separately implicated ferroptosis in PMOP, OA, and IVDD and suggested a protective role for estrogen, the estrogen–ferroptosis relationship has not yet been systematically integrated across these disorders. In particular, the extent to which this axis is shared across different musculoskeletal cell types, and the involvement of ferroptosis-related mechanisms beyond the canonical Nrf2/GPX4 pathway remain unclear. These gaps limit a comprehensive understanding of its role in degenerative musculoskeletal diseases. Accordingly, this review systematically evaluates the estrogen–ferroptosis regulatory axis in PMOP, OA, and IVDD, while distinguishing direct experimental evidence from indirect mechanistic inference. By comparing the current evidence across these disorders, we aim to identify common mechanistic features, clarify disease-specific differences and evidence gaps, and discuss the potential therapeutic implications of this regulatory axis. 2 Molecular mechanisms linking estrogen signaling to ferroptosis regulation As a pivotal sex hormone, the biological effects of estrogen are primarily mediated by two classes of receptors: the classical nuclear receptors, ERα and ERβ, and the membrane receptor, GPER. Among these receptors, ERα and ERβ mainly mediate genomic effects. Upon ligand binding, these receptors undergo conformational rearrangement, form dimers, and translocate into the nucleus, where they bind to estrogen response elements within the promoter regions of target genes, thereby regulating the transcription of a broad range of genes involved in cell proliferation, differentiation, and redox homeostasis ( 15 , 19 ). Conversely, GPER mediates more rapid non-genomic signaling responses, which can promptly alter cellular stress states and survival programs through pathways such as PI3K/AKT, ERK, cAMP/PKA, and Ca² + signaling ( 20 ). This dual mode of action, combining nuclear receptor-mediated transcriptional regulation with membrane receptor-mediated rapid signal transduction, enables estrogen to coordinate multiple cellular functions at the upstream level, including the remodeling of ferroptosis susceptibility. Importantly, the influence of estrogen on ferroptosis is not entirely restricted to receptor-mediated signaling. Its unique phenolic structure, particularly the free phenolic hydroxyl group on the A ring, is considered one of the chemical bases underlying its direct antioxidant activity. This structural feature allows estrogen to scavenge free radicals and suppress lipid peroxidation, thereby alleviating oxidative stress-mediated cellular damage to some extent ( 21 , 22 ). Therefore, mechanistically, estrogen does not merely target a single ferroptosis-related molecule; rather, it is more likely to exert broad regulatory effects on the initiation and progression of ferroptosis by modulating cellular redox status, lipid peroxidation, and the iron homeostasis-associated microenvironment ( Figure 1 ). Figure 1 Molecular mechanisms linking estrogen signaling to ferroptosis regulation. Estrogen modulates ferroptosis through ERα/ERβ-mediated genomic signaling, GPER-mediated non-genomic signaling, and receptor-independent direct antioxidant activity. These pathways converge on the regulation of antioxidant defense, iron homeostasis, and lipid remodeling, collectively limiting lipid peroxidation and iron-dependent oxidative damage and thereby reducing ferroptosis susceptibility. 2.1 Estrogen suppresses ferroptosis by enhancing antioxidant defense Uncontrolled lipid peroxidation is the executional core of ferroptosis. Accordingly, the preservation of cellular antioxidant defense represents a primary mechanism by which estrogen suppresses ferroptosis. Early studies demonstrated that 17β-estradiol reduces reactive oxygen species (ROS) generation in vascular cells and upregulates the expression and activity of manganese superoxide dismutase (MnSOD) and extracellular superoxide dismutase (ecSOD), thereby attenuating oxidative stress ( 23 ). In addition, estrogen enhances glutathione-dependent reducing systems. Studies have shown that estrogen can activate the Nrf2-dependent antioxidant