Mitochondria as integrative regulators of ferroptosis in the female reproductive system.

Future therapeutic strategies should prioritize cell-type-specific and temporally controlled modulation of ferroptosis, integrating mitochondrial health, iron metabolism, and redox signaling. Combination approaches that enhance mitochondrial function while fine-tuning ferroptotic sensitivity may offer greater efficacy than single-target interventions. Rigorous assessment of safety, dosage, and treatment windows will be essential for clinical translation. Future high-impact work in this field should move beyond descriptive associations and prioritize causal, cell-type-resolved studies. In particular, single-cell and spatial omics, longitudinal studies linked to In vitro fertilisation (IVF) outcomes, and mechanistic models capable of separating ferroptosis from broader oxidative injury will be essential. It will also be important to define whether therapeutic modulation of ferroptosis can be applied within safe temporal and cellular windows, especially in tissues such as the ovary, where mitochondrial function is tightly linked to steroidogenesis, genome inheritance, and developmental competence. These priorities may help convert the current conceptual framework into clinically meaningful strategies for preserving female reproductive health.

This review positions ferroptosis as a context-dependent, mitochondria-regulated process integral to female reproductive homeostasis. Rather than a uniform death pathway, ferroptosis represents a spectrum of redox-driven cellular states determined by mitochondrial fitness, iron handling, lipid composition, and antioxidant capacity. Across reproductive tissues, MQC mechanisms—including biogenesis, dynamics, and mitophagy—set ferroptotic thresholds that distinguish adaptive remodeling from pathological cell loss. In the ovary, mitochondrial dysfunction lowers ferroptotic thresholds, contributing to GC loss and declining ovarian reserve. In contrast, uterine physiology requires active suppression and precise modulation of ferroptosis to support decidualization and implantation. Emerging regulators, such as YAP/TAZ, further link mechanical and metabolic cues to ferroptotic susceptibility, particularly in the uterine environment. Clinically, these insights redefine ferroptosis as both a therapeutic target and a biological constraint. While excessive ferroptotic activity contributes to infertility and reproductive failure, indiscriminate inhibition risks disrupting essential physiological processes. Targeted, context-specific modulation of the mitochondrial–ferroptosis axis therefore represents a nuanced yet promising strategy in reproductive medicine. Ferroptosis should be perceived as a graded mitochondria-governed process. This perspective provides a unifying framework for understanding reproductive aging and dysfunction, and offers new directions for mechanistic and translational research.

Recognition of ferroptosis as a metabolically regulated form of cell death has expanded therapeutic possibilities for female reproductive disorders. Because mitochondrial function governs ferroptotic sensitivity, strategies that preserve mitochondrial integrity represent a promising translational approach. However, effective clinical application requires careful consideration of tissue specificity, timing, and physiological context ( Table 7 ). Therapeutic strategies targeting the mitochondrial–ferroptosis axis Female fertility depends on the tightly regulated coordination of cell survival, differentiation, and selective elimination within the ovary and uterus. Ferroptosis contributes to these processes, functioning as either a pathological driver or a regulated remodeling mechanism. This review conceptualizes ferroptosis as a mitochondria-governed process whose activation threshold varies across reproductive cell types, linking MQC to reproductive aging, ovarian dysfunction, and implantation failure. In the ovary, excessive ferroptotic signaling has been implicated in follicular loss associated with premature ovarian insufficiency, chemotherapy-induced damage, and reproductive aging [ 131–134 ]. In experimental models, pharmacological ferroptosis inhibitors and iron chelators preserve GC viability and follicular structure, supporting their potential utility in fertility preservation [ 132 , 134 , 135 ]. Complementary strategies that enhance mitochondrial antioxidant capacity, including NRF2 activation or mitochondria-targeted antioxidants, further reduce ferroptotic vulnerability in ovarian cells [ 136 , 137 ]. Importantly, complete suppression of ferroptosis is unlikely to be desirable, as regulated cell death is essential for physiological follicular atresia [ 138 , 139 ]. Therapeutic approaches should therefore aim to restore redox and metabolic balance rather than abolish ferroptotic processes altogether ( Figure 3 ). The overview of mitochondrial biogenesis–ferroptosis interplay in female fertility. (a) Ferroptosis. Schematic representation of iron-dependent lipid peroxidation and oxidative stress–driven ferroptotic cell death. (b) Ferroptosis and mitochondrial biogenesis. Illustration of the bidirectional crosstalk between mitochondrial metabolism, redox balance, iron handling, and ferroptosis regulation. (c) Mitochondrial biogenesis. Overview of key regulatory pathways governing mitochondrial biogenesis, dynamics, and antioxidant capacity. (d) Fertility implications. Disrupted mitochondrial biogenesis–ferroptosis balance in female reproductive tissues, affecting oocyte quality, follicular development, implantation, and pregnancy outcomes. In the uterus, ferroptosis plays a dual role. During