Research progress of ferroptosis in gynecological diseases

The metal element iron operates as a linchpin in the coordinated sequence constituting ferroptosis, a specialized subset of programmed cell death [ 1–4 ]. Before transitioning to mature analytical frameworks, Dixon and colleagues made groundbreaking descriptions of ferroptosis. They established ferroptosis as a novel erastin-dependent mechanism of non-apoptotic cell death fundamentally dependent on iron [ 5 ]. This paradigm-defining articulation furnished indispensable theoretical scaffolding for subsequent scholarly exploration. The specific manifestation of this cell death pathway presents multiple sets of morphological, biochemical, and genetic hallmarks. From a morphological perspective, cells undergoing ferroptosis show significant mitochondrial shrinkage. Normally functioning mitochondria gradually decrease in volume and their structure becomes irregular. Notably, the dissolution or loss of mitochondrial cristae is particularly striking. Functionally imperative mitochondrial cristae, products of the inner membrane’s cristae formation, rely on intact architecture; breaches in this barrier exert deleterious impacts on mitochondrial operations. Mitochondria, known as the “powerhouses” of the cell, when impaired, jeopardize the cell’s energy supply. Additionally, the outer mitochondrial membrane damage precipitates structural collapse and functional breakdown, negating mitochondria’s ability to uphold cellular metabolism, thereby posing a serious threat to the survival of the entire cell ( Figure 1 ). Ferroptotic cell model: Ferroptosis initiates a lipid peroxidation cascade, generating hydroxyl radicals that attack the mitochondrial inner membrane. GSH depletion leads to GPX4 inactivation, resulting in compromised antioxidant capacity that exacerbates membrane damage and oxidative stress. Excessive iron accumulation disrupts mitochondrial electron transport processes, producing ROS such as superoxide anions. From a biochemical perspective, ferroptosis is characterized by intracellular GSH depletion. As a central antioxidant, GSH neutralizes reactive oxygen species (ROS) and maintains redox balance; its exhaustion during ferroptosis severely weakens cellular oxidative defense. Concurrently, GPX4 activity declines, directly disabling the clearance of lipid peroxides and triggering lethal oxidative membrane damage— GPX4 dysfunction thus serves as a core driver of pathological cell and tissue injury in gynecological diseases. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) -dependent lipid peroxidation and iron‑dependent ROS production further amplify this process. ROS and lipid peroxides act as pivotal markers that form a self‑reinforcing vicious cycle to sustain ferroptotic progression, shaping cell fate and promoting disease development [ 1 , 5 , 6 ]. Excessive ROS and lipid peroxidation disrupt membrane structure and integrity, increase permeability, and ultimately induce cell death, which underlies malignant progression, chemoresistance, chronic inflammation, and organ dysfunction in EC, OC, EMS, and PCOS [ 7 , 8 ]. This mechanistic cascade highlights the GSH/ GPX4 /lipid peroxidation axis as a clinically actionable target for predicting disease prognosis, reversing drug resistance, and developing targeted therapies against gynecological diseases [ 9–11 ]. At the genetic level, there are also specific regulatory mechanisms related to it. Ferroptosis stands validated in its correlation with multiple human pathologies, notably ischemia-reperfusion injury, degenerative maladies, and carcinogenesis [ 5 , 8 , 12–19 ]. In obstetric and gynecological science, the fledgling field of ferroptosis research is overshadowed by its profound implication—the unique control it exerts over cell death demands detailed study in disease contexts. Such findings may unlock transformative opportunities in managing complex disease entities through advanced diagnostic tools and targeted interventions, introducing hitherto uncharted solutions. By clarifying defined regulatory roles and biochemical cascades of ferroptosis in obstetric and gynecological diseases, we can not only more accurately understand the patterns of disease development but also develop more targeted and effective treatments, thereby bringing substantial improvements and enhancements to the health and well-being of women.

Pharmacophores eliciting ferroptotic responses operate via divergent biological mechanisms, broadly comprising regulators of iron metabolism, antagonists targeting the System xc⁻ transporter, and compounds disrupting GPX4 enzymatic activity. As an iron-mediated mode of cellular demise, ferroptosis is intrinsically linked to iron regulation [ 199–203 ]. Its dependence on iron manifests in two key ways: first, labile iron catalyzes the Fenton reaction, generating abundant hydroxyl radicals that drive non-enzymatic lipid autoxidation; second, the pro-oxidant activity of lipoxygenase enzymes requires iron to sustain their function [ 6 , 204–208 ]. Consequently, artemisinin emerges as a potent neuroprotective agent against ferroptosis. It acts by activating the KEAP1/NRF2 pathway, restoring neuronal health, depleting GSH, and suppressing lipid peroxidation – a mechanism beneficial in combatting neurodegenerative conditions like Alzheimer’s disease [ 176 , 209 , 210 ]. Tellingly, a growing body of evidence indicates that artemisinin and its derivatives can effectively modulate ferroptosis in tumor cells [ 211–213 ]. For example, Artemisinin (ART) and artemisinin derivatives (ARTEs) can affect the metabolic processes of cancer cells through various pathways. They can interfere with the energy metabolism of cancer cells and reduce ATP production by inhibiting mitochondrial function, thereby weakening the proliferative capacity of the tumor spheroids. In addition, ARTEs exert their effects partly by activating the oxidative stress response in cancer cells, subsequently boosting intracellular ROS production. Consequently, this oxidative stress compromises the integrity of cancer cell DNA and organelles, setting a course for cell death [ 214 ]. Currently, quercetin has also been discovered as a potential agent for preventing preeclampsia (PE). Prophylactic supplementation with low-dose quercetin can rescue endothelial dysfunction in mice. Beyond this, targeting the epidermal growth factor receptor (EGFR) offers a mechanism to reduce occurrences of selective uterine-placental perfusion reduction, as demonstrated in mouse experiments [ 215 ]. Recent years have witnessed mounting evidence from studies indicating that natural products such as resveratrol, curcumin, and baicalein can exert antitumor effects by modulating ferroptosis through multiple targets. Their mechanisms involve iron metabolism remodeling, regulation of the GPX4 /GSH antioxidant system, modulation of lipid peroxidation, and intervention in ferritin autophagy, yielding novel knowledge that informs the design of cancer treatments with a superior benefit-to-toxicity profile. These agents particularly show potential advantages in overcoming drug resistance associated with conventional chemotherapy [ 216–222 ]. Remarkably, researchers discovered that carnitine palmitoyl transferase 1 A (CPT1A) acts as a potent guardian against ferroptosis in lung cancer cells. Its strategy involves bolstering antioxidant defenses via NRF2/GPX4 and throttling back polyunsaturated phospholipid supply by suppressing ACSL4 . Far from being purely detrimental, this survival mechanism powerfully synergizes with immunotherapy [ 223 ]. Ubiquitin-specific protease 7 (USP7) regulates ferroptosis by deubiquitinating stearoyl-CoA desaturase (SCD) , achieving the effect of treating gastric cancer [ 224 ]. Whereas Fatty Acid Desaturase 2 (FADS2) usually promotes tumorigenesis, its downregulation paradoxically initiates ferroptosis by lowering the levels of key antioxidative mediators such as GSH, SLC7A11 and GPX4 . Consequently, this induced ferroptosis heightens cancer cell susceptibility to oxaliplatin and impedes tumor growth [ 225 ]. In recent years, scientists have gradually developed new types of ferroptosis nano-drugs and shown good effects in inducing ferroptosis. Currently, new research indicates that hybrid nanocomposites MnFe2O4/ART/salinomycin (Sali) NPs formed by combining ART, Sali and MnFe 2 O 4 can significantly increase intracellular Fe 2+ content and produce more ROS, enhancing their killing effect and showing good antitumor effects, charting a new course for the rational design of superior ferroptosis-inducing agents [ 226 ]. The compelling nature of this evidence is reinforced by consistent results across laboratory models and animal models, showing that the specialized micelles (comprising ART, Fe 3 O 4 , and Tween 80) effectively block tumor growth with an inhibition efficiency of up to 85% [ 227 ]. Another study found that a core-shell nanoparticle composed of copper (Cu) and erastin (Er) can synergize copper death and ferroptosis, enhancing lipid peroxidation and inducing a strong immune response to promote tumor cell death [ 228–233 ]. In addition, several studies have reported that simultaneously loading Fe 3 O 4 , ZnO, and other agents or drugs such as curcumin, cisplatin, or drugs and lactoferrin in nanomaterials can achieve “killing two birds with one stone” and enhance the ability to induce ferroptosis [ 234–239 ]. Despite advances, several currently available ferroptosis agents face challenges including poor bioavailability and off-target effects, their clinical prospects are somewhat hindered. However, the development of new ferroptosis nano-drugs is expected to solve these problems. The System xc⁻ transporter, comprising solute carrier family 3 member 2 (SLC3A2) and SLC7A11 subunits, is assembled anchored to the plasma membrane. Here, SLC7A11 serves as the critical effector, facilitating cystine influx essential for GSH biosynthesis [ 240–244 ]. Hence, curbing SLC7A11 expression proves effective in triggering ferroptosis. The realm of System xc- inhibitors features prominently erastin and its derivatives, such as sorafenib, sulfasalazine, glutamate, etc. Dolma et al.’s 2003 research yielded a small molecule exhibiting remarkable selectivity in eradicating engineered tumor cells and named it erastin [ 5 ]. In cells dying induced by erastin, no classic features of apoptosis were found, and this death pathway showed no susceptibility to pharmacological blockade by apoptotic inhibitors [ 245 , 246 ]. Treatment with erastin initiates a cascade beginning with the direct inhibition of System xc-. This restricts cystine availability, causing a significant drop in GSH synthesis. Failing to curb ROS effectively, low GPX4 levels in tumor cells predispose cellular systems to iron-fueled L-ROS amplification, setting off the chain reaction that breaks down polyunsaturated fatty acids [ 247–250 ]. Currently, Pu et al.’s study shows that targeting protein arginine methyltransferase 4 (PRMT4) may be a potential strategy against nasopharyngeal carcinoma, because the enzyme PRMT4 provides a defensive function against erastin-initiated ferroptosis in cisplatin-resistant CNE cells, accomplishing this through transcriptional activation of GPX4 by NRF2 [ 251 ]. Acting upon this premise, Li et al. built bovine serum albumin-stabilized selenium nanoparticles (BSA-SeNPs) functioning as a potent NRF2 activator. This maneuver orchestrated elevated GPX4 expression across mRNA and protein compartments, effectively restraining ROS production during erastin-inflicted ferroptosis. This work opens new avenues for developing anti-ferroptosis treatments [ 252 ]. Supporting this, recent research has shown that Early Growth Response 1 (EGR1) activates the NRF2/HMOX1 pathway in breast cancer, not only curbing proliferation but also sensitizing cells to erastin-triggered ferroptosis [ 253 ]. Conversely, Golgi Phosphoprotein 3 (GOLPH3) overexpression in colorectal cancer promotes cell survival by diminishing susceptibility to erastin-induced ferroptosis, identifying it as a promising molecular target to overcome treatment resistance [ 254 ]. Lei et al.’s research demonstrates that BRCA1 deficiency negates Voltage Dependent Anion Channel 3 (VDAC3) -mediated resistance to erastin-induced ferroptosis, thereby inhibiting GPX4 and rendering cancer cells susceptible to ferroptosis. This study not only elucidates the cascade relationship of the BRCA1/VDAC3/GPX4 pathway in ferroptosis regulation but also pinpoints a potential vulnerability for therapy in BRCA1 -mutant colorectal cancer [ 255 ]. As a result, diminished SLC7A11 function leads to both the halted proliferation and the deliberate execution of ferroptosis in multiple myeloma cells, while long noncoding RNA (lncRNA) is identified as a key regulatory factor. In addition, by activating TP53 , erastin consequently enhances the rate of ferroptosis. This process is because erastin can induce tumor cells to produce ROS, activate TP53 , and then act on downstream pathways. Notably, when TP53 is activated, it triggers an increase in ROS, serving to intensify erastin’s pro-ferroptotic effects in tumor cells [ 256–260 ]. Recent studies have demonstrated that erastin analogs exhibit promising efficacy in inducing ferroptosis and suppressing ferroptosis-related diseases. With relatively stable water solubility and metabolic stability, these compounds demonstrate potent effects, notably their significant capacity to set in motion ferroptosis in tumor cells [ 261–264 ]. According to recent evidence, sorafenib possesses ferroptosis-inducing properties. It achieves this effect primarily by blocking the System xc– transporter, thereby restricting cystine entry into cