The iron-ferroptosis axis in bone homeostasis: a potential complementary pathway for osteoporosis in endometriosis

Rather than supplanting the classical estrogen-deficiency model, the iron–ferroptosis axis is better conceptualized as a synergistic or complementary pathway that amplifies hormonally driven bone loss. The primary drivers of osteoporosis in many women with endometriosis remain hypoestrogenic states, whether from premature ovarian insufficiency or GnRH agonist therapy. However, evidence suggests that estrogen withdrawal itself can induce iron accumulation in osteocytes, thereby predisposing them to ferroptosis [ 46 ]. We, therefore, hypothesize that the systemic pro-oxidative state potentially emanating from endometriosis does not act in isolation. Instead, it may serve as a powerful amplifier of hormonally initiated bone loss. In this model, the skeleton is already "primed" for damage by the loss of estrogen's protective effects on bone cells. The additional systemic burden of dysregulated iron and inflammatory mediators originating from the pelvic pathology could then push bone cells past a critical threshold, triggering widespread ferroptosis and accelerating the rate of bone deterioration. This synergistic model offers a more nuanced explanation for the particularly severe bone loss sometimes observed in endometriosis patients undergoing GnRH agonist therapy. The treatment induces profound hypoestrogenism (the primary hit), while the underlying disease provides a continuous systemic iron and inflammatory stress (the synergistic second hit). This combination could lead to a more severe osteoporotic phenotype than would be expected from either factor alone [ 47 , 48 ]. The molecular intersections between these pathways can be summarized by distinguishing between established and hypothesized roles. The conventional view of bone loss under GnRH agonist therapy only accounts for hypoestrogenism. However, the ferroptosis axis suggests a mechanism for acceleration. While direct studies are not yet available, parallel mechanisms in skeletal tissue provide strong evidence for sensitization [ 49 ]. Specifically, insights from chondrocyte biology—a lineage closely related to osteocytes—provide a template for this mechanism. In chondrocytes, IL-6 has been shown to independently induce ferroptosis by upregulating hepcidin expression locally via the STAT3 signaling pathway [ 50 ]. This autocrine/paracrine hepcidin traps iron within the cell, increasing the labile iron pool and reducing GPX4 activity [ 51 , 52 ]. While direct evidence in osteocytes is yet to be confirmed, we extrapolate this mechanism to the endometriosis context with caution. We hypothesize that the chronic elevation of circulating IL-6 in endometriosis patients may activate a similar IL-6/STAT3/ HAMP axis within the bone microenvironment. In this "Triple Hit" model: Hit 1 (systemic): GnRH agonist therapy or ovarian insufficiency induces hypoestrogenism, compromising Nrf2/GPX4 antioxidant defenses [ 53 ]. Hit 2 (systemic): The underlying disease provides a continuous supply of labile iron and oxidative stress [ 54 ]. Hit 3 (local): Chronic inflammatory cytokines (specifically IL-6) act locally on bone cells to potentially upregulate hepcidin, effectively "locking" the iron inside the cell and preventing its export via ferroportin [ 55 ]. Hit 1 (systemic): GnRH agonist therapy or ovarian insufficiency induces hypoestrogenism, compromising Nrf2/GPX4 antioxidant defenses [ 53 ]. Hit 2 (systemic): The underlying disease provides a continuous supply of labile iron and oxidative stress [ 54 ]. Hit 3 (local): Chronic inflammatory cytokines (specifically IL-6) act locally on bone cells to potentially upregulate hepcidin, effectively "locking" the iron inside the cell and preventing its export via ferroportin [ 55 ]. In summary, the Triple Hit model illustrates how the convergence of systemic endocrine loss, disease-driven iron stress, and local inflammatory signaling (specifically IL-6-mediated iron sequestration) creates a compounded molecular insult. By simultaneously weakening antioxidant defenses and enhancing intracellular iron accumulation, this synergy drives the accelerated and severe osteoporotic phenotype often observed in patients undergoing GnRH agonist therapy. This iron-centric mechanism, however, does not operate in isolation but acts as a central convergence point for various other non-hormonal cofactors, as explored in the following section [ 56 – 58 ] (Fig.  1 ). Fig. 1 The proposed iron-ferroptosis axis as a mechanistic link between endometriosis and osteoporosis The proposed iron-ferroptosis axis as a mechanistic link between endometriosis and osteoporosis While this review emphasizes the interplay between estrogen and iron, the pathogenesis of endometriosis-associated osteoporosis is inherently multifactorial. We propose that the iron–ferroptosis axis may serve as a key downstream effector for other established non-hormonal mechanisms, acting as a convergence point for diverse insults: Inflammatory cytokines (TNF-α and IL-1β): Endometriosis is characterized by elevated systemic levels of TNF-α and IL-1β. While these cytokines are classic activators of osteoclast genesis via the RANKL pathway, they may also potentiate ferroptosis. Inflammation is known to downregulate GPX4 and alter iron transport