decidualization and implantation, ferroptotic signaling must be tightly restrained to preserve stromal and epithelial cell viability. By contrast, localized lipid peroxidation may contribute to controlled tissue remodeling [ 120 ]. Dysregulation at either extreme may impair endometrial receptivity. Hormonal therapies commonly used in reproductive medicine may indirectly influence ferroptotic sensitivity by modulating mitochondrial biogenesis, lipid metabolism, and antioxidant defenses [ 99 ]. Elucidating how estrogen and progesterone regulate the mitochondrial–ferroptosis axis may inform personalized interventions for implantation failure and recurrent pregnancy loss [ 99 , 140 ]. In parallel, recent studies showed that YAP/TAZ signaling modulates mitochondrial function and ferroptotic thresholds in endometrial cells, although clinical data remain limited. Identifying reliable biomarkers is essential for translating ferroptosis-targeted therapies into clinical practice. Expression levels of ferroptosis regulators such as GPX4, SLC7A11, and ACSL4, as well as indicators of mitochondrial health, hold promise as diagnostic or prognostic markers in ovarian and endometrial disorders [ 134 , 141 , 142 ]. Cumulus and granulosa cells obtained during assisted reproductive procedures represent accessible sources for assessing ferroptotic and mitochondrial status [ 141–143 ]. Despite these advances, significant challenges remain. Most evidence supporting ferroptosis-targeted interventions in reproductive tissues derives from preclinical models, with limited human data. Moreover, the long-term effects of modulating ferroptosis on reproductive lifespan, offspring health, and transgenerational inheritance remain largely unexplored ( Figure 3 ). From a translational perspective, it is unlikely that a single marker will adequately capture ferroptosis-related reproductive dysfunction. More informative approaches may require integrated biomarker panels combining ferroptosis-associated regulators, indices of mitochondrial function, and follicular-fluid metabolomic or lipidomic signatures. Emerging single-cell and multi-omics studies of ovarian aging further suggest that cell-type-specific molecular states can now be resolved with greater precision, offering an opportunity to distinguish generalized oxidative stress from bona fide ferroptosis-related vulnerability in human reproductive tissues [ 144 ].

Mitochondria are central regulators of female reproductive physiology, integrating energy production, redox balance, calcium signaling, and iron homeostasis to support follicular development, oocyte maturation, and uterine remodeling [ 1 , 2 ]. Disruption of mitochondrial redox control increases oxidative damage and sensitizes reproductive cells to regulated cell death pathways [ 3 ]. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and mechanistically distinct from apoptosis and necrosis [ 4 ]. Because ferroptosis is closely linked to iron metabolism, lipid peroxidation, and antioxidant capacity, mitochondria function as active determinants of ferroptotic susceptibility. Both mitochondrial dysfunction and ferroptosis have been implicated in reproductive disorders, including Polyendocrine metabolic ovarian syndrome (PMOS), endometriosis, and premature ovarian insufficiency (POI); however, their functional interaction in female fertility remains incompletely understood [ 5 , 6 ]. Female reproductive tissues are particularly vulnerable to mitochondrial perturbations due to their high metabolic demand and cyclical remodeling. In this review, we examine mitochondrial regulation of ferroptosis across female reproductive tissues and propose that dysregulation of this axis contributes to impaired reproductive function and fertility.

Mitochondria are dynamic organelles that adapt to cellular demands through coordinated biogenesis, fission–fusion dynamics, and mitophagy, collectively ensuring mitochondrial quality-control (MQC) [ 7 , 8 ]. Mitochondrial biogenesis extends beyond numerical expansion and functions as a regulatory process integrating metabolic signaling, redox balance, and stress responses. This process is critical in female reproductive tissues due to their high energetic demands and continuous remodeling. Mitochondrial dynamics are regulated by fission and fusion processes. Fission is mediated by dynamin-related protein 1 (DRP1), whereas mitofusin 1/2 (MFN1/2) and optic atrophy 1 (OPA1) promote fusion of the outer and inner mitochondrial membranes, respectively [ 9 , 10 ]. Disruption of the fission–fusion balance compromises mitochondrial function, enhances oxidative stress, and sensitizes cells to regulated cell death pathways, including ferroptosis. Excessive fission is commonly associated with mitochondrial dysfunction, whereas fusion supports metabolic stability under stress. Mitochondrial biogenesis requires coordinated transcription of nuclear and mitochondrial genes, replication of mitochondrial DNA (mtDNA), and assembly of respiratory complexes [ 11 , 12 ]. This process is tightly coupled to the removal of damaged mitochondria, ensuring that increases in mitochondrial content do not occur at the expense of organelle quality. Maintenance of this coupling is essential to limit excessive reactive oxygen species (ROS) generation and preserve redox homeostasis. Transcriptional regulation of mitochondrial biogenesis is primarily controlled by peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which activates nuclear respiratory factors and mitochondrial transcription factor A (TFAM) [ 13 ]. PGC-1α activity is modulated by metabolic and stress-responsive kinases, including AMP-activated protein kinase (AMPK) and