transcriptional program, promoting the expression of antioxidant and detoxification-related molecules, including heme oxygenase-1 (HO-1), superoxide dismutase (SOD), glutathione S-transferase (GST), and glutamate-cysteine ligase (GCL), thereby strengthening the cellular capacity to eliminate free radicals and maintain glutathione homeostasis ( 24 , 25 ). Given that the Nrf2–GPX4 axis constitutes a central defense system for detoxifying lipid peroxides and preserving membrane redox homeostasis, activation of this pathway is directly relevant to the suppression of ferroptosis. Recent studies have further demonstrated that estrogen deficiency accelerates lipid peroxidation and iron deposition through inhibition of the Nrf2/GPX4 pathway, thereby triggering ferroptosis in endothelial cells and promoting the progression of postmenopausal atherosclerosis ( 17 ). In summary, these findings suggest that estrogen inhibits ferroptosis by reinforcing cellular antioxidant defenses and preserving the function of the Nrf2/GPX4 protective axis, ultimately limiting lipid peroxide accumulation and reducing the likelihood of ferroptotic cell death. 2.2 Estrogen reduces ferroptosis susceptibility by remodeling iron homeostasis and lipid metabolism Beyond strengthening antioxidant defenses, estrogen may also reduce ferroptosis by remodeling iron homeostasis and lipid metabolism. The occurrence of ferroptosis depends on two key conditions: first, expansion of the intracellular labile iron pool, which facilitates Fenton chemistry; and second, enrichment of membrane phospholipids containing polyunsaturated fatty acids (PUFAs), which are highly prone to peroxidation. Therefore, any mechanism capable of limiting free iron accumulation, promoting iron efflux, or reducing the availability of peroxidation-susceptible lipid substrates may suppress ferroptosis at an upstream level. Available evidence indicates that 17β-estradiol suppresses the transcription of hepcidin through an estrogen response element-dependent mechanism, thereby favoring the maintenance of ferroportin (FPN1) and cellular iron export ( 26 ). At the cellular level, estrogen can also affect the expression of multiple iron metabolism-related molecules, including ferroportin, transferrin receptor (TfR), and ferritin (FTH1), thereby altering the cellular states of iron uptake, storage, and export ( 27 ). Mechanistically, such regulation helps limit the accumulation of pro-oxidant Fe² + and reduces the probability of triggering lipid peroxidation chain reactions. In other words, estrogen does not merely passively buffer oxidative damage after ferroptosis has been initiated; rather, it lowers the iron-dependent basis required for ferroptosis by reshaping intracellular iron trafficking at its source. On the other hand, the enrichment of PUFA-containing phospholipids in cellular membranes and their subsequent peroxidation are closely associated with ferroptosis. Recent studies have shown that MBOAT1, a membrane phospholipid remodeling enzyme, can be transcriptionally upregulated by ER and suppress ferroptosis by reshaping cellular phospholipid composition, an effect that appears to be at least partially independent of the GPX4/FSP1 system ( 15 ). In another study, 17β-estradiol was found to induce the expression and activity of the lipid metabolic enzyme stearoyl-CoA desaturase 1 (SCD1) in estrogen receptor-positive cells, thereby increasing the intracellular ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) ( 28 ). Since MUFA enrichment is known to inhibit membrane lipid peroxidation, this finding suggests that estrogen may enhance cellular resistance to ferroptosis by promoting fatty acid desaturation and remodeling membrane lipid composition. Taken together, these studies indicate that the regulatory effects of estrogen on membrane lipid composition and fatty acid metabolism may constitute another important mechanism through which estrogen modulates ferroptosis ( Table 1 ). Table 1 Estrogen action mode Signaling or regulatory context Main mechanistic implication Ferroptosis-related effect Representative molecules ERα/ERβ-mediated genomic signaling Ligand-bound