proteins. Thus, systemic inflammation may not only directly degrade bone but also "prime" bone cells for ferroptotic death by weakening their antioxidant defenses [ 59 , 60 ]. Mechanical unloading and disuse: Chronic pelvic pain often leads to reduced physical activity in endometriosis patients. Mechanical loading is essential for maintaining the antioxidant capacity of osteocytes (e.g., Nrf2 pathway activity). We hypothesize that pain-induced disuse compromises this mechanoprotection, rendering bone cells hypersensitive to the systemic iron burden [ 38 , 61 ]. Vitamin D and calcium malabsorption: Co-morbidities such as gastrointestinal symptoms or dietary restrictions in endometriosis can lead to Vitamin D and calcium deficits [ 62 ]. Vitamin D has been shown to inhibit ferroptosis in other tissue types by regulating iron modulation proteins [ 63 ]. Its deficiency, therefore, removes another layer of protection, allowing the systemic pro-oxidative state to inflict greater damage on the skeletal microenvironment [ 64 , 65 ]. Inflammatory cytokines (TNF-α and IL-1β): Endometriosis is characterized by elevated systemic levels of TNF-α and IL-1β. While these cytokines are classic activators of osteoclast genesis via the RANKL pathway, they may also potentiate ferroptosis. Inflammation is known to downregulate GPX4 and alter iron transport proteins. Thus, systemic inflammation may not only directly degrade bone but also "prime" bone cells for ferroptotic death by weakening their antioxidant defenses [ 59 , 60 ]. Mechanical unloading and disuse: Chronic pelvic pain often leads to reduced physical activity in endometriosis patients. Mechanical loading is essential for maintaining the antioxidant capacity of osteocytes (e.g., Nrf2 pathway activity). We hypothesize that pain-induced disuse compromises this mechanoprotection, rendering bone cells hypersensitive to the systemic iron burden [ 38 , 61 ]. Vitamin D and calcium malabsorption: Co-morbidities such as gastrointestinal symptoms or dietary restrictions in endometriosis can lead to Vitamin D and calcium deficits [ 62 ]. Vitamin D has been shown to inhibit ferroptosis in other tissue types by regulating iron modulation proteins [ 63 ]. Its deficiency, therefore, removes another layer of protection, allowing the systemic pro-oxidative state to inflict greater damage on the skeletal microenvironment [ 64 , 65 ]. In this expanded framework, the iron–ferroptosis axis acts as a central funnel, amplifying the detrimental effects of hormonal loss, inflammation, mechanical unloading, and nutritional deficits (Table  1 ). Table 1 Known and hypothesized roles of key molecules in endometriosis and osteoporosis Molecule/Pathway Established role in endometriosis Established role in osteoporosis Hypothesized interacting role in this framework Iron metabolism Localized iron overload from hemorrhage drives ROS production and inflammation Systemic iron overload is an independent risk factor, impairing osteoblasts and promoting osteoclasts Hypothesized to link the two pathologies, with systemic dysregulation from endometriosis providing the iron substrate for ferroptosis in bone cells, amplifying hormonally induced bone loss Reactive oxygen species (ROS) Generated via the Fenton reaction; contributes to oxidative stress andpersistence of lesions Mediate bone loss in various contexts by damaging osteoblasts and activating osteoclasts Proposed as the common executioner molecule, driving both ferroptosis in osteoblasts/osteocytes and activation of NF-kappaB in osteoclast precursors Lipid peroxidation A key mechanism of cellular damage; endometriotic tissues exhibit altered ferroptosis resistance markers despite high oxidative stress A defining biochemical hallmark of ferroptosis in multiple cell types, including bone cells The central event of ferroptosis in bone cells, triggered by the systemic pro-oxidative state originating from pelvic pathology GPX4 Downregulated in stromal cells of endometriotic lesions, suggesting a shared molecular vulnerability to ferroptosis Inactivation is the critical checkpoint for initiating ferroptosis; deficiency in bone cells leads to cell death Systemic oxidative stress and hypoestrogenism are hypothesized to overwhelm already compromised GPX4 capacity in bone cells, triggering widespread cell death NF-kappaB Activated by inflammation and ROS, promoting proliferation and survival of endometriotic cells A master regulator of osteoclastogenesis; its activation by ROS or cytokines (e.g., TNF-) drives bone resorption Represents a key convergence point, where inflammatory signals and iron-induced ROS from the endometriosis milieu directly promote bone resorption Known and hypothesized roles of key molecules in endometriosis and osteoporosis

