The interaction between endoplasmic reticulum stress and ferroptosis in ovarian diseases

Abstract

Background

Ovarian diseases including polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and ovarian cancer, critically impact women’s reproductive health. Growing evidence implicates endoplasmic reticulum (ER) stress and ferroptosis as key collaborative pathways in their pathogenesis.

Objective

This review aims to systematically clarify the molecular mechanisms of ER stress and ferroptosis, deeply explore the crosstalk between them, and evaluate their specific roles in the occurrence, development and treatment of major ovarian diseases.

Methods

We conducted a systematic review (up to July 2025) using PubMed and Web of Science, focusing on studies linking these pathways to ovarian pathophysiology.

Results

ER stress restores intracellular homeostasis by activating the unfolded protein response (UPR), but sustained or severe stress ultimately leads to cell death. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Studies have found that common regulatory factors such as activating transcription factor 4 (ATF4), glutathione metabolism key enzyme ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) and nuclear factor erythroid 2-related factor 2 (Nrf2) constitute the key molecular bridges for the interaction between the two. These mechanisms collectively regulate core pathophysiological processes such as follicular atresia, ovarian dysfunction and malignant progression of tumors.

Conclusion

The interaction network between ER stress and ferroptosis plays a central role in the pathophysiological process of ovarian diseases. Targeting this interactive axis is expected to provide new strategies for the protection of ovarian dysfunction and the therapeutic intervention of gynecological tumors. More in vivo studies and clinical transformation explorations are needed in the future to verify these findings and promote their clinical application.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13048-026-01968-4.

Introduction

Ovarian diseases generally refer to a series of pathological conditions that affect the normal structure and function of the ovaries, and they are the main causes of decreased fertility and impaired reproductive health in women. Among numerous ovarian diseases, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and ovarian cancer are the most common and clinically significant. PCOS is characterized by chronic anovulation, hyperandrogenism and metabolic dysfunction, affecting 4%–21% of reproductive-aged women globally, a variance reflecting heterogeneous diagnostic criteria and populations [1]. POI is manifested by the premature depletion of ovarian follicle reserve before the age of 40, which not only causes infertility but also significantly increases the risk of developing metabolic diseases and cardiovascular diseases [2]. Ovarian cancer accounts for 3.4% of all cancers in women; it lacks specific early clinical symptoms and effective screening methods, making it the gynecological malignant tumor with the highest mortality rate [3].

Recent advances in molecular biology highlight the endoplasmic reticulum (ER) as a central organelle for protein folding, lipid synthesis, and calcium homeostasis. When its function is impaired by factors such as excessive protein folding load, endoplasmic reticulum stress (ER stress) is triggered. As an adaptive response, the unfolded protein response (UPR) can restore cellular homeostasis in the early stage of stress; however, if the stress persists or intensifies, the UPR will switch to pro-apoptotic signals, ultimately inducing cell death [4, 5]. Ferroptosis is an iron-dependent form of programmed cell death, characterized primarily by iron-induced generation of reactive oxygen species (ROS) via the Fenton reaction, which in turn triggers lipid peroxidation (LP) chain reactions. This process is driven by glutathione (GSH) depletion, dysregulation of glutathione peroxidase 4 (GPX4), and iron homeostasis disorders [6]. Critically, ER stress and ferroptosis are not isolated events but exhibit extensive crosstalk across diverse pathological contexts [7].

In the field of ovarian biology, ER stress and ferroptosis have been confirmed to jointly participate in the regulation of multiple core processes, including follicular atresia (FA), oocyte maturation, steroid hormone synthesis, and tumorigenesis and progression. However, their interaction network and synergistic effects in specific diseases such as PCOS, POI, and ovarian cancer remain incompletely understood, and urgent systematic and in-depth exploration is required. Delineating the crosstalk between ER stress and ferroptosis is essential for understanding ovarian disease pathogenesis and for developing novel targeted therapies. Based on this, this review aims to systematically summarize the key molecular mechanisms of ER stress and ferroptosis, and clarify the interaction network between them. In addition, it evaluates their specific roles in major ovarian diseases such as PCOS, POI, and ovarian cancer. Finally, we integrate current evidence to identify translational therapeutic targets and outline future directions for this emerging field.

Mechanisms of ER stress

The ER is a core organelle that regulates protein folding, lipid synthesis, and calcium ion homeostasis, and its functional integrity is crucial for cell survival. When disturbed by factors such as oxidative stress, hypoxia, toxic stimulation, or metabolic disorders, unfolded or misfolded proteins accumulate abnormally in the ER lumen, thereby triggering ER stress. To cope with this challenge, cells rapidly activate their core adaptive signaling pathway—the UPR. Meanwhile, three transmembrane sensors are activated, collectively forming a signaling network to respond to ER homeostasis imbalance [8, 9].

Structure and function of the ER

The ER is a dynamic network composed of membranous tubules and vesicles, widely distributed in the cytoplasm [10]. Morphologically and functionally, it is divided into the rough ER and smooth ER. The former, studded with ribosomes, is the primary site for protein synthesis and initial processing. The latter is involved in lipid metabolism, steroid synthesis, and calcium storage/release. Molecular chaperones like BiP/GRP78 within the ER lumen assist in nascent peptide folding and assembly, forming the ER quality control system. Failure of this system due to disrupted intracellular homeostasis triggers cellular stress responses [11].

The UPR pathway

The UPR is mediated by three transmembrane transmembrane transmembrane sensor proteins on the ER membrane: protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). Under homeostasis, they remain inactive through binding to the molecular chaperone binding immunoglobulin protein (BiP). During ER stress, BiP dissociates and instead binds to unfolded proteins, thereby releasing and activating these sensors to initiate downstream signaling networks. These three pathways operate synergistically to restore ER homeostasis.

Upon activation, PERK rapidly inhibits global protein translation by phosphorylating eukaryotic initiation factor 2α (eIF2α), thereby reducing the folding load on the ER [12]. Concurrently, phosphorylated eIF2α selectively promotes the translation of activating transcription factor 4 (ATF4). ATF4 then upregulates a variety of target genes including C/EBP-homologous protein (CHOP), which are involved in redox homeostasis, amino acid metabolism, and regulation of cell death [13, 14]. Notably, ATF4 can also upregulate growth arrest and DNA damage-inducible protein 34, which promotes the dephosphorylation of eIF2α, thereby forming a negative feedback loop to restore protein synthesis [15]. Additionally, the PERK pathway can regulate the activity of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator that not only governs cellular metabolism and antioxidant responses but also plays a pivotal role in the onset and progression of various diseases [16].

IRE1α possesses both kinase and endoribonuclease activities. Upon activation, it mediates the atypical splicing of X-box binding protein 1 (XBP1) mRNA, generating the active transcription factor XBP1s. XBP1s then upregulates a series of genes related to ER-associated degradation, lipid synthesis, and molecular chaperones, enhancing the ER’s clearance and repair capabilities [17]. Additionally, activated IRE1α can degrade select ER-localized mRNAs via regulated IRE1α-dependent decay (RIDD), a process linked to apoptosis under prolonged stress [18]. Additionally, IRE1α can activate the JNK signaling pathway via the tumor necrosis factor receptor-associated factor 2 (TRAF2) adapter protein. Activated JNK can phosphorylate and inhibit the anti-apoptotic function of Bcl-2, thereby promoting cell death [19, 20].

During ER stress, ATF6 translocates to the Golgi apparatus, where it is cleaved by site-1 and site-2 proteases to release its active cytoplasmic fragment (ATF6p50). This fragment enters the nucleus to transcribe UPR target genes, including chaperones (e.g., BiP) and endoplasmic reticulum-associated degradation (ERAD) components [21]. Notably, ATF6α, often in synergy with XBP1, regulates genes involved in phospholipid synthesis, fatty acid desaturation, and cholesterol metabolism, thereby remodeling lipid composition under stress [22]. ATF6 can also upregulate the transcription of XBP1, acting synergistically with the IRE1α pathway to further amplify UPR signals and enhance the protein-processing capacity of the ER [23]. Given that lipid metabolic homeostasis, particularly the balance of polyunsaturated fatty acid phospholipids (PUFA-PLs), is a core factor determining ferroptosis sensitivity, the activation status of the ATF6 pathway provides a key molecular bridge for crosstalk between ER stress and ferroptosis [24].

Collectively, these three UPR branches form an elaborate network to restore homeostasis. However, if ER stress is severe or prolonged, the UPR switches from pro-survival to pro-apoptotic signaling, determining cell fate.

ER stress-induced cell death

Prolonged, unresolved ER stress is a critical determinant of cell fate, initiating programmed cell death when adaptive capacity is exceeded. This occurs through conserved pathways. First, the sustained high expression of the transcription factor CHOP can downregulate key anti-apoptotic proteins such as Bcl-2, while exacerbating oxidative stress, thereby driving apoptosis. Second, activated IRE1α recruits the TRAF2 adapter protein to activate the JNK signaling pathway, which in turn phosphorylates and inhibits the anti-apoptotic functions of the Bcl-2 family. Third, ER stress specifically activates cysteine-aspartic acid specific proteinase (Caspase)-12 (with its human homolog being caspase-4), which cleaves downstream effector caspases or mediates calcium release to activate mitochondrial apoptosis [25, 26].

Notably, beyond apoptosis, ER stress is also closely associated with various novel forms of regulated cell death, forming a complex network of cell fate decisions. For instance, studies have shown that ER stress can directly activate receptor-interacting serine/threonine kinase 1 and receptor-interacting serine/threonine kinase 3 via tumor necrosis factor receptor 1, independent of death receptor ligands, thereby initiating necroptosis [27]. Additionally, ER stress-triggered calcium release and ROS bursts are key upstream signals for NOD-like receptor pyrin domain-containing protein 3 inflammasome activation, leading to gasdermin D cleavage and pyroptosis [28].

Naturally, the association between ER stress and ferroptosis is particularly close, with mechanisms primarily involving the regulation of GSH metabolism and LP by ATF4, as well as the remodeling of lipid composition by ATF6. These findings reveal that ER dysfunction influences cell fate through diverse death mechanisms, with broad pathophysiological implications. The specific details of the interaction between ER stress and ferroptosis will be discussed in detail in subsequent sections. (Fig. 1).

Fig. 1.

The core mechanism of endoplasmic reticulum stress and cellular fate decision. Multiple stressors (e.g., hypoxia, oxidative stress, toxicant stimulation, and metabolic disturbances) disrupt ER protein homeostasis, leading to the accumulation of unfolded/misfolded proteins. This causes the dissociation of the molecular chaperone BiP/GRP78, subsequently activating three key transmembrane sensors of the unfolded protein response (UPR): PERK, IRE1α, and ATF6. The diagram outlines the distinct signaling cascades initiated by each sensor. Initially, these pathways coordinate adaptive programs to restore ER homeostasis. However, under prolonged or severe stress, the UPR switches to pro-death signaling, ultimately driving cell death via apoptosis, necroptosis, pyroptosis, or ferroptosis

Mechanisms of ferroptosis

Ferroptosis is an iron-dependent, regulated form of non-apoptotic cell death, first proposed by Dixon et al. in 2012 [29]. It differs from apoptosis, necrosis, and autophagy in morphological, biochemical, and genetic characteristics, with typical manifestations including massive accumulation of lipid peroxidation (LPO), particularly phospholipid hydroperoxides (PLOOHs) containing polyunsaturated fatty acids (PUFAs), and functional failure of the cellular antioxidant defense system. Ferroptosis plays crucial roles in various pathologies, including cancers (e.g., liver cancer [30]), neurodegenerative diseases [31], ischemia-reperfusion injury [32], and gynecological diseases such as ovarian cancer [33].

Definition and morphological characteristics

At the ultrastructural level, ferroptotic cells exhibit unique morphological changes, mainly including mitochondrial shrinkage, increased membrane density, reduced or absent cristae, and outer membrane rupture. Meanwhile, they lack typical apoptotic features such as chromatin condensation [34]. Biochemically, ferroptosis is independent of caspase activation and does not involve DNA fragmentation. The core of its occurrence lies in intracellular iron overload, uncontrolled LP reactions, and failure of key antioxidant defense systems.

Core molecular pathways

The occurrence of ferroptosis is regulated by an elaborate molecular network involving iron metabolism, LP, and cellular redox balance.

Iron metabolism and oxidative damage

Iron, an essential trace element in the human body, is widely involved in key physiological processes such as oxygen transport, energy metabolism, and immune function [35]. Iron metabolic disorder is a hallmark of ferroptosis. Circulating Fe³⁺ binds to transferrin (Tf) and enters cells through transferrin receptor 1 (TFR1)-mediated endocytosis. Intracellularly, Fe³⁺ is reduced to Fe²⁺ by the metal reductase STEAP3. Cytosolic Fe²⁺ partitions into the labile iron pool (LIP) for metabolic use or is stored inertly within ferritin [36]. The iron-storage function of ferritin is a key component of cellular antioxidant defense, whereas ferritinophagy mediated by NCOA4 can re-release stored iron into the LIP, potentially mediating ferroptosis [37]. Iron export mainly depends on ferroportin, which promotes Fe²⁺ efflux to maintain homeostasis during intracellular iron overload [38]. When free iron accumulates excessively, Fe²⁺ catalyzes the generation of highly reactive hydroxyl radicals (•OH) from H₂O₂ via the Fenton reaction; these radicals can induce extensive oxidative damage to lipids, proteins, and DNA, ultimately driving ferroptosis [39].

Lipid peroxidation

PUFAs, with their multiple double bonds, are primary substrates for LP. In membrane phospholipids, PUFAs like arachidonic acid (AA) are esterified into phospholipids by acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) to form PUFA-PLs. This ACSL4/LPCAT3-mediated step is critical for determining ferroptosis sensitivity [40]. LP can be initiated through two pathways: enzymatic and non-enzymatic. The enzymatic reaction is mainly catalyzed by the arachidonate lipoxygenase (ALOXs) family, which directly oxidizes PUFA-PE. The non-enzymatic pathway relies on ROS generated by the Fenton reaction to trigger lipid radical chain reactions. Regardless of the pathway, the core product is membrane-toxic PLOOH. When cellular antioxidant defenses fail, the massive accumulation of PLOOH disrupts membrane integrity and function, ultimately leading to ferroptosis [41].

Antioxidant defense system

The primary cellular defense against ferroptosis is the GSH-GPX4 axis. GPX4 can utilize GSH to reduce toxic PLOOH to corresponding harmless phospholipids, thereby directly inhibiting LP and preventing ferroptosis [42]. GSH biosynthesis depends on cysteine availability. Cystine uptake is mediated by system Xc⁻, a cystine/glutamate antiporter composed of SLC7A11 and SLC3A2 subunits. Intracellular cystine is then reduced to cysteine, which is used for GSH synthesis. The integrity of the system Xc⁻–GSH–GPX4 functional axis plays a central role in maintaining cellular redox homeostasis and resisting ferroptosis [43].