calcium/calmodulin-dependent protein kinase IV (CaMKIV) [ 14 ]. Additional regulators, such as sirtuin 1 (SIRT1), nitric oxide, and CREB-related coactivators, further fine-tune mitochondrial biogenesis by linking metabolic flexibility to antioxidant capacity [ 11 , 15 , 16 ]. In female reproduction, intact mitochondrial biogenesis is essential for follicular development, steroidogenesis, and oocyte maturation. Impaired mitochondrial renewal has been associated with reduced oocyte quality, granulosa cell dysfunction, and accelerated reproductive aging [ 17–20 ]. Recent studies show that defective mitochondrial biogenesis lowers the threshold for ferroptosis by weakening antioxidant defenses and iron-handling capacity. Whether impaired biogenesis actively initiates ferroptosis or primarily sensitizes reproductive cells to ferroptotic triggers remains a subject of ongoing research. At the molecular level, ferroptosis is a form of cell death that arises from the convergence of iron overload, lipid peroxidation, and failure of antioxidant defense systems [ 21 ]. Iron catalyzes ROS generation through Fenton reaction, accelerating peroxidation of polyunsaturated fatty acid (PUFA)–containing membrane phospholipids [ 22 , 23 ]. Incorporation of PUFAs into membrane phospholipids is mediated by acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), which enhance susceptibility to ferroptotic damage [ 24–26 ]. Cells with high mitochondrial content and metabolic activity, such as granulosa cells and oocytes, may therefore be particularly vulnerable to iron dysregulation. The principal antioxidant defense against ferroptosis is glutathione peroxidase 4 (GPX4), which reduces lipid hydroperoxides using glutathione (GSH) as a cofactor [ 27 , 28 ]. GSH availability depends on cystine uptake via system Xc − , composed of cystine/glutamate antiporter subunit (SLC7A11) and 4F2hc/CD98 (SLC3A2) [ 29 ]. Disruption of GPX4 activity or cystine transport shifts redox balance toward unchecked lipid peroxidation. In reproductive cells, where redox equilibrium is critical for developmental competence, even modest impairment of this system may have significant functional consequences. Ferroptosis is increasingly recognized as a graded, metabolically dependent process rather than a binary death pathway. Its activation reflects cellular metabolic state, iron availability, and mitochondrial fitness, all of which play critical roles in physiological remodeling processes in reproductive tissues. Mitochondria serve as central regulators of ferroptotic sensitivity through their roles in ROS production, iron metabolism, and lipid biosynthesis [ 30 ]. A more precise mechanistic distinction is needed between direct and indirect mitochondrial contributions to ferroptosis. Direct contributions include mitochondrial ROS generation, mitochondrial iron handling, and metabolic support for lipid peroxidation under conditions of impaired antioxidant defense. In contrast, indirect contributions include ATP depletion, defective stress adaptation, altered steroidogenic function, and broader metabolic insufficiency, which do not necessarily trigger ferroptosis on their own but can lower the threshold for ferroptotic damage. Framing mitochondrial regulation in this way helps explain why mitochondria can function as either active participants in ferroptotic execution or as context-dependent amplifiers of ferroptotic susceptibility [ 31 ]. An additional layer of regulation is provided by mitochondria-to-nucleus communication. Through redox-sensitive signaling, metabolic stress pathways, and retrograde transcriptional responses, dysfunctional mitochondria can reshape nuclear programs governing antioxidant defense, lipid remodeling, iron metabolism, and cellular stress tolerance. In reproductive tissues, this suggests that mitochondrial dysfunction may influence ferroptotic sensitivity not only through local biochemical changes but also through transcriptional reprogramming that alters cells’ ability to adapt to persistent oxidative stress [ 32–34 ]. Mitochondrial iron is imported via Mitoferrin-1 (SLC25A37) and Mitoferrin-2 (SLC25A28) and utilized for heme synthesis and iron–sulfur cluster assembly or stored by mitochondrial ferritin [ 35 ]. Mitochondrial metabolism further influences ferroptosis through the tricarboxylic acid cycle and electron transport chain (ETC). Anaplerotic flux in the TCA cycle facilitates the continuous generation of reduced form of nicotinamide adenine dinucleotide (NADH) and reduced form of flavin adenine dinucleotide (FADH 2 ). Electron leakage from ETC complexes I and III, fueled by these cofactors, generates ROS and sensitizes cells to ferroptosis [ 36 ]. Conversely, suppression of mitochondrial respiration or a shift toward glycolysis limits the mitochondrial pool of NADH/FADH 2 and attenuates ferroptosis, underscoring its dependence on mitochondrial energetic output [ 37 ]. Together, these findings indicate that mitochondrial metabolic states directly determine ferroptotic thresholds: oxidative states characterized by TCA cycle flux and ETC activity lower the threshold for ferroptosis, whereas metabolic shifts toward reduced mitochondrial respiration increase resistance to ferroptosis. While mitochondrial ROS can directly initiate lipid peroxidation in mitochondrial membranes, their role in ferroptosis appears to be modulatory rather than strictly essential [ 38 ]. In many cellular contexts, cytosolic lipid peroxidation is the dominant execution mechanism, with the endoplasmic reticulum as the main site for propagating lipid hydroperoxides [ 24 ]. Mitochondrial dynamics also modulate ferroptotic susceptibility. Excessive