Osteoporosis is a systemic skeletal disease characterized by compromised bone strength, predisposing to an increased risk of fracture. Its pathogenesis is inherently multifactorial, arising from a complex interplay of genetic, hormonal, mechanical, and environmental factors [ 7 ]. While estrogen deficiency is a critical driver of postmenopausal osteoporosis, bone homeostasis is regulated by a complex endocrine network [ 7 ]. Several other hormonal systems are pivotal: Parathyroid hormone (PTH): As a primary regulator of calcium homeostasis, chronic excess of PTH, as seen in primary hyperparathyroidism, leads to high bone turnover with resorption exceeding formation, resulting in significant bone loss, particularly in cortical bone [ 8 ]. Glucocorticoids: Endogenous or exogenous glucocorticoid excess is the most common cause of secondary osteoporosis. Glucocorticoids directly suppress osteoblast differentiation and function while promoting the apoptosis of both osteoblasts and osteocytes, leading to a rapid reduction in bone formation [ 9 ]. Thyroid hormones: Hyperthyroidism accelerates the entire bone remodeling cycle. Because the resorption phase is significantly shorter than the formation phase, this rapid turnover results in a net loss of bone mass over time [ 10 ]. Other reproductive hormones: Beyond gonadal steroids, emerging evidence highlights the influence of upstream reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and kisspeptin, on bone physiology, underscoring the intricate crosstalk between the reproductive and skeletal systems [ 11 ]. Parathyroid hormone (PTH): As a primary regulator of calcium homeostasis, chronic excess of PTH, as seen in primary hyperparathyroidism, leads to high bone turnover with resorption exceeding formation, resulting in significant bone loss, particularly in cortical bone [ 8 ]. Glucocorticoids: Endogenous or exogenous glucocorticoid excess is the most common cause of secondary osteoporosis. Glucocorticoids directly suppress osteoblast differentiation and function while promoting the apoptosis of both osteoblasts and osteocytes, leading to a rapid reduction in bone formation [ 9 ]. Thyroid hormones: Hyperthyroidism accelerates the entire bone remodeling cycle. Because the resorption phase is significantly shorter than the formation phase, this rapid turnover results in a net loss of bone mass over time [ 10 ]. Other reproductive hormones: Beyond gonadal steroids, emerging evidence highlights the influence of upstream reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and kisspeptin, on bone physiology, underscoring the intricate crosstalk between the reproductive and skeletal systems [ 11 ]. Bone is a dynamic tissue that adapts its mass and architecture in response to mechanical forces, a principle encapsulated by Frost's "mechanostat" theory. Osteocytes, entombed within the bone matrix, function as the primary mechanosensors. They detect strain-induced fluid flow within the lacuno-canalicular network, transducing these mechanical signals into biochemical responses. This signaling cascade modulates the activity of bone-forming osteoblasts and bone-resorbing osteoclasts to align bone structure with mechanical demand, a process essential for maintaining skeletal integrity [ 12 ]. Muscle contractions are the primary source of physiological loads on the skeleton, forming an integrated "muscle–bone unit" [ 13 ]. Consequently, disuse, immobilization, and age-related muscle loss (sarcopenia) are potent contributors to bone loss by diminishing this critical mechanical stimulus [ 12 ]. Secondary osteoporosis is defined as bone loss resulting from specific, often reversible, clinical disorders or medications [ 14 ]. Numerous conditions contribute to skeletal fragility through diverse mechanisms: Inflammatory conditions: Chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease promote bone loss through the systemic release of pro-inflammatory cytokines [e.g., tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6)], which are potent stimulators of osteoclast differentiation and activity [ 15 ]. Gastrointestinal and malabsorptive disorders: Conditions like celiac disease can impair the intestinal absorption of calcium and vitamin D, leading to secondary hyperparathyroidism and a state of negative calcium balance that is detrimental to bone [ 16 ]. Chronic kidney disease (CKD): Renal dysfunction leads to a complex syndrome of mineral and bone disorders (CKD–MBD), involving altered phosphate and calcium homeostasis, vitamin D metabolism, and secondary hyperparathyroidism, which collectively degrade skeletal health [ 14 ]. Inflammatory conditions: Chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease promote bone loss through the systemic release of pro-inflammatory cytokines [e.g., tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6)], which are potent stimulators of osteoclast differentiation and activity [ 15 ]. Gastrointestinal and malabsorptive disorders: Conditions like celiac disease can impair the intestinal absorption of calcium and vitamin D, leading to secondary hyperparathyroidism and a state of negative calcium balance that is detrimental to bone [ 16 ]. Chronic kidney disease (CKD): Renal dysfunction leads to a complex syndrome of mineral and bone disorders (CKD–MBD), involving altered phosphate and calcium homeostasis, vitamin D metabolism, and secondary hyperparathyroidism, which collectively degrade skeletal health [ 14 ]. This multifactorial landscape reveals that diverse pathogenic insults often converge on a limited number of final common pathways, such as the dysregulation of the Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)/Osteoprotegerin (OPG) signaling axis or the induction of oxidative stress. This underscores that any single proposed pathway, including the iron–ferroptosis axis, must be considered within a broader context of interacting genetic, hormonal, and mechanical determinants of skeletal health.

The pathophysiology of endometriosis is inextricably linked to iron. Recurrent hemorrhage from ectopic endometrial lesions, a consequence of retrograde menstruation, leads to the accumulation of erythrocytes in the peritoneal cavity. Phagocytosis of these cells by peritoneal macrophages results in a massive localized iron burden. This excess iron catalyzes the Fenton reaction, generating highly reactive hydroxyl radicals(•OH) and fostering a microenvironment of intense oxidative stress and chronic inflammation [ 17 , 18 ]. A critical and speculative component of our hypothesis is the mechanism by which this localized pathology could induce a systemic effect on bone. The transition from a localized to a systemic inflammatory state. These mediators can induce systemic endothelial dysfunction, increase vascular permeability, and cause damage to distant organs [ 19 ]. It is plausible that endometriosis, as a state of chronic, albeit lower-grade, inflammation, may operate via a similar mechanism over a much longer timescale. The peritoneal cavity may function as a "bioreactor," continuously releasing pro-inflammatory cytokines and iron-related molecules into the systemic circulation [ 19 ]. Such a state may be reflected by elevated levels of systemic markers like serum ferritin, which has been independently correlated with lower BMD in postmenopausal women [ 20 , 21 ]. Therefore, the proposed "bridge" is not merely the physical translocation of iron atoms, but an information transfer mediated by inflammatory signals that, in turn, dysregulate systemic iron homeostasis and sensitize distant tissues, like bone, to subsequent damage. Localized pelvic pathology, primarily characterized by recurrent hemorrhage and subsequent iron overload within the peritoneal cavity, must translate into systemic signals to affect distant bone tissue. This transition involves sophisticated metabolic and transport mechanisms that bypass or modify conventional endocrine signaling. Hepcidin regulation: resolving the systemic iron paradox Hepcidin regulation: resolving the systemic iron paradox The mechanism by which localized inflammation translates into systemic iron dysregulation presents a crucial paradox. In models of chronic inflammatory diseases, the cytokine interleukin-6 (IL-6) typically drives the hepatic production of hepcidin, the master iron-regulatory hormone. High hepcidin traps iron within macrophages and reduces intestinal absorption, leading to the "anemia of chronic disease" [ 22 ]. However, non-human primate (NHP) models of endometriosis reveal a counter-intuitive finding: despite the histologic presence of abdominal inflammation, these subjects exhibited significantly lower levels of hepcidin compared to controls, representing a 73% decrease. Although serum IL-6 levels showed an increase, this inflammatory signal was functionally over-ridden by systemic iron deficiency resulting from chronic blood loss and sequestration in the lesions [ 23 ]. This finding is paramount, as low hepcidin ensures the systemic upregulation of the sole iron exporter, ferroportin (FPN1), allowing macrophages and intestinal cells to release iron into the circulation [ 22 ].This physiological attempt to correct anemia results in a critical consequence for the skeletal system: it guarantees a sustained elevation of the highly reactive Labile Iron Pool (LIP) in the circulation. This readily available LIP, rather than bulk iron overload, provides the necessary substrate (Fe 2+ ) for the Fenton reaction and subsequent lipid peroxidation in susceptible distant cells, thereby initiating ferroptosis [ 24 ]. Thus, the paradoxically suppressed hepcidin acts as the functional bridge, ensuring the availability of the critical ferroptotic substrate systemically. Exosomal transport: extracellular vesicles as carriers of pro-ferroptotic cargo Exosomal transport: extracellular vesicles as carriers of pro-ferroptotic cargo Extracellular Vesicles (EVs), particularly exosomes, represent a robust physical and informational bridge between the iron-loaded pelvic environment and the distant skeletal system. Exosomes are increasingly recognized as regulators of ferroptosis by delivering biological materials to recipient cells [ 25 ]. One demonstrated mechanism involves the transport of ferritin-bound iron out of the cell [ 26 ]. Endometriotic cells and the iron-laden peritoneal macrophages exhibit resistance to the intense local oxidative stress [ 27 ]. It is proposed that these cells use exosomal efflux of ferritin and iron as a protective mechanism to avoid self-induced ferroptosis, effectively exporting the toxic cargo systemically [ 28 ]. Furthermore, exosomes carry epigenetic cargo, specifically MicroRNAs (miRNAs) that can regulate key components of the ferroptosis defense system in distant cells. Studies have shown that iron-overloaded ovarian follicular fluid in endometriosis patients induces granulosa cell ferroptosis and simultaneously releases granulosa cell exosomes containing abnormal miRNAs [ 28 ]. For instance, specific miRNAs, such as miR-30b-5p and miR-124, are known to target and inhibit the expression of the iron exporter FPN1. If these or similar pro-ferroptotic