Other regulatory pathways

In recent years, multiple GPX4-independent ferroptosis inhibitory pathways have been successively discovered, revealing the complexity of the cellular defense network. Ferroptosis suppressor protein 1 (FSP1, formerly known as AIFM2) localizes to the plasma membrane and reduces coenzyme Q10 (CoQ10) to ubiquinol, a potent lipophilic radical-trapping antioxidant that halts LP propagation [44]. Guanosine triphosphate cyclohydrolase 1 (GCH1) and its product tetrahydrobiopterin (BH4) form another important defense axis. It selectively regulates PUFA-PL synthesis, and its oxidation product BH2 also exhibits antioxidant activity, collectively protecting against ferroptosis [45]. Dihydroorotate dehydrogenase in mitochondria inhibits mitochondrial LP by reducing CoQ10 in mitochondria; it acts synergistically with GPX4 and FSP1 to provide multi-level protection for cells [46]. These parallel systems deepen our understanding of ferroptosis regulation and offer novel therapeutic targets for related diseases (Fig. 2).

Fig. 2.

The core molecular regulatory network of ferroptosis. This schematic illustrates the balance between ferroptosis drivers and cellular defenses. Intracellular iron overload fuels reactive oxygen species production, which drives peroxidation of polyunsaturated fatty acid phospholipids. This lethal process is antagonized by the central glutathione-GPX4 axis and parallel systems including FSP1/CoQ10, GCH1/BH4, and DHODH, forming a multi-layered antioxidant defense network

Crosstalk between ER stress and ferroptosis

As two important cellular stress responses, ER stress and ferroptosis exhibit extensive crosstalk in their molecular mechanisms. Their interaction, mediated through shared regulatory factors, integrated metabolic stress signals, and feedback amplification loops, constitutes a complex network that co-regulates cell fate.

Induction and regulation of ER stress by ferroptosis

The occurrence of ferroptosis can further induce or exacerbate ER stress, forming a positive feedback. Studies have shown that treatment with the ferroptosis inducer erastin can significantly upregulate the expression of the ER stress marker HSPA5. As a key chaperone, HSPA5 can stabilize GPX4, thereby enhancing cellular antioxidant defense and attenuating ferroptosis [47]. In addition, NCOA4-mediated ferritinophagy promotes iron release and induces ferroptosis, and the resulting ER iron overload has also been confirmed as a direct factor triggering ER stress; for example, in models such as nanoparticle toxicity, the activation of ferritinophagy is closely associated with the occurrence of ER stress [48]. More direct evidence shows that pharmacological inhibition of cystine-glutamate exchange (System Xc⁻), a classic initiating event for inducing ferroptosis, is confirmed to directly trigger ER stress, mechanistically establishing ferroptosis as an upstream inducer of ER stress [49]. In a paraquat-induced lung injury model, both the ferroptosis inhibitor deferoxamine and the ER stress inhibitor 4-PBA can cross-relieve the pathological processes dominated by each other, providing strong in vivo evidence for the bidirectional regulatory relationship between the two [50].

Regulation of ferroptosis by ER stress via the UPR pathway

The UPR, activated by ER stress, orchestrates the regulation of ferroptosis through its three major branches: PERK, IRE1α, and ATF6. The PERK-ATF4 signaling axis occupies a central position, exhibiting environment-dependent dual functions. It can promote ferroptosis by downregulating the expression of key anti-ferroptotic proteins such as SLC7A11, GPX4, and FTH1 [51], yet its basal activity is also crucial for maintaining SLC7A11 expression to resist ferroptosis [52]. Furthermore, under high glucose, the ER protein CNPY2 activates CHAC1 via PERK-ATF4 to deplete GSH and induce ferroptosis [53]. This axis also crosstalks with p53 signaling, adding another layer of fine-tuning in tumor cells [54, 55]. HSPA5 (also known as GRP78), as a major regulatory protein of the UPR, has been extensively studied in terms of its gene function and expression regulation [56]. This molecule plays a hub role in the cross-regulation of ER stress and ferroptosis, with cell type-specific functions. In glioma cells, ER stress induced by dihydroartemisinin promotes HSPA5 expression via the PERK-ATF4 axis, which in turn upregulates GPX4 and inhibits ferroptosis [57]. In contrast, in renal tubular epithelial cells, the ATF4/CHOP/ACSL4 pathway is involved in promoting ER stress-related ferroptosis [58]. The IRE1α pathway primarily functions as a ferroptosis promoter through multiple mechanisms. Beyond the canonical IRE1α/XBP1 branch [59], it utilizes its RIDD activity to degrade mRNAs of GSH-synthesis genes, sensitizing cells to ferroptosis [60]. Additionally, IRE1α can activate JNK signaling [61] or synergistically regulate the activity of ALOXs (such as ALOX12) with G protein signals (such as Gα12) [62]. Finally, the ATF6 pathway links ferroptosis to lipid stress. ATF6 uniquely senses lipid bilayer stress and sphingolipid stimulation [63]. Given the centrality of lipid peroxidation in ferroptosis, ATF6’s regulation of lipid metabolism profoundly affects cellular susceptibility. For instance, ATF6 can upregulate the E3 ligase TRIM37 to promote degradation of the key lipid-metabolizing enzyme ACSL4, thereby inhibiting ferroptosis [24]. Collectively, these UPR branches form an intricate network that integrates ER and lipid stress signals to determine cellular fate towards ferroptosis.

ROS and Ca²⁺-mediated cross-signal amplification

As key second messengers, ROS and Ca²⁺ serve as core bridges in the crosstalk between ER stress and ferroptosis. The ROS burst during ferroptosis execution, particularly LPO, is a powerful stimulator of ER stress, leading to misfolding of luminal proteins and activation of the UPR [64, 65]. Mechanistically, ROS can regulate calcium channels on the ER membrane, induce Ca²⁺ release from the lumen, disrupt cytoplasmic calcium homeostasis, and thereby further exacerbate ER stress [66]. Thus, crosstalk between ferroptosis and organelle stress responses forms a vital part of the regulated cell death network [67].

Conversely, ER stress itself can significantly exacerbate oxidative stress. Activation of the UPR increases cellular energy demand, promoting mitochondrial oxidative phosphorylation and ROS production [68]; meanwhile, abnormal leakage of Ca²⁺ from the ER to mitochondria can enhance electron transport chain activity, thereby facilitating the generation of superoxide and H₂O₂ [69]. Studies have shown that the ER stress sensor IRE1α can precisely control Ca²⁺ transfer to mitochondria by regulating the composition of mitochondria-associated ER membranes, directly linking ER stress to mitochondrial metabolism [70]. Additionally, ER stress-induced elevation of cytoplasmic Ca²⁺ can regulate the activity of specific transcription factors, affect intracellular iron metabolism, and promote ferroptosis in models such as colon cancer cells [71]. These interactions collectively form a self-reinforcing positive feedback loop that drives ferroptosis. Recent studies have further revealed that “calcium bursts” induced by targeting the ER can irreversibly amplify this stress state, ultimately leading to cell membrane rupture and ferroptosis [72]. (Fig. 3).

Fig. 3.

The interactive regulatory network between ER stress and ferroptosis. This schematic elucidates the complex bidirectional crosstalk between endoplasmic reticulum (ER) stress and ferroptosis. The initiation of ferroptosis (e.g., via System Xc⁻ inhibition or NCOA4-mediated ferritinophagy) induces or amplifies ER stress through iron overload and lipid peroxidation-derived damage. In turn, the unfolded protein response (UPR) branches—PERK, IRE1α, and ATF6—orchestrate ferroptosis by targeting the System Xc⁻-GSH-GPX4 axis, glutathione synthesis, and lipid peroxidation. A self-amplifying feedforward loop, mediated by reactive oxygen species (ROS) and Ca²⁺, functionally links ER stress, disrupted calcium homeostasis, and enhanced ferroptotic drivers

In summary, ER stress and ferroptosis form a complex network involving redox regulation, lipid metabolism, and stress signal integration through ROS and Ca²⁺ signals. In ovarian tissue, their crosstalk directly influences the decision of cell fate. Future research should dissect their tissue-specific mechanisms to identify novel biomarkers and therapeutic targets.