fission, mediated by DRP1 and FIS1, promotes mitochondrial fragmentation and oxidative stress, whereas fusion mediated by MFN1, MFN2, and OPA1 supports functional complementation and redox stability [ 30 ]. This balance functions as a regulatory continuum rather than a simple pro- or anti-death switch, particularly in ovarian cells undergoing dynamic remodeling ( Figure 1 ). Mitochondrial regulation of ferroptosis. Overview of mitochondrial contributions to ferroptosis, including electron transport chain–derived reactive oxygen species, mitochondrial iron handling, metabolic regulation via the TCA cycle and AMPK signaling, and NRF2-mediated redox and mitochondrial homeostasis. Through mitochondrial calcium uptake mechanisms, mitochondria play an essential role in intracellular calcium homeostasis and also participate in mitochondrial fission and fusion [ 39 ]. Calcium signaling is pivotal in oocyte activation, granulosa cell communication, and overall metabolic activity [ 39 ]. Dysregulated calcium homeostasis may increase oxidative stress and lipid peroxidation, thereby enhancing ferroptosis susceptibility [ 39 ]. Therefore, mitochondrial calcium dynamics may represent another mechanism linking mitochondrial dysfunction to ferroptosis regulation, particularly in reproductive tissues. Mitophagy intersects with ferroptosis in a context-dependent manner. Basal mitophagy limits ROS accumulation and protects against ferroptosis, whereas excessive mitochondrial turnover may increase ferroptotic vulnerability by releasing redox-active iron through ferritinophagy [ 40 , 41 ]. Nuclear factor erythroid 2-related factor 2 (NRF2) integrates mitochondrial homeostasis and ferroptosis resistance by regulating antioxidant genes, iron metabolism, and mitochondrial function [ 42 ]. Dysregulated NRF2 signaling has been linked to increased ferroptotic damage in ovarian and uterine cells under oxidative stress and aging ( Figure 2 ). In addition, mitochondrial-specific defense systems, including mitochondrial GPX4 and dihydroorotate dehydrogenase (DHODH), suppress lipid peroxidation within the inner mitochondrial membrane [ 30 ]. While mitochondrial ROS and iron handling promote pro-ferroptotic signaling, mitochondrial defense systems selectively limit lipid peroxidation within mitochondrial membranes, highlighting compartmentalized control of ferroptosis. The balance between these opposing processes ultimately determines whether ferroptosis occurs. Mitochondrial control of ferroptosis. Key mitochondrial processes that influence ferroptosis, including reactive oxygen species generation, iron handling, metabolic regulation, and NRF2-dependent redox regulation and mitochondrial homeostasis. These findings support an integrated model in which mitochondria modulate ferroptotic sensitivity through both direct and context-dependent mechanisms across metabolic and redox states. MQC coordinates metabolic flux, iron handling, and redox balance to regulate ferroptotic sensitivity. In female reproductive tissues, disruption of this mitochondrial–ferroptosis interface may contribute to follicular loss, oocyte dysfunction, and impaired uterine receptivity. Key mitochondrial pathways influencing ferroptosis are summarized in Tables 1 – 3 . Key regulators linking mitochondrial biogenesis to ferroptosis susceptibility Core molecular components of ferroptosis and their mitochondrial interfaces Mitochondrial dynamics and quality control pathways modulating ferroptosis Mitochondrial–nuclear communication is established via a bidirectional pathway, pivotal for the maintenance of cellular homeostasis [ 43 ]. Mitochondria are found to use retrograde signaling pathways to allow their functional state to be known by the nucleus [ 43 ]. This process is also shown to allow the cell to adapt to mitochondrial stress [ 43 ]. The retrograde signaling pathway helps maintain tissue homeostasis by adjusting the ferroptotic in response to cellular needs. This process is especially important in metabolically active tissues, like those in the reproductive system [ 44 ]. Conversely, if retrograde signaling is disrupted, it can lead to “miscommunication” between the nucleus and mitochondria, resulting in ferroptosis and impaired mitochondrial biogenesis. Several key signaling pathways influence the expression of ferroptosis-related mechanisms, such as ROS-mediated signaling, the SIRT4 -ANT2-AMPK-PGC1α axis, and the integrated stress response (ISR) [ 30 , 45 ]. ROS-mediated signaling is dependent on and sensitive to ROS generated by the mitochondrial transport chain. It acts as a secondary messenger that controls the expression of the SLC7A11 and iron storage proteins [ 30 ]. A critical component of this retrograde signaling pathway is the SIRT4 -ANT2-AMPK-PGC1α axis, which functions as a feedback loop when mitochondria experience energy or stress-related shifts [ 46 ]. This pathway is activated during mitochondrial dysfunction and can either promote or inhibit ferroptosis, depending on the cell’s needs [ 46 ]. Inhibition of the ferroptotic pathway is achieved by suppressing lipid synthesis, whereas promotion occurs by sensitizing cells to nutrient deprivation [ 46 ]. This mechanism allows the nucleus to maintain cellular homeostasis by regulating mitochondrial biogenesis and ferroptosis [ 46 ]. The ISR pathway mediates ferroptosis resistance to mitochondrial stress, leading to upregulation of Activating Transcription Factor 4 (ATF4), a transcription factor that modulates the cellular response to oxidative stress and amino acid availability [ 45 ]. ATF4 increases the activation of cytoprotective genes, which, in turn, triggers a local proteostatic response [ 45 ].