miRNAs are carried systemically by endometriosis-derived EVs and delivered to osteocytes, they would function as epigenetic suppressors, dismantling the bone cell's intrinsic defense mechanism [such as FPN1 or glutathione peroxidase 4 (GPX4)] [ 29 ]. This systematic reduction in iron export and antioxidant capacity effectively sensitizes the skeletal cells, making them highly vulnerable to the circulating LIP established by the low hepcidin state. Bone iron uptake: inflammatory priming of bone cells Bone iron uptake: inflammatory priming of bone cells The systemic inflammatory milieu characteristic of endometriosis also provides non-iron-dependent signals that actively increase the iron uptake capacity of bone cells, ensuring maximum delivery of the ferroptotic substrate [ 5 , 30 ]. The key systemic inflammatory cytokine, IL-6, which is persistently elevated in endometriosis patients, has been implicated in upregulating key iron import proteins. Specifically, the activation of the IL-6/PI3K/AKT signaling pathway has been shown to induce the expression of both Transferrin Receptor 1 (TfR1) and Divalent Metal Transporter 1 (DMT1) [ 31 ]. This cytokine-mediated upregulation in bone-forming cells, such as osteoblasts or osteocytes, would dramatically increase their cellular appetite for iron. Coupled with the systemically high LIP, this inflammatory priming acts as a lethal funnel, driving toxic levels of iron into the skeletal cells [ 32 , 33 ]. Moreover, the impact is observed in both bone-forming and bone-resorbing lineages. Genes encoding iron uptake receptors, specifically Tfrc (TFR1) and Slc11a2 (DMT1), are reported to be upregulated in mature osteoclasts [ 34 ]. This observation suggests that the systemic iron dysregulation caused by endometriosis delivers a two-pronged attack: it kills the regulatory and forming cells (osteocytes/osteoblasts) via ferroptosis while simultaneously providing the substrate to potentially fuel the activity of the bone-resorbing osteoclasts through ROS generation [ 33 ].

The proposed framework is speculative and requires rigorous experimental validation. Its primary value lies in generating a new set of testable hypotheses that could advance our understanding of endometriosis-associated comorbidities. Rather than offering premature therapeutic conclusions, this section outlines critical questions that future research should address. Clinical and translational questions: Addressing Heterogeneity and Subtypes A major limitation in current literature is the fragmentation of data regarding systemic iron markers. Future clinical validation must move beyond general associations and address the specific phenotypes of the disease: Subtype stratification: Does the impact on bone metabolism differ by clinical subtype? We hypothesize that Ovarian Endometriomas (OMA), which represent encapsulated cysts with high concentrations of heme and iron ("chocolate cysts"), may act as more potent "iron bioreactors" compared to Superficial Peritoneal Endometriosis or Deep Infiltrating Endometriosis (DIE). Prospective cohort studies: Large-scale studies are needed to measure a comprehensive panel of iron markers (serum ferritin, transferrin saturation, hepcidin, and LIP) alongside BMD. Crucially, these studies must stratify patients by the presence of endometrioma versus other lesions to determine if the "Iron–Ferroptosis Axis" is a subtype-specific mechanism. Subtype stratification: Does the impact on bone metabolism differ by clinical subtype? We hypothesize that Ovarian Endometriomas (OMA), which represent encapsulated cysts with high concentrations of heme and iron ("chocolate cysts"), may act as more potent "iron bioreactors" compared to Superficial Peritoneal Endometriosis or Deep Infiltrating Endometriosis (DIE). Prospective cohort studies: Large-scale studies are needed to measure a comprehensive panel of iron markers (serum ferritin, transferrin saturation, hepcidin, and LIP) alongside BMD. Crucially, these studies must stratify patients by the presence of endometrioma versus other lesions to determine if the "Iron–Ferroptosis Axis" is a subtype-specific mechanism. Proposed core biomarker panel for clinical validation To transition from a theoretical framework to actionable clinical research, we propose a "Core Ferroptosis–Bone Panel" for evaluating patients with endometriosis. This panel should include: Systemic iron markers: Beyond routine serum ferritin, measurements should include Transferrin Saturation (TSAT) and Serum Hepcidin to evaluate the iron-sequestration paradox observed in endometriosis. The labile iron pool (LIP): Measurement of Non-Transferrin Bound Iron (NTBI) as a direct indicator of the redox-active iron available to trigger ferroptosis in distant tissues. Ferroptosis-specific markers: Assessment of systemic lipid peroxidation via Malondialdehyde (MDA) or 4-hydroxynonenal (4-HNE), alongside serum levels of GPX4 as a proxy for the systemic antioxidant defense status. Bone remodeling markers: Monitoring RANKL/OPG ratio and Sclerostin (an osteocyte-derived inhibitor of bone formation) to correlate systemic iron stress with active skeletal remodeling Systemic iron markers: Beyond routine serum