Roles of ER stress and ferroptosis in ovarian diseases

PCOS, POI, and ovarian cancer are major ovarian diseases that seriously threaten women’s reproductive health and lives. Recent studies have shown that ER stress and ferroptosis not only jointly participate in the pathogenesis and progression of the above diseases, but the crosstalk between them also plays a core role in regulating ovarian cell survival, function, and disease mechanisms. This section will systematically elaborate on the pathophysiological roles of ER stress and ferroptosis in PCOS, POI, and ovarian cancer, as well as their mutual regulatory mechanisms.

PCOS

PCOS is characterized by clinical features including hyperandrogenism, insulin resistance, and chronic anovulation, and is often accompanied by oxidative stress and metabolic dysfunction [73]. Currently, there is no specific drug for PCOS, and clinical treatment mainly uses anti-androgens and insulin sensitizers for symptomatic management.

Role and mechanism of ER stress in PCOS

ER stress is deeply involved in the occurrence and development of PCOS through multiple interrelated mechanisms. Within the ovary, ER stress is persistently activated in ovarian granulosa cells (GCs) from PCOS models and patients, with significantly upregulated expression of its markers GRP78 and CHOP, which are closely associated with follicular microenvironment disorders and disease pathology [74, 75]. As a key pro-apoptotic factor, the upregulation of CHOP induces GCs apoptosis, interfering with follicular development and ovulation [76]. Metabolically, ER stress, via JNK pathway activation, causes phosphorylation of insulin receptor substrate-1 (IRS-1), impairing insulin signaling and exacerbating insulin resistance [77]. In addition, ER stress affects steroid hormone synthesis, promotes androgen production, and aggravates hyperandrogenism; alleviating ER stress can effectively reduce abnormally elevated androgen levels [78]. Physiologically, ER stress also regulates ovarian steroidogenesis; for example, in musk shrews, fluctuations in ER stress associated with seasonal reproductive cycles directly affect ovarian hormone synthesis capacity [79]. In terms of inflammation, the UPR pathway can activate the canonical pro-inflammatory NF-κB signaling via the IRE1α–TRAF2 axis, promoting the release of factors such as IL-6 and TNF-α, thereby contributing to the disruption of the ovarian functional microenvironment [80]. ER stress can also upregulate pro-fibrotic factors such as TGF-β1 and CTGF, promoting ovarian stromal fibrosis and collagen deposition, a process that can be reversed by ER stress inhibitors like TUDCA [76]. Additionally, ER stress is involved in regulating the expansion of cumulus-oocyte complexes and the AGE/RAGE signaling pathway, synergizing with factors such as insulin resistance and oxidative stress to disrupt follicular physiological balance [81, 82]. In summary, ER stress contributes to PCOS pathology by disrupting insulin signaling, inducing GC apoptosis, and promoting inflammation and fibrosis.

Role and mechanism of ferroptosis in PCOS

Studies have directly confirmed that hyperandrogenism is a key upstream factor driving ovarian ferroptosis in PCOS. A study revealed that androgens can directly induce ferroptosis in ovarian GCs, and this event plays an important role in the pathogenesis of PCOS [83]. PCOS patients exhibit significant systemic and ovarian local iron metabolism disorders, characterized by elevated serum ferritin, decreased expression of ferritin heavy chain 1 (FTH1) in GCs, and upregulated expression of NCOA4 (a key mediator of ferritinophagy). These changes lead to the accumulation of free iron, which generates large amounts of ROS through the Fenton reaction, thereby enhancing the sensitivity of GCs to ferroptosis [84]. Mechanistically, low expression of miR-128-3p in exosomes derived from PCOS results in increased expression of its target gene CSF1, which activates the p38/JNK/MAPK signaling pathway and inhibits the NRF2/SLC7A11 antioxidant axis, ultimately inducing ferroptosis in GCs. In animal models, the application of the ferroptosis inhibitor Ferrostatin-1 can reverse the above phenotypes, restore follicular development, and rebalance estrogen levels [85]. The ferroptosis process is accompanied by obvious mitochondrial dysfunction, manifested by morphological changes such as mitochondrial membrane shrinkage and reduced cristae structure, which exacerbate energy metabolism disorders and oxidative damage. The natural compound plumbagin can restore the expression of GPX4 and ferritin, improve mitochondrial structure, and resist DHT-induced ferroptosis by inhibiting the YTHDF1/SLC7A5 axis [86]. In summary, ferroptosis directly leads to GCs loss, FA, and ovulatory dysfunction. Ferroptosis-mediated oxidative stress further exacerbates insulin resistance and chronic inflammation, linking reproductive abnormalities to metabolic disorders in PCOS.

Crosstalk between ER stress and ferroptosis

In PCOS pathology, ER stress and ferroptosis form a close interactive network that jointly promotes disease progression. For example, research on KGN cells has shown that androgen treatment can simultaneously induce typical phenotypes of ER stress and ferroptosis, characterized by iron accumulation, enhanced LP, and decreased GPX4 expression. The use of the ER stress inhibitor TUDCA can alleviate ferroptotic characteristics, and the ferroptosis inhibitor Ferrostatin-1 can also reverse androgen-induced cell damage, confirming that ER stress is a key upstream trigger of ferroptosis. This study further revealed that hyperandrogenism drives ER stress, which in turn activates the PERK–eIF2α–ATF4–CHOP pathway, leading to ROS accumulation and promoting the ferroptosis process. The specific molecular events ultimately causing follicular dysfunction provide direct evidence for the pathogenic role of the ER stress-ferroptosis axis in PCOS [87]. In a palmitic acid-induced PCOS-like model, the ER stress inhibitor 4-PBA can reduce cellular sensitivity to ferroptosis and improve ovarian function, with the underlying mechanism possibly mediated through the ATF4/TXNIP/ACSL4 signaling axis [88]. Mechanistically, ER stress synergistically promotes ferroptosis through multiple pathways: it activates SREBP-1c to promote de novo lipogenesis and increase PUFA levels (e.g., AA), providing LP substrates; and, synergistically with hyperandrogenism, it inhibits fatty acid desaturase 1 (FADS1), impairs GPX4 function, and increases ferroptosis susceptibility. This hyperandrogen-driven vicious cycle of ER stress-ferroptosis has become one of the core mechanisms underlying ovarian dysfunction in PCOS.

POI

As a reproductive endocrine disease characterized by premature exhaustion of follicular reserve, POI has been confirmed to have ER stress and ferroptosis as important factors driving ovarian function decline.

Role of ER stress in POI

ER stress is a key molecular event in POI pathogenesis, directly participating in FA by inducing GCs dysfunction and apoptosis. Sustained ER stress can activate the pro-apoptotic branch of the UPR and form crosstalk with the mitochondrial apoptotic pathway, jointly mediating GCs loss. Studies have shown that exogenous metabolic stressors such as trimethylamine oxide (TMAO) can induce ER stress, which in turn promotes GCs apoptosis through mitochondrial pathways, ultimately leading to POI [89]. Mechanistically, TMAO binds and activates the UPR sensor PERK, initiating the PERK pathway, driving metabolic disorders, and ultimately exacerbating GCs apoptosis and FA [90]. IRE1α, another key sensor of the UPR, plays a core role in integrating stress signals. After activation, it splices XBP1 mRNA to enhance the adaptive capacity of the ER; however, under sustained stress, it can switch to pro-apoptotic signals, thereby determining the fate of GCs [91]. In POI, the function of the IRE1α–XBP1 axis is crucial. Studies have shown that knocking down XBP1 in mouse GCs can significantly induce cell apoptosis, arrest the cell cycle, and inhibit estradiol synthesis, confirming the indispensability of this axis in maintaining GCs survival and endocrine function [92]. Similarly, ATF6 pathway activation directly regulates GCs apoptosis, cell cycle, and progesterone/estrogen production [93]. The function of these core pathways depends on the synergistic support of protein homeostasis mechanisms such as ERAD to alleviate ER stress and ensure the high secretory function of GCs [94]. Furthermore, cutting-edge research has revealed a profound interaction between ER stress and mitochondrial function. For example, the PERK-eIF2α axis was found to promote the assembly of respiratory chain supercomplexes, which provides a new perspective for understanding how GCs coordinate energy metabolism to support their energy-intensive hormone synthesis process under stress [95]. Notably, there is a bidirectional positive feedback regulation between ER stress and oxidative stress: the ROS burst induced by ER stress can further increase the ER folding load, forming a vicious cycle that promotes the development of POI [96]. In this process, toxic substances such as advanced oxidation protein products produced by sustained oxidative stress can inhibit the autophagy-lysosomal pathway through the ROS-dependent mTOR–TFEB pathway, impairing the clearance capacity of GCs and thus exacerbating ovarian failure [97]. In addition, excessive oxidative stress can also induce GCs senescence by activating factors such as TRIM28. Senescent cells disrupt the homeostasis of the follicular microenvironment through their secretory phenotype, which constitutes another important mechanism for the development of POI [98]. In summary, ER stress contributes to POI through UPR signaling, organelle interaction, redox imbalance, and impaired cellular quality control.

Role of ferroptosis in POI

Ferroptosis plays an important role in the occurrence and development of POI, with its core mechanisms involving iron metabolism disorders, LP accumulation, and dysregulation of the GPX4 antioxidant defense, which collectively lead to GCs loss and FA [99]. In a cisplatin-induced ovarian injury model, specific inhibition of the ferroptosis-promoting protein ACSL4 can effectively reduce GCs death and protect ovarian reserve, suggesting that this pathway can serve as an intervention target for POI [100]. Genetically, BNC1 gene deficiency can directly induce GCs ferroptosis by activating the NF2–YAP signaling pathway [101, 102] ; similarly, LRRC4 deficiency exacerbates LP by disrupting GCs metabolic homeostasis, further establishing the pathogenic pathway of “genetic defect–metabolic disorder–ferroptosis–ovarian failure” [103]. Exogenous stressors also play a critical role. Cigarette smoke exposure can inhibit GPX4 expression and induce ferroptosis, leading to a decline in ovarian reserve [104]; while the chemotherapeutic drug cyclophosphamide drives GCs ferroptosis by upregulating HO-1, inducing mitochondrial dysfunction and ROS bursts, providing mechanistic insights for the prevention and treatment of iatrogenic POI [105]. Notably, ferroptosis is involved in fibrotic remodeling in various tissue injuries [106], suggesting a potential role in ovarian stromal fibrosis in POI. In summary, ferroptosis participates in POI through genetic, metabolic, and exogenous stress mechanisms, providing a new theoretical framework for its treatment.

Crosstalk

In POI pathology, ER stress and ferroptosis form a mutually reinforcing pathogenic axis, synergistically exacerbating GCs damage. UFL1, as a key regulator of this interactive axis, has been confirmed in human granulosa-like cells to alleviate lipopolysaccharide (LPS)-induced ER stress and cell apoptosis by directly inhibiting ferroptosis [107]. In the cisplatin-induced POI model, UFL1 has also been shown to act as a key regulator of the ER stress-ferroptosis crosstalk axis. Its mechanism involves inhibiting LP, maintaining GSH metabolic homeostasis, and protecting ovarian function by alleviating ER stress [108], suggesting that relieving ER stress may simultaneously reduce cellular sensitivity to ferroptosis. Moreover, environmental factors such as heat stress are also thought to activate ferroptosis and ER stress, forming a positive feedback loop that disrupts GCs function [109]. In summary, targeting the ER stress-ferroptosis crosstalk axis (e.g., via hub molecules like UFL1) rather than a single pathway offers a promising new strategy for POI prevention and treatment.

Ovarian cancer

As one of the gynecological malignancies with the highest mortality rate, ovarian cancer is characterized by late diagnosis and treatment resistance as the main causes of poor prognosis, and ER stress and ferroptosis play key roles in this process.

Role of ER stress in ovarian cancer

ER stress plays a complex and multifaceted role in ovarian cancer through mechanisms involving UPR activation, the balance between cell survival and death, immune microenvironment regulation, and chemoresistance [110]. In human ovarian cancer cells, ER stress induces the translocation of calreticulin from the ER to the cell membrane surface; this process, as a key event in immunogenic cell death, can enhance the phagocytosis of tumor cells by dendritic cells, thereby directly linking intracellular ER stress to anti-tumor immune responses [111]. This fate decision is mediated by UPR signaling pathways. Sustained ER stress, via core branches like PERK/ATF4/CHOP and IRE1α/TRAF2/JNK, drives ovarian cancer cell death. For example, specific inhibition of IRE1α ribonuclease activity disrupts adaptive XBP1 splicing and enhances ASK1-JNK phosphorylation, promoting apoptosis [112]. These pathways not only regulate traditional apoptosis, but also interact with processes such as autophagy, profoundly affecting the pathological process of ovarian cancer [113]. Notably, the “dark side” of ER stress lies in the fact that while its excessive activation induces cell death, moderate UPR is essential for maintaining protein homeostasis in rapidly proliferating tumor cells. Unexpectedly, angiotensin II was found to promote ovarian cancer spheroid formation and metastasis by upregulating lipid desaturation and suppressing basal ER stress [114]. This indicates that cancer cells actively “manage” ER stress to maintain malignancy, highlighting its extreme complexity as a bidirectional regulator.

Role of ferroptosis in ovarian cancer

Ferroptosis is crucial in the progression and therapeutic resistance of ovarian cancer, with its activity tightly regulated by lipid metabolism, iron homeostasis, and antioxidant defense systems. Regarding lipid metabolism, studies have shown that stearoyl-CoA desaturase 1 (SCD1) and fatty acid desaturase 2 (FADS2) act as key metabolic checkpoints determining the sensitivity of ovarian cancer cells—especially ascites-derived drug-resistant cells—to ferroptosis by balancing the ratio of monounsaturated fatty acids to PUFAs [115]. On the other hand, ACSL1 promotes platinum resistance through a non-classical pathway: it enhances the N-myristoylation modification and protein stability of FSP1, thereby strengthening the resistance of ovarian cancer cells to ferroptosis [116]. Additionally, the Golgi-associated protein VIPAS39 significantly reduces LP by promoting extracellular export of the ferroptosis driver ACSL4, conferring resistance [117]. Beyond lipid reprogramming, iron homeostasis is equally critical. Studies have shown that the oncogene c-MYC can limit the accumulation of intracellular free iron by regulating NCOA4-mediated ferritinophagy, thereby inhibiting ferroptosis and promoting immune evasion of ovarian cancer cells [118]. The classical antioxidant defense axis is also a key determinant. In platinum-tolerant cells, Frizzled-7-positive cancer stem cells exhibit unique metabolic vulnerability by downregulating SLC7A11 (a key component of System Xc⁻), rendering them abnormally sensitive to ferroptosis induced by GPX4 inhibitors [119]. Notably, extracellular signals are also involved. Pharmacological inhibition of the leukemia inhibitory factor autocrine loop reveals an inherent vulnerability of ovarian cancer cells to ferroptosis, providing a strategy to target the tumor microenvironment [120].