The functional consequences of mitochondrial–ferroptosis crosstalk vary markedly across reproductive cell types, reflecting differences in metabolic demand, mitochondrial plasticity, and physiological roles ( Table 4 ). Within the ovary, this interplay influences follicular survival, oocyte competence, and reproductive lifespan via cell-type-specific mechanisms. Cell type–specific ferroptosis engagement in the ovary The ovary is a metabolically dynamic organ in which folliculogenesis, steroidogenesis, and oocyte maturation depend on tightly regulated mitochondrial function and redox homeostasis. Ovarian cells exhibit pronounced mitochondrial plasticity to accommodate fluctuating energetic demands; however, this same adaptability also renders them vulnerable to mitochondrial dysfunction and ferroptotic stress. Within this framework, ferroptotic sensitivity in the ovary should be interpreted as a cell-type-specific and threshold-dependent process rather than a uniform death program ( Table 4 ). Beyond ATP production, mitochondria act as central organizers of ovarian physiology. In ovarian somatic and germ cells, they support steroid biosynthesis, calcium buffering, mitochondrial genome maintenance, iron handling, lipid metabolism, and stress-responsive communication with the nucleus. These functions are directly relevant to ferroptosis because they determine whether mitochondrial stress remains adaptive, triggers sublethal lipid peroxidation, or progresses to irreversible ferroptotic injury. Thus, ovarian ferroptosis is best understood within a broader framework of mitochondrial reproductive fitness. Mitochondrial calcium handling provides an additional mechanistic bridge between ovarian physiology and ferroptotic vulnerability. Calcium signaling contributes to oocyte maturation, fertilization-associated activation, granulosa cell communication, and metabolic regulation [ 39 ]. When calcium homeostasis is disrupted, mitochondrial membrane potential, ROS production, and lipid peroxidation may be altered, thereby lowering the threshold for ferroptosis-related injury [ 39 ]. In this context, calcium dysregulation should be viewed as a permissive mechanism that amplifies ferroptotic susceptibility rather than as an isolated trigger of ferroptotic cell death [ 47 ]. Mitochondrial biogenesis and mtDNA integrity are also essential for follicular growth, maintenance of ovarian reserve, and oocyte competence. During oogenesis, mitochondria are transmitted to the embryo; therefore, the quality of the mitochondrial genome and the efficiency of mitochondrial quality-control mechanisms have implications beyond the individual oocyte. Age- or stress-associated mtDNA damage, impaired mitochondrial renewal, and defective organelle selection may compromise oocyte developmental potential and increase vulnerability to ferroptosis-related oxidative injury [ 48 ]. Impaired mitochondrial renewal disrupts steroid hormone synthesis, alters follicular development, and accelerates ovarian aging [ 17–20 ]. Because ovarian mitochondria coordinate redox balance, iron utilization, lipid metabolism, and endocrine output, mitochondrial dysfunction places the ovary at a critical intersection between metabolic adaptation and ferroptotic susceptibility. Experimental evidence indicates that ferroptosis contributes to ovarian dysfunction by promoting follicular atresia under conditions of oxidative stress and iron dysregulation [ 5 , 6 ]. In this setting, ferroptosis may represent an exaggerated activation of physiological follicular quality-control mechanisms. While controlled cell elimination is necessary for follicular selection and turnover, excessive or dysregulated ferroptotic signaling may deplete the follicular pool and compromise fertility. Ovarian aging exemplifies this interaction between mitochondrial quality control and ferroptotic vulnerability. Age-associated mtDNA mutations, including large-scale deletions and point mutations in oxidative phosphorylation genes, impair ETC efficiency, increase electron leakage, and increase ROS production [ 20 ]. Concurrently, mitochondrial biogenesis declines with age, partly through reduced activity of key regulators, such as PGC-1α, TFAM, and AMPK, leading to insufficient mitochondrial renewal [ 49 , 50 ]. Aging also disrupts mitochondrial dynamics by shifting the balance toward excessive fission at the expense of fusion, thereby promoting mitochondrial fragmentation, loss of membrane potential, and persistent oxidative stress [ 10 ]. Although mitophagy may initially limit the accumulation of damaged mitochondria, chronic or dysregulated mitochondrial turnover may further perturb iron homeostasis and enhance ferroptotic vulnerability. Together, these features establish mitochondrial dysfunction as a mechanistic bridge linking reproductive aging, declining ovarian reserve, and ferroptosis-related fertility impairment. Cumulus cells form a specialized metabolic and redox interface between the oocyte and its microenvironment within the cumulus–oocyte complex (COC). Through gap junction-mediated exchange, they regulate oocyte energy metabolism, antioxidant support, and developmental competence, thereby buffering the oocyte against oxidative and metabolic stress. Mitochondrial biogenesis in cumulus cells is critical for sustaining this supportive function. Because oocytes have limited glycolytic capacity, cumulus cells supply metabolic intermediates, antioxidants, and signaling molecules required for maturation [ 47 ]. Reduced