ER activation and transcriptional regulation Modulates genes involved in redox balance, antioxidant defense, and cellular stress adaptation Reduced lipid peroxide accumulation Nrf2, GPX4, GSH, HO-1, GCL ER-associated regulation of iron metabolism May influence iron uptake, storage, and export, thereby limiting intracellular pro-oxidant iron availability Reduced labile iron burden Hepcidin, FPN1, TfR, FTH1 Regulation of phospholipid remodeling and fatty acid metabolism Alters membrane lipid composition and reduces susceptibility to lipid peroxidation Reduced PUFA-phospholipid peroxidation susceptibility MBOAT1, SCD1 GPER-mediated non-genomic signaling Rapid membrane-initiated signal transduction Activates pro-survival and stress-response pathways that may affect ferroptosis sensitivity Reduced ferroptosis susceptibility GPER, PI3K/AKT, ERK, cAMP/PKA, Ca² + Receptor-independent antioxidant effect Direct chemical antioxidant activity of estrogen Phenolic hydroxyl group can scavenge radicals and suppress lipid peroxidation Reduced ferroptosis initiation 17β-estradiol Molecular mechanisms linking estrogen signaling to ferroptosis regulation. 3 Role of the estrogen–ferroptosis axis in PMOP, OA, and IVDD PMOP, OA, and IVDD frequently overlap in aging women after estrogen decline, reflecting shared features such as oxidative stress, iron dyshomeostasis, inflammation, and progressive extracellular matrix or skeletal tissue deterioration. 3.1 Role of the estrogen–ferroptosis axis in PMOP PMOP is fundamentally characterized by an imbalance in bone remodeling coupling under conditions of estrogen deficiency. This imbalance manifests as reduced bone formation, enhanced bone resorption, and disruption of bone microenvironment homeostasis. In recent years, ferroptosis has been recognized as a critical nexus linking estrogen decline, increased oxidative stress, iron metabolism dysregulation, and dysfunction of bone cells ( 29 ). Emerging evidence suggests that estrogen regulates bone metabolism not only through classical endocrine mechanisms but also by modulating iron homeostasis pathways, thereby influencing the tolerance of bone tissue to lipid peroxidative damage ( 30 ) ( Figure 2 ). Figure 2 Role of the estrogen–ferroptosis axis in bone remodeling imbalance in PMOP. Estrogen deficiency increases ferroptotic susceptibility in bone cells. Enhanced ferroptosis in BMSCs and osteoblasts impairs osteogenic differentiation and function, leading to reduced bone formation, whereas osteocyte ferroptosis promotes RANKL-mediated osteoclastogenesis and increases bone resorption. Meanwhile, ferroptosis-associated lipid peroxidation, ROS, DAMPs, and inflammatory signaling further disrupt the bone microenvironment, collectively amplifying bone remodeling imbalance and progressive bone loss in PMOP. 3.1.1 Estrogen deficiency-induced ferroptosis in osteoblasts and BMSCs Within the osteogenic lineage, osteoblasts represent the cell type with the most direct mechanistic evidence linking estrogen deficiency to ferroptosis. Estrogen maintains osteoblast ferroptosis resistance by promoting GPX4 expression through ERβ, whereas estrogen deficiency disrupts this axis, leading to impaired detoxification of phospholipid peroxides, increased lipid peroxidation, and accumulation of 4-hydroxynonenal (4-HNE). The elevated 4-HNE promotes integrin-linked kinase (ILK) degradation, suppresses RUNX2/OSX-mediated osteogenic differentiation, and ultimately impairs bone formation. Consistently, osteoblast-specific Gpx4 deficiency or GPX4 inhibition exacerbates ferroptotic damage and bone loss, while ferroptosis inhibition or GPX4 activation restores osteogenic activity ( 30 ). In addition to ERβ–GPX4 regulation, other mechanisms may contribute to osteoblast ferroptosis in osteoporotic conditions. Increased DNMT activity promotes GPX4 promoter hypermethylation and suppresses GPX4 expression in OVX models and osteoporotic bone, whereas inhibition of DNMTs alleviates ferroptosis and bone loss ( 31 ). Moreover, activation of the CEBPA/ALOX15B axis enhances lipid peroxidation and osteob
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