Crosstalk between ER stress and ferroptosis

ER stress and ferroptosis form a tightly interacting network in ovarian cancer, and crosstalk profoundly affecting tumor cell fate via metabolic and signaling pathways. Global metabolomic analyses provide systematic evidence: in human ovarian cancer cells, the ferroptosis inducer erastin triggers LP and extensive metabolic reprogramming involving glutamine and purine metabolism, offering a metabolic basis for the mutual exacerbation of ER stress and ferroptosis [121]. Molecularly, this crosstalk is intricate. Ferroptosis inducers can trigger ER stress and activate the pro-apoptotic protein Bid; cleaved tBid then acts as a key bridge, significantly enhancing the apoptotic signals triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This clearly reveals direct crosstalk between ferroptosis, ER stress, and the extrinsic apoptotic pathway [122]. In addition, environmental factors can also initiate this interactive axis. Studies have shown that copper exposure can specifically trigger ER stress in ovarian cells, which in turn activates autophagic flux; this induced “ER stress-autophagy axis” fails to protect and instead becomes a key link in promoting the ferroptosis process. This reveals a unique pathway through which coordinated organelle stress leads to cell death under environmental toxic stress [123]. In summary, ER stress and ferroptosis form complex interactive networks in PCOS, POI, and ovarian cancer, with their core pathological mechanisms summarized in Table 1.

Table 1.

Pathological roles and crosstalk mechanisms of ER stress and ferroptosis in major ovarian diseases

Feature dimensions	PCOS	POI	Ovarian Cancer
Core pathology	Hyperandrogenism, insulin resistance, chronic anovulation, and metabolic disorders [73].	Premature ovarian reserve depletion causes fertility loss and endocrine abnormalities.	Malignant proliferation, late-stage diagnosis, therapeutic resistance, and high mortality.
Key roles of ER stress	1.Induce GCs apoptosis (CHOP↑) [74–76]. 2. Aggravate insulin resistance (JNK/IRS-1) [77]. 3.Promote androgen production and inflammation (IRE1α-TRAF2-NF-κB) [78, 80]. 4. Drive ovarian fibrosis (TGF-β1, CTGF↑) [76].	1. Drives GCs apoptosis and FA [89, 90]. 2. UPR imbalance (PERK, IRE1α, ATF6 pathways) [90–93]. 3. Forms a positive feedback loop with oxidative stress, exacerbating functional failure [96].	1. "Bidirectional regulator”: moderate UPR promotes survival, while excessive UPR induces death [110, 114]. 2. Induces immunogenic cell death (calreticulin translocation) [111]. 3. Closely associated with chemoresistance [110, 112].
Key roles of ferroptosis	1.Hyperandrogens directly induce ferroptosis in GCs [83]. 2.Iron metabolism disorders (ferritin ↑, FTH1 ↓, NCOA4 ↑) [84]. 3. Impaired antioxidant defense (miR-128-3p/CSF1/p38/JNK inhibits NRF2/SLC7A11) [85].	1. Genetic factors (BNC1, LRRC4 deficiency) and exogenous stimuli (cisplatin, cyclophosphamide) induce ferroptosis in GCs [100–103, 105]. 2. Accumulation of LP and dysregulation of GPX4 defense [99].	1. Metabolic reprogramming determines sensitivity (SCD1, FADS2, ACSL1, VIPAS39) [115–117]. 2. Iron homeostasis disorder (c-MYC-regulated ferritinophagy) [118]. 3. Novel targets for overcoming chemoresistance [119, 120].
Key axes/nodes of their crosstalk	1. Hyperandrogen → ER stress (PERK–eIF2α–ATF4–CHOP) → ferroptosis [87]. 2. ER stress promotes the production of lipid substrates (SREBP-1c/PUFAs) and impairs defense mechanisms (FADS1/GPX4) [88].	1. UFL1 acts as a key node to synergistically inhibit ER stress and ferroptosis [107, 108]. 2. Environmental factors (heat stress) can activate both to form a positive feedback loop [109].	1. Metabolic crosstalk: Ferroptosis inducers trigger extensive metabolic reprogramming, exacerbating ER stress [121]. 2. Signal crosstalk: Ferroptosis enhances TRAIL-mediated apoptosis via tBid [122]. 3. Environmental trigger: Copper exposure promotes ferroptosis through the “ER stress-autophagy axis” [123].
Representative intervention strategies and targets	1. Inhibition of ER stress: TUDCA, 4-PBA [76, 88]. 2. Inhibition of ferroptosis: Ferrostatin-1 [85].	1. Inhibition of ferroptosis: Inhibition of ACSL4 [100]. 2. Synergistic targeting: Upregulation of UFL1 [107, 108].	1. Inducing ferroptosis: Erastin, GPX4 inhibitors [119, 121]. 2. Regulating ER stress: IRE1α inhibitors [112]. 3. Synergistic targeting: Combined induction of ER stress and ferroptosis [122, 123].

Therapeutic implications and future directions

The interaction between ER stress and ferroptosis in ovarian diseases not only underpins complex pathology but also unveils unique dimensions for therapeutic intervention. Targeting the ER stress-ferroptosis crosstalk axis thus shows broad prospects in alleviating ovarian dysfunction, protecting fertility, and enhancing therapeutic sensitivity in ovarian cancer. This chapter will systematically sort out existing and emerging therapeutic strategies targeting this crosstalk axis, and prospect future research directions in this field.

Intervention strategies targeting ER stress

Targeting ER stress: ovarian protection strategies

Substantial evidence confirms that alleviating ER stress is an effective strategy for protecting ovarian function. For example, in a cisplatin-induced ovarian injury model, it has been confirmed to directly reduce ovarian damage, establishing the core position of targeting ER stress in ovarian protection [124]. In PCOS models, metformin alleviates testosterone-induced ER stress in GCs by inhibiting the p38 MAPK signaling pathway, providing a mechanistic basis for using this drug to protect ovarian function [125]. Similarly, the natural flavonoid quercetin alleviates ER stress and subsequent apoptosis in GCs, suggesting its potential for preserving ovarian reserve [126]. Similar protective effects have also been observed in iatrogenic ovarian injury models. Syringic acid reduces cisplatin-induced ovarian damage by modulating ER stress, inhibiting inflammation, and activating the NRF2 pathway, expanding the scope of potential clinical applications [127]. The clinical relevance of this strategy is further confirmed by the role of gonadotropin-releasing hormone agonists (GnRHa). Studies have shown that GnRHa effectively protects ovarian reserve function during cyclophosphamide chemotherapy by alleviating ER stress, which provides a key mechanistic explanation for the widely used clinical ovarian protection protocols [128].

Targeting ER stress: therapeutic strategies for ovarian cancer

Targeting UPR pathways (e.g., PERK, IRE1α) is an emerging area in ovarian cancer therapy, and its link to immunogenic cell death informs combination strategies [129]. Specifically, benzene sulfonamide-based mitochondrial uncouplers can specifically induce ER stress and trigger immunogenic cell death, offering a novel targeted strategy for the treatment of epithelial ovarian cancer [130]. Artificially induced ER stress effectively promotes apoptosis and reverses chemoresistance in human ovarian cancer cells, establishing a classical rationale for ER stress-targeted therapy [131]. Additionally, the macrolide compound Elaiophylin can induce paraptosis through excessive activation of MAPK; this form of cell death, closely linked to ER stress, preferentially eliminates drug-resistant ovarian cancer cells, providing a new approach to overcome therapeutic resistance [132]. The algal-derived natural product fucosterol inhibits ovarian cancer progression by inducing mitochondrial dysfunction and ER stress. This further highlights the universality and application potential of targeting such stress pathways in anticancer therapy [133]. In summary, targeting ER stress is a key direction, with strategies categorized into ovarian protection and ovarian cancer treatment; representative agents and mechanisms are summarized in Table 2.

Table 2.

Intervention strategies and representative agents targeting ER stress

Strategy Type	Targeted Pathway/Target	Representative Drug/Molecule	Primary Mechanism and Efficacy	Potential Application Scenario	Ref.
ER Stress Inhibition (Ovarian Protection)	Broad UPR Inhibition	TUDCA, 4-PBA	Alleviates ER stress, reduces cell apoptosis, and reverses ovarian fibrosis.	PCOS, Iatrogenic ovarian injury	[76, 88, 124]
	p38 MAPK Pathway	Metformin	Inhibits p38 MAPK to alleviate testosterone-induced ER stress in GCs.	PCOS	[125]
	PERK/CHOP	Quercetin	Relieves ER stress in GCs and the resulting apoptosis.	Ovarian reserve function protection	[126]
	NRF2 Pathway	Syringic Acid	Regulates ER stress, inhibits inflammation, and activates the NRF2 pathway to reduce ovarian injury.	Chemotherapy-induced ovarian injury	[127]
	Hypothalamic-Pituitary-Gonadal Axis	GnRHa	Reduces ER stress and protects ovarian reserve function.	Iatrogenic POI prevention	[128]
ER Stress Induction (Ovarian Cancer Therapy)	Mitochondrial Function/UPR	Benzene Sulfonamide-Based Mitochondrial Uncouplers	Specifically induces ER stress and triggers immunogenic cell death.	Epithelial ovarian cancer	[130]
	Classical UPR Pathway	Artificial Induction Strategy	Promotes apoptosis of ovarian cancer cells and reverses chemoresistance.	Ovarian cancer	[131]
	MAPK/ Paraptosis	Elaiophylin	Induces excessive activation of MAPK to trigger paraptosis and eliminate drug-resistant cells.	Drug-resistant ovarian cancer	[132]
	Mitochondria/UPR	Fucosterol	Induces mitochondrial dysfunction and ER stress to inhibit cancer cells.	Ovarian cancer	[133]

Therapeutic potential of regulating ferroptosis

Regulating ferroptosis: maintaining ovarian function

Targeted inhibition of ferroptosis has emerged as a core strategy for preserving ovarian health, with its efficacy validated in basic research, pharmacological interventions, and applications of natural products. The specific ferroptosis inhibitor ferrostatin-1 significantly mitigates cisplatin-induced ovarian toxicity, establishing ferroptosis as a key executor of ovarian injury [134]. The repurposed drug metformin improves PCOS phenotypes by inhibiting ovarian ferroptosis, providing a novel mechanism for its therapeutic effects [135]. Among natural products: the endogenous polyamine spermidine synergistically inhibits ferroptosis via activating pathways such as Nrf2/HO-1/GPX4 [136]; the natural flavonoid baicalein reduces oxidative stress and ferroptosis in the ovary and placenta, thereby effectively alleviating PCOS symptoms [137]; and platycodin D reveals a non-classical pathway for relieving PCOS-associated ferroptosis through upregulating CD44 [138]. A traditional Chinese medicine formulas, Erzhi Tianguifang, delays ovarian aging by regulating mitochondrial homeostasis and inhibiting ferroptosis [139]. Additionally, systems biology studies link ferroptosis-related genes to the ovarian aging process, providing clues for prospective directions such as nutritional interventions [140].

Regulating ferroptosis: targeted elimination of tumors

Inducing ferroptosis offers multi-level potential in ovarian cancer therapy. The metabolite sodium citrate can activate the Ca²⁺/CAMKK2 pathway while inducing both apoptosis and ferroptosis, demonstrating the multiple anti-tumor effects of a single compound [141]. In terms of combination therapy, strategies are more diverse. The natural product shikonin, when combined with cisplatin, can promote iron accumulation by upregulating HMOX1, thereby reversing chemoresistance [142]; PARP inhibitors promote ferroptosis by inhibiting SLC7A11, synergizing with ferroptosis inducers to kill BRCA-proficient tumors [143]. To overcome intrinsic resistance, studies have found that the kinase SGK1 is a key node in cancer cells’ resistance to ferroptosis. Inhibiting SGK1 can effectively enhance the sensitivity to ferroptosis-based therapies [144]. Finally, systematic reviews point out that targeting ferroptosis is a common mechanism by which numerous natural compounds exert anti-ovarian cancer effects, highlighting the great potential of natural product libraries in developing novel ferroptosis agonists [145]. Similar to ER stress, regulating ferroptosis also shows the potential for bidirectional intervention. Specific intervention strategies and representative agents are listed in Table 3.

Table 3.

Intervention strategies and representative agents for regulating ferroptosis

Strategy Type	Targeted Pathway/ Target	Representative Drug/Molecule	Primary Mechanism and Efficacy	Potential Application Scenario	Ref.
Ferroptosis Inhibition (Ovarian Protection)	LP	Ferrostatin-1	Directly scavenges lipid free radicals to inhibit ferroptosis.	Cisplatin-induced ovarian toxicity, PCOS	[85, 134]
	Multi-targets (Ovary)	Metformin	Improves PCOS phenotypes by inhibiting ovarian ferroptosis.	PCOS	[135]
	Nrf2/HO-1/GPX4 Axis	Spermidine	Activates endogenous antioxidant pathways to synergistically inhibit ferroptosis.	Ovarian aging, PCOS	[136]
	Oxidative Stress/Ferroptosis	Baicalein	Reduces ovarian oxidative stress and ferroptosis to improve PCOS.	PCOS	[137]
	CD44 Pathway	Platycodin D	Alleviates PCOS-related ferroptosis by upregulating CD44.	PCOS	[138]
	Mitochondrial Homeostasis	Erzhi Tianguifang (a TCM compound formula)	Regulates mitochondrial homeostasis and inhibits ferroptosis to delay ovarian aging.	Age-related ovarian aging	[139]
Ferroptosis Induction (Ovarian Cancer Therapy)	Ca²⁺/CAMKK2 Pathway	Sodium Citrate	Activates the Ca²⁺/CAMKK2 pathway to induce apoptosis and ferroptosis.	Ovarian cancer	[141]
	HMOX1/Iron Accumulation	Shikonin	Combined with cisplatin, upregulates HMOX1 to promote iron accumulation and reverse chemoresistance.	Chemoresistant ovarian cancer	[142]
	SLC7A11 (System Xc⁻)	PARP Inhibitors	Inhibits SLC7A11 to promote ferroptosis, and synergizes with ferroptosis inducers to kill tumors.	BRCA-proficient ovarian cancer	[143]
	SGK1 Kinase	SGK1 Inhibitors	Inhibits SGK1 to enhance the sensitivity of cancer cells to ferroptosis-based therapies.	Sensitization of ferroptosis therapy	[144]
	Multi-targets (Natural Products)	Multiple Natural Compounds	Targeting ferroptosis is a common mechanism for exerting anti-ovarian cancer effects.	Ovarian cancer (drug development library)	[145]

Synergistic targeting and precision therapy

Synergistic applications in ovarian function therapy

Synergistic targeting of ER stress and ferroptosis is expected to provide innovative therapeutic strategies for ovarian dysfunctional diseases (such as POI). The efficacy of this strategy has been verified in various experimental models. For example, in a mouse model of ovarian injury caused by hepatolenticular degeneration, berberine significantly alleviated the pathological damage of ovarian tissue by synergistically inhibiting ER stress and ferroptosis, demonstrating clear protective effects [146]. Notably, the hub molecule UFL1 has been confirmed as a precise target for achieving synergistic intervention. In human granulosa-like cells, UFL1 effectively alleviated LPS-induced ER stress and cell apoptosis by directly blocking the ferroptosis pathway [107]. This finding reveals the feasibility of targeting key nodes in the interactive network, indicating that precise regulation of such core factors is expected to achieve synergistic intervention on the ER stress-ferroptosis axis, thereby laying a molecular foundation for the development of new precision therapies to protect ovarian function and delay functional decline.