mitochondrial DNA copy number or impaired mitochondrial membrane potential in cumulus cells correlates with poor oocyte quality and decreased fertilization potential [ 51 , 52 ]. Although direct evidence for canonical ferroptosis in cumulus cells remains limited, mitochondrial dysfunction, calcium dysregulation, and oxidative stress may induce ferroptosis-like lipid peroxidation under pathological conditions [ 52 , 53 ]. In this scenario, ferroptotic injury in cumulus cells would compromise oocyte competence indirectly by disrupting metabolic and antioxidant support rather than inducing oocyte death. Clinically, altered expression of MQC regulators, including sirtuin-3 (SIRT3), has been observed in cumulus cells from infertile patients [ 54 ]. This supports the potential utility of cumulus cells as accessible, non-invasive indicators of oocyte mitochondrial health. Thus, cumulus cells function as metabolic and redox sentinels, with mitochondrial integrity indirectly shaping oocyte developmental potential. Granulosa cells (GCs) are central regulators of follicular development, providing metabolic substrates, antioxidant protection, steroidogenic support, and paracrine signals essential for oocyte survival and maturation [ 55 , 56 ]. Their high mitochondrial content and mitochondria-dependent steroidogenic activity increase metabolic flux and ROS generation, making GCs particularly sensitive to disruptions in mitochondrial function and redox balance [ 39 ]. Physiological granulosa cell loss underlies follicular atresia. Although apoptosis has traditionally been considered the dominant mechanism, increasing evidence indicates that ferroptosis is a complementary pathway that contributes to GC demise under oxidative and iron-rich conditions. Ferroptosis in GCs is characterized by lipid peroxidation, mitochondrial dysfunction, and compromised antioxidant defenses, thereby linking metabolic stress directly to follicular fate [ 21 , 27 , 57 ]. Granulosa cell mitochondrial dysfunction has consequences that extend beyond oxidative injury alone. Because mitochondria initiate steroid hormone biosynthesis, mitochondrial dysfunction may reduce steroidogenic efficiency while simultaneously sensitizing GCs to ferroptosis-related damage. This dual effect is biologically important because GC injury may impair not only follicular survival but also the endocrine support required for normal oocyte maturation. Accordingly, mitochondrial injury in GCs should be interpreted as both a cell-death-promoting and an endocrine-disrupting event within the follicular microenvironment [ 58–60 ]. Polyendocrine metabolic ovarian syndrome (PMOS) exemplifies pathological activation of ferroptosis in GCs. In PMOS, suppression of anti-ferroptotic pathways, including GPX4, SLC7A11, and NRF2, promotes lipid peroxidation and ferroptotic cell death [ 61–63 ]. MicroRNA-mediated repression of these protective systems may further sensitize GCs to ferroptosis, linking post-transcriptional regulation to mitochondrial vulnerability [ 64 ]. Granulosa cell ferroptosis has also been implicated in premature ovarian insufficiency, particularly following chemotherapy exposure [ 65 ]. Experimental inhibition of ferroptosis partially rescues granulosa cell viability and preserves follicular architecture, underscoring the mechanistic and therapeutic relevance of this pathway. With advancing age, cumulative mitochondrial damage and reduced biogenesis further lower ferroptotic thresholds in GCs, accelerating follicular depletion and declining ovarian reserve [ 66 , 67 ]. Collectively, granulosa cells emerge as primary executors of ferroptosis-associated follicular loss. They occupy a central position in ovarian ferroptosis biology because their mitochondrial state determines not only their own survival but also the metabolic, endocrine, and antioxidant support available to the oocyte. Oocyte maturation is a highly energy-dependent process requiring precise coordination of meiotic progression, spindle assembly, cytoskeletal remodeling, and organelle redistribution [ 68–70 ]. Oocytes contain exceptionally high mitochondrial copy numbers, but maintain relatively restrained oxidative phosphorylation activity, which may help limit ROS generation during maturation [ 49 , 71–73 ]. During maturation, mitochondrial redistribution and biogenesis ensure adequate ATP supply while minimizing oxidative damage [ 73 , 74 ]. Disruption of mitochondrial membrane potential, spatial organization, or mitochondrial dynamics is consistently associated with impaired fertilization and embryo development competence [ 75 ]. Unlike granulosa cells, oocytes appear relatively resistant to overt ferroptotic cell death, likely due to robust mitochondrial antioxidant systems and metabolic buffering by surrounding somatic cells [ 56 , 76 ]. Nevertheless, iron dysregulation and lipid peroxidation can induce sublethal ferroptosis-related stress [ 76–78 ]. Such stress impairs spindle integrity, chromosomal alignment, and developmental competence without immediately triggering terminal cell death [ 79–81 ]. Oocyte competence depends not only on mitochondrial abundance and distribution but also on mtDNA integrity and the transmission of functionally competent mitochondria to the embryo. During oogenesis, mitochondrial quality-control mechanisms help preserve mtDNA stability and restrict the persistence of severely damaged mitochondrial populations. With reproductive aging, however, mtDNA instability and defective mitochondrial quality control