ferritin, measurements should include Transferrin Saturation (TSAT) and Serum Hepcidin to evaluate the iron-sequestration paradox observed in endometriosis. The labile iron pool (LIP): Measurement of Non-Transferrin Bound Iron (NTBI) as a direct indicator of the redox-active iron available to trigger ferroptosis in distant tissues. Ferroptosis-specific markers: Assessment of systemic lipid peroxidation via Malondialdehyde (MDA) or 4-hydroxynonenal (4-HNE), alongside serum levels of GPX4 as a proxy for the systemic antioxidant defense status. Bone remodeling markers: Monitoring RANKL/OPG ratio and Sclerostin (an osteocyte-derived inhibitor of bone formation) to correlate systemic iron stress with active skeletal remodeling Preclinical and mechanistic questions: Can ferroptosis be definitively demonstrated in vivo within bone cells in a relevant animal model of endometriosis-associated osteoporosis? This requires applying specific assays for lipid peroxidation (e.g., C11-BODIPY staining) and electron microscopy to bone tissue from such models. A critical next step would be to determine if treatment with a specific ferroptosis inhibitor (e.g., Ferrostatin-1) or a clinically relevant iron chelator (e.g., Deferasirox) can mitigate or prevent bone loss in these animal models, which would provide strong evidence for a causal role of this pathway. What is the precise molecular mechanism linking the inflammatory pelvic environment to systemic iron dysregulation? Future studies could investigate whether peritoneal cytokines from endometriosis patients or animal models can directly modulate the expression of the master iron-regulatory hormone, hepcidin, in hepatocytes. Can ferroptosis be definitively demonstrated in vivo within bone cells in a relevant animal model of endometriosis-associated osteoporosis? This requires applying specific assays for lipid peroxidation (e.g., C11-BODIPY staining) and electron microscopy to bone tissue from such models. A critical next step would be to determine if treatment with a specific ferroptosis inhibitor (e.g., Ferrostatin-1) or a clinically relevant iron chelator (e.g., Deferasirox) can mitigate or prevent bone loss in these animal models, which would provide strong evidence for a causal role of this pathway. What is the precise molecular mechanism linking the inflammatory pelvic environment to systemic iron dysregulation? Future studies could investigate whether peritoneal cytokines from endometriosis patients or animal models can directly modulate the expression of the master iron-regulatory hormone, hepcidin, in hepatocytes.

The incorporation of genetic and epigenetic factors introduces essential dimensions of individual variability and molecular regulation to the hypothesis. Polymorphisms: inherent predisposition Genetic factors predisposing individuals to iron dysregulation strongly correlate with osteoporosis risk, validating the iron axis as a fundamental determinant of skeletal health. Specifically, relevant single nucleotide polymorphisms (SNPs) in iron metabolism genes, such as HFE (associated with systemic iron overload/hemochromatosis), are linked to an increased risk of osteoporosis. Similarly, genetic deficiencies in the iron exporter gene SLC40A1 (FPN) lead to excessive iron accumulation within osteoblasts, promoting osteoclast genesis and reduced bone mass [ 40 ]. These findings demonstrate that certain women with endometriosis may possess an inherent genetic predisposition to the precise intracellular iron accumulation that triggers ferroptosis in bone cells, accelerating their skeletal decline. Furthermore, a significant molecular connection to the local disease is found in the ferroptosis defense mechanism itself. Immunohistochemical analysis of endometriotic tissue revealed a significant downregulation of GPX4 in the stromal cells of endometriosis patients. GPX4 is the critical molecular checkpoint for ferroptosis [ 66 ]. Its compromised status in the endometriotic lesion suggests a shared molecular vulnerability: the mechanism (low GPX4) that predisposes bone cells to ferroptosis due to hormonal loss is already a pathological feature of the ectopic tissue itself [ 67 ]. MicroRNA crosstalk: epigenetic attack on anti-ferroptotic pathways The concept of epigenetic sensitization through circulating microRNAs is highly mechanistic. Specific miRNAs are known to target and suppress the core machinery of ferroptosis defense, proving that epigenetic attacks can induce this form of cell death. MicroRNAs such as miR-30b-5p and miR-124 are documented to target and inhibit the iron exporter FPN1. Separately, other miRNAs, such as miR-541-3p, directly target and inhibit GPX4, thereby enhancing ferroptosis susceptibility [ 29 ]. The implication for the endometriosis–osteoporosis axis is profound: if the exosomes released from the iron-loaded peritoneal environment carry a cocktail of these specific miRNAs, they deliver an epigenetic dual-strategy attack to distant osteocytes. This dual action—iron retention (via FPN1 suppression) and defense elimination (via GPX4 suppression)—provides a clear, non-hormonal, non-cytokine-mediated mechanism for systemic skeletal sensitization [ 68 – 70 ].