Synergistic potentiation in tumor therapy

In ovarian cancer, targeting the ER stress-ferroptosis crosstalk is a highly promising strategy. Systematic reviews indicate that simultaneous targeting of this interactive axis is expected to overcome drug resistance and achieve synergistic potentiation, providing a framework for novel combinations [147]. Although studies directly focusing on ovarian cancer are limited, evidence from other tumor models strongly supports the feasibility of this strategy. At the technical level, for example, an ER-targeted biomimetic nanoparticle successfully synergistically induced apoptosis and ferroptosis in tumor cells by regulating ER function in a colon cancer model [148]. While this study was not specific to ovarian cancer, it validated the universality of the strategy of “precision targeting of ER to synergistically activate multiple death pathways”. In drug repurposing, the antipsychotic haloperidol promotes ER stress in glioblastoma, mediating autophagy-dependent ferroptosis and sensitizing cells to temozolomide [149]. This offers a translatable idea for using marketed drugs in ovarian cancer to synergistically activate this axis. Furthermore, mechanistic studies on novel targeted drugs (e.g., anlotinib in thyroid cancer) confirm the central role of bidirectional ER stress-ferroptosis crosstalk in their efficacy [150]. These findings collectively indicate that synergistic targeting of the ER stress-ferroptosis axis is not only a combination therapy strategy but may also constitute the core mechanism of action of certain modern targeted drugs, greatly expanding the application dimensions of this strategy in precision therapy for ovarian cancer. Synergistic targeting of the ER stress-ferroptosis interactive axis represents a promising emerging strategy, with application examples shown in Table 4.

Table 4.

Intervention strategies and representative agents for synergistic targeting of the ER Stress-Ferroptosis crosstalk axis

Strategy Type	Targeted Pathway/Target	Representative Drug/Molecule	Primary Mechanism and Efficacy	Potential Application Scenario	Ref.
Synergistic Targeting (Ovarian Protection)	ER Stress & Ferroptosis	Berberine	Synergistically inhibits both pathways to alleviate pathological damage of ovarian tissue.	POI (hepatolenticular degeneration model)	[146]
	UFL1	UFL1	A hub molecule that inhibits ferroptosis and alleviates ER stress as well as cell apoptosis.	POI, GCs protection	[107, 108]
Synergistic Targeting (Ovarian Cancer Therapy)	ER Stress & Ferroptosis	(Combination Strategy)	Simultaneous targeting of this crosstalk axis is expected to overcome drug resistance and achieve synergistic potentiation.	Ovarian cancer (theoretical framework)	[147]
	ER-Targeted Delivery	Biomimetic Nanoparticles	Targets ER to synergistically induce apoptosis and ferroptosis in tumor cells.	Tumor therapy (e.g., colon cancer model)	[148]
	ER Stress-Autophagy-Ferroptosis	Haloperidol	Promotes ER stress, mediates autophagy-dependent ferroptosis, and enhances chemosensitivity.	Chemotherapy sensitization (e.g., glioblastoma model)	[149]
	Multi-Target Drug	Anlotinib	Its antitumor efficacy is regulated by bidirectional signaling crosstalk between ER stress and ferroptosis.	Tumor therapy (e.g., thyroid cancer model)	[150]

Future research priorities and challenges

Although proof-of-concept exists for targeting the ER stress-ferroptosis axis in ovarian diseases, key challenges remain. Future research should focus on several key areas. At the mechanistic level, there is an urgent need to systematically clarify the upstream regulatory networks of key modulators (such as ATF4, CHOP, and NRF2) in ovarian tissues and the logic of their functional switching under different pathological contexts. To this end, using single-cell sequencing and multi-omics integration analysis to map disease-specific molecular profiles of ER stress and ferroptosis in PCOS, POI, and ovarian cancer forms the theoretical basis for achieving precise subtyping and intervention. Concurrently, at the technical and translational level, at the technical level, developing drugs or delivery systems that can specifically target this interactive axis is crucial for improving therapeutic precision. However, although multiple candidate compounds have shown potential in preclinical studies, clinical trials for ovarian diseases with ferroptosis as a clear target remain extremely limited, making promoting their clinical translation an important immediate task. Furthermore, systematically evaluating the potential long-term impacts of modulating ER stress or iron metabolism on the female reproductive system, metabolic homeostasis, and neurological function. Ultimately, interdisciplinary collaboration integrating molecular biology, pharmacology, and reproductive medicine will be the inevitable path to advance this field from mechanistic exploration to clinical application.

Conclusions

As two key cellular stress and death mechanisms, ER stress and ferroptosis form a dynamically interactive core regulatory network in ovarian physiological and pathological processes. ER stress is an adaptive response of cells to folding load, while ferroptosis is driven by iron-dependent LP; although originating from different sources, they engage in extensive crosstalk at the molecular level. In major ovarian diseases such as PCOS, POI, and ovarian cancer, this interactive network profoundly affects GCs function, follicular development, oocyte quality, and malignant tumor progression. Dysregulation of key nodes including ATF4, CHAC1, GPX4, SLC7A11, and HO-1 connects irreversible ER stress to the execution of ferroptosis, ultimately disrupting the balance between cell survival and death.

From a therapeutic perspective, the ER stress-ferroptosis axis holds dual regulatory value. On one hand, inhibiting pathological ER stress and enhancing antioxidant defense helps protect normal ovarian tissues from ferroptosis-related damage, which is particularly important for maintaining fertility in POI and PCOS. On the other hand, specifically inducing ferroptosis in ovarian cancer—especially in combination with ER stress activation strategies—can effectively eliminate drug-resistant tumor cells, demonstrating synergistic therapeutic potential. An ideal therapeutic regimen should achieve precise balance between protective effects in normal cells and pro-death effects in diseased cells, which will be a crucial breakthrough direction in reproductive medicine and tumor therapy.

Despite advancing mechanistic exploration, this field is still in its infancy. Future research needs to focus on revealing the specific regulatory patterns of ER stress and ferroptosis in different ovarian cell types and disease stages; identifying reliable biomarkers and novel targets within the shared molecular network; and ultimately developing safe drugs or delivery systems that can precisely and controllably regulate this interactive axis.

In summary, in-depth research on the crosstalk mechanisms between ER stress and ferroptosis not only deepens our understanding of the essence of ovarian biology but also opens up new intervention pathways for infertility prevention, ovarian function maintenance, and gynecological tumor treatment. Translating these scientific insights into clinical practice is expected to bring about a paradigm shift in the overall management of ovarian diseases, thereby improving women’s health throughout the reproductive cycle.

Authors’ contributions

Min Xing: Conceptualization, Writing - Original Draft Preparation, Visualization. Jing Li: Writing - Review & Editing, Investigation. Xiaolan Wu: Writing - Review & Editing, Investigation, Validation. Ruyi Zhang: Writing - Review & Editing. Lan Li: Writing - Review & Editing. Huiping LIU: Conceptualization, Funding acquisition, Writing - Review & Editing, Supervision, Project Administration.

Data availability

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Declarations

Competing interests

The authors declare no competing interests.