may impair developmental competence before overt cell death becomes apparent. These changes may also lower the threshold for ferroptosis-related oxidative injury, thereby linking mitochondrial genome maintenance to both oocyte quality and stress vulnerability [ 71 , 82–84 ]. Mitochondrial calcium handling represents another important determinant of oocyte fitness. By buffering calcium oscillations and coupling calcium fluxes to ATP production, mitochondria support meiotic progression, fertilization-associated signaling, and early developmental competence. Disturbances in calcium homeostasis may increase mitochondrial stress, promote ROS accumulation, and favor lipid peroxidation-prone conditions. Calcium dysregulation may therefore act as a permissive factor connecting mitochondrial dysfunction to ferroptosis-related oocyte injury, even when direct evidence of terminal ferroptotic death remains limited [ 73 , 84–86 ]. Stringent MQC mechanisms, including selective mitophagy, operate during oocyte maturation to preserve mitochondrial fitness and prevent transmission of damaged organelles to the embryo [ 87 , 88 ]. Failure of these processes during aging or environmental stress amplifies oxidative damage and ferroptosis-associated dysfunction [ 88–91 ]. Thus, oocyte maturation represents a biological setting in which ferroptosis is tightly constrained, whereas ferroptosis-related oxidative stress functions as a quality-limiting factor. This distinction emphasizes that ferroptosis in reproduction exists along a spectrum, influencing developmental potential without necessarily culminating in cell death. Differences in metabolic activity, antioxidant capacity, intercellular communication, and iron regulation shape differential ferroptosis sensitivity between GCs and oocytes. Oocytes possess highly efficient MQC mechanisms, including selective mitophagy and robust redox-buffering systems, which help prevent excessive lipid peroxidation [ 87–91 ]. Despite their high mitochondrial content, oocytes maintain relatively low oxidative phosphorylation activity, thereby limiting ROS generation and reducing their susceptibility to overt ferroptosis [ 49 , 71–73 ]. In contrast, granulosa cells are more metabolically active because of their roles in steroidogenesis, follicular growth, and oocyte support [ 55 , 56 ]. This elevated metabolic demand increases ROS production, making GCs particularly vulnerable to ferroptotic injury, especially under conditions of iron overload or impaired antioxidant defense [ 61–65 ]. Differences in iron metabolism further contribute to this cell-type-specific vulnerability. Granulosa cells appear more sensitive to fluctuations in follicular iron availability and are therefore more prone to iron-dependent lipid peroxidation [ 61–65 ]. By contrast, oocytes seem to maintain stricter control of iron homeostasis, which may protect them from overt ferroptotic cell death while still allowing low-level ferroptosis-related stress that can impair developmental competence [ 76–81 ]. Granulosa cells and oocytes should therefore be considered as functionally interconnected but ferroptosis-distinct compartments within the follicle. Through gap junction–mediated communication, GCs provide metabolic substrates and antioxidant support to the oocyte while buffering it from oxidative stress [ 47 , 56 ]. Consequently, ferroptotic damage in GCs may indirectly compromise oocyte quality even in the absence of direct ferroptotic death within the oocyte itself ( Table 1 ). The uterus is a highly dynamic organ that undergoes cyclical remodeling in response to hormonal cues, requiring precise coordination of cellular proliferation, differentiation, and regulated turnover [ 87 , 88 ]. These processes impose substantial metabolic and redox demands, positioning mitochondrial function as a central determinant of endometrial integrity and reproductive success [ 89 ]. Unlike the ovary, where cell loss is largely irreversible, uterine physiology depends on regenerative mechanisms that balance survival and elimination pathways to sustain tissue renewal. Mitochondria support endometrial ATP production, hormone responsiveness, and redox signaling, with epithelial and stromal cells exhibiting cycle-dependent changes in mitochondrial biogenesis and activity [ 90 , 91 ]. Disruption of mitochondrial homeostasis during transitions between proliferative and secretory phases may predispose uterine cells to oxidative and ferroptotic stress [ 92 ]. This vulnerability is amplified by the unique uterine iron environment, shaped by recurrent menstrual bleeding and local iron release [ 93 ]. Under physiological conditions, antioxidant and iron-sequestration systems limit lipid peroxidation; failure of these mechanisms may shift the balance toward ferroptotic injury [ 94 , 95 ]. Ferroptosis dysregulation is linked to uterine pathologies, including endometriosis, adenomyosis, and implantation failure [ 76 ]. In endometriosis, iron-rich peritoneal environments promote oxidative stress and lipid peroxidation, while ectopic lesions paradoxically acquire resistance to ferroptosis, facilitating persistence and invasion [ 21 , 93 , 95 , 96 ]. This reflects context-dependent regulation of ferroptosis within uterine-derived tissues. Endometrial stromal cell (ESC) decidualization is a critical differentiation process required for successful implantation and maintenance of pregnancy [ 97 ]. Impaired mitochondrial function during decidualization has been linked to oxidative stress and defective antioxidant responses. These conditions may sensitize stromal cells to ferroptosis and compromise endometrial receptivity [ 98 ]. Hormonal signaling further modulates the mitochondrial–ferroptosis axis. Estrogen and progesterone regulate mitochondrial biogenesis, antioxidant defenses, and lipid metabolism in endometrial cells [ 92 , 99 ]. Disruption of hormonal balance in infertility or recurrent pregnancy loss may therefore indirectly alter ferroptotic sensitivity by perturbing mitochondrial and redox homeostasis [ 92 , 99 ]. Collectively, uterine physiology requires tight restraint of ferroptosis to permit cyclic regeneration while preventing oxidative damage ( Table 5 ). Causal vs consequential roles of ferroptosis across reproductive contexts ESCs undergo progesterone-driven decidualization, a differentiation process essential for implantation and maintenance of pregnancy [ 100 ]. This transition involves extensive transcriptional, metabolic, and mitochondrial reprogramming, imposing high energetic and redox demands [ 101 ]. Decidualizing ESCs increase mitochondrial mass and oxidative capacity to support biosynthetic and secretory functions [ 82 ], and failure to adequately enhance mitochondrial biogenesis is associated with oxidative stress and impaired endometrial receptivity [ 102 , 103 ]. Iron and lipid metabolism are dynamically regulated during decidualization. While controlled iron utilization supports mitochondrial function, excess iron accumulation amplifies lipid peroxidation and threatens decidual cell survival [ 94 , 104–106 ]. To counteract this risk, decidualizing ESCs upregulate ferroptosis-inhibitory genes, including GPX4 and glutathione synthesis [ 107 ]. This indicates that active suppression of ferroptosis is required to sustain decidual cell viability and ensure their prolonged survival during early pregnancy. The Hippo pathway effectors Yes-Associated Protein (YAP) and Transcriptional Co-Activator with PDZ-Binding (TAZ) are key regulators of decidualization, influencing ESC proliferation, differentiation, and metabolic state [ 108–112 ]. Through effects on mitochondrial function, lipid metabolism, and antioxidant gene expression, YAP/TAZ signaling may indirectly regulate ferroptotic sensitivity. Dysregulation of this pathway has been associated with defective decidualization and implantation failure, suggesting that inappropriate ferroptotic activation may contribute to these outcomes. Oxidative stress represents a critical checkpoint during decidualization [ 113 ]. Clinical studies have linked impaired decidualization to infertility, recurrent implantation failure, and recurrent pregnancy loss [ 114 ]. Thus, decidualization requires coordinated enhancement of mitochondrial function alongside stringent restraint of ferroptosis. Disruption of this balance may represent a convergent mechanism underlying implantation failure and early pregnancy loss. Endometrial epithelial cells (EECs) form the first maternal interface with the implanting embryo and establish a transient window of receptivity characterized by controlled polarity, adhesion, and tissue remodeling [ 115 ]. These processes impose significant metabolic and redox demands, making mitochondrial fitness and ferroptosis regulation critical determinants of implantation success [ 116 , 117 ]. Across the menstrual cycle, EEC mitochondria undergo functional remodeling as cells transition from proliferative to receptive states [ 102 , 103 ]. During implantation, epithelial cells reduce proliferation while enhancing secretory and adhesive functions, requiring adaptive mitochondrial reprogramming that supports energy demands while limiting excessive ROS production [ 118 ]. Disruption of this balance compromises epithelial receptivity. Ferroptosis at the implantation interface must be precisely constrained. While localized lipid peroxidation may facilitate epithelial remodeling and embryo invasion, excessive ferroptotic signaling would disrupt epithelial integrity and impair implantation [ 119–121 ]. EECs, therefore, appear to maintain a tightly regulated ferroptotic threshold that permits physiological remodeling without triggering cell death. YAP/TAZ signaling plays a central role in epithelial polarity and adhesion and responds to mechanical and cell–cell contact cues [ 122 , 123 ]. By influencing mitochondrial metabolism, lipid synthesis, and antioxidant capacity, YAP/TAZ may indirectly modulate ferroptotic susceptibility at the epithelial surface [ 110 , 124–126 ]. In parallel, effective iron sequestration is required to counteract the iron-rich uterine microenvironment and prevent oxidative damage [ 127 , 128 ]. Studies report altered expression of mitochondrial biogenesis factors, antioxidant enzymes, and ferroptosis regulators in endometrial tissue from women with implantation failure or unexplained infertility [ 117 , 120 , 121 , 129 , 130 ]. These findings suggest that sublethal ferroptosis-related stress at the epithelial interface may disrupt embryo–endometrium communication without overt tissue injury ( Table 6 ). Ferroptosis dysregulation in uterine cells and implantation In summary, uterine receptivity depends on the precise integration of mitochondrial function, redox balance, and the restriction of ferroptosis. In both stromal and epithelial compartments, failure to appropriately suppress ferroptosis compromises implantation competence and reproductive success, underscoring the tissue-specific nature of mitochondrial–ferroptosis regulation.