This review proposes that the iron–ferroptosis axis may function as a crucial, yet unexplored, complementary mechanism contributing to osteoporosis in women with endometriosis. We have moved beyond the traditional, exclusively hormonal explanation to present a synergistic framework, where chronic pelvic inflammation and iron overload generate a systemic pro-oxidative state. This state, it is hypothesized, does not act as the sole cause of bone loss but rather as a potent amplifier, exacerbating the skeletal damage initiated by hypoestrogenism. By triggering ferroptosis in bone-forming and orchestrating cells while simultaneously promoting bone resorption, this axis provides a plausible cellular mechanism for accelerated skeletal fragility. This is a conceptual framework based on the synthesis of disparate lines of evidence that requires rigorous experimental validation. If substantiated, this hypothesis could not only deepen our understanding of the systemic consequences of endometriosis but also pave the way for novel therapeutic strategies aimed at preserving skeletal health in this vulnerable patient population.

Ferroptosis is a form of regulated cell death distinct from apoptosis, characterized biochemically by iron-dependent accumulation of lipid hydroperoxides and functionally by the inactivation of the key antioxidant enzyme GPX4 [ 18 ]. A growing body of evidence suggests that ferroptosis may play a significant role in bone biology and the pathogenesis of osteoporosis. Existing evidence, while still emerging, provides a plausible cellular basis for how systemic iron dysregulation could disrupt bone homeostasis: Impact on osteoblasts: In vitro studies suggest that iron overload can induce ferroptosis in osteoblasts, leading to impaired differentiation and function and thereby directly reducing bone formation. This effect has been shown to be reversible by treatment with ferroptosis inhibitors like ferrostatin-1 or iron chelators, such as deferoxamine, indicating a causal link between iron accumulation, ferroptotic cell death, and diminished osteogenic capacity [ 35 ]. Impact on osteocytes: Research using animal models of postmenopausal osteoporosis indicates that estrogen withdrawal may promote iron accumulation and subsequent ferroptosis in osteocytes. As the primary orchestrators of bone remodeling, the ferroptotic death of osteocytes is a potentially major contributor to the enhanced osteoclastogenesis and bone resorption seen in hypoestrogenic states [ 36 ]. Impact on osteoclasts: The effect on osteoclasts appears to be indirect but complementary. The reactive oxygen species (ROS) generated by excess iron, which are the ultimate executioners of ferroptosis, are also known to be potent activators of signaling pathways, such as nuclear factor kappa-B (NF-ƙ), that promote osteoclast differentiation and resorptive activity [ 37 ]. Impact on osteoblasts: In vitro studies suggest that iron overload can induce ferroptosis in osteoblasts, leading to impaired differentiation and function and thereby directly reducing bone formation. This effect has been shown to be reversible by treatment with ferroptosis inhibitors like ferrostatin-1 or iron chelators, such as deferoxamine, indicating a causal link between iron accumulation, ferroptotic cell death, and diminished osteogenic capacity [ 35 ]. Impact on osteocytes: Research using animal models of postmenopausal osteoporosis indicates that estrogen withdrawal may promote iron accumulation and subsequent ferroptosis in osteocytes. As the primary orchestrators of bone remodeling, the ferroptotic death of osteocytes is a potentially major contributor to the enhanced osteoclastogenesis and bone resorption seen in hypoestrogenic states [ 36 ]. Impact on osteoclasts: The effect on osteoclasts appears to be indirect but complementary. The reactive oxygen species (ROS) generated by excess iron, which are the ultimate executioners of ferroptosis, are also known to be potent activators of signaling pathways, such as nuclear factor kappa-B (NF-ƙ), that promote osteoclast differentiation and resorptive activity [ 37 ]. Thus, the same pro-oxidative, iron-rich state that may trigger ferroptotic death in bone-forming osteoblasts and orchestrating osteocytes could simultaneously stimulate the activity of bone-resorbing osteoclasts. This dual-pronged assault provides a robust cellular mechanism for how iron dysregulation could drive a rapid net loss of bone [ 5 , 38 ]. The traditional hormonal paradigm establishes estrogen deficiency as the primary sensitizer of bone loss. Mechanistic studies reveal that estrogen’s protective role extends directly to the ferroptosis defense system. Estrogen deficiency, mimicking postmenopausal osteoporosis, results in the direct downregulation of the critical antioxidant signaling axis, Nrf2/GPX4/HO-1, in osteocytes. The reduction in this pathway leads to increased accumulation of reactive oxygen species (ROS) and a subsequent decrease in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), culminating in trabecular bone loss [ 39 ]. This defines how hypoestrogenism serves as the foundational "sensitizing hit": it transcriptionally dismantles the bone cell's intrinsic capacity to detoxify lipid peroxides, which is essential for preventing ferroptosis [ 40 ]. The necessity of this defense system is confirmed by data showing that inhibition of Nrf2 by ML385 is sufficient to induce ferroptosis in osteocytes [ 41 ]. Therefore, the synergy between endometriosis and hormonal status is clear: estrogen loss removes the cell's shield (Nrf2/GPX4), and the systemic iron axis provides the weapon (LIP/oxidative stress), resulting in accelerated and widespread bone cell death. Osteocytes are the primary mechanosensory and orchestrating cells of the bone remodeling unit. Their fate determines the rate and balance of resorption and formation. The ferroptotic death of osteocytes is far from benign; it actively promotes bone resorption [ 42 , 43 ]. Mechanistic studies employing iron overload to induce ferroptosis in osteocytes demonstrate that this cell death actively signals to the bone microenvironment by significantly increasing the secretion of powerful pro-osteoclastogenic cytokines. These include RANKL, macrophage colony-stimulating factor (M-CSF), IL-1β, IL-6, and tumor necrosis factor- (TNF-). The release of these factors, particularly RANKL, directly fuels the differentiation and activation of osteoclast precursors, dramatically accelerating bone resorption [ 44 ]. The critical nature of ferroptosis in this cascade is confirmed by the finding that the increased secretion of these pro-resorptive cytokines can be effectively inhibited by treatment with specific ferroptosis inhibitors (e.g., liproxstatin-1 or ferrostatin-1). This provides strong causal evidence that ferroptosis in the osteocyte functions as an "active cellular alarm," coupling cell death with a pathological pro-resorptive signal. This dual mechanism—impaired bone formation due to osteoblast/osteocyte death, coupled with enhanced bone resorption—provides a robust cellular explanation for rapid net bone loss [ 41 , 44 , 45 ].

A well-documented clinical association exists between endometriosis, a chronic inflammatory gynecological disorder, and an increased risk of low bone mineral density (BMD) and osteoporosis. The dominant and well-supported paradigm explaining this connection is centered on hypoestrogenism [ 1 ]. This estrogen deficiency can arise endogenously, as endometriosis is associated with conditions like premature ovarian insufficiency that curtail the reproductive lifespan, or latrogenically, through the use of gonadotropin-releasing hormone (GnRH) agonists, which induce a profound, albeit reversible, hypoestrogenic state to manage disease symptoms [ 2 ]. However, the observation that a pathologically localized inflammatory disease can precipitate a systemic skeletal disorder suggests the potential for additional, non-hormonal mediating pathways. The persistence of this clinical link warrants a more nuanced exploration of factors that may bridge the two pathologies beyond a purely endocrine framework [ 2 , 3 ]. Endometriosis is fundamentally characterized by localized iron overload resulting from recurrent intrapelvic hemorrhage, which fosters a pro-inflammatory and pro-oxidative microenvironment [ 4 ]. It is plausible that this chronic, localized state of iron dysregulation and inflammation could translate into a low-grade systemic pro-oxidative stress, thereby rendering bone cells more susceptible to ferroptosis—a distinct, iron-dependent form of regulated cell death [ 5 , 6 ]. Here, we propose a complementary hypothesis: that the iron–ferroptosis axis may represent a potential, yet unproven, mechanistic link that synergizes with hormonal factors. We explicitly acknowledge that this framework relies on synthesizing indirect evidence from separate fields and currently remains a hypothesis awaiting direct experimental validation. This review will first contextualize osteoporosis within its known multifactorial framework, then explore the evidence for the iron–ferroptosis axis in bone biology, and finally propose a synergistic model that integrates this axis with established hormonal paradigms, outlining key questions for future research.

Supplementary material 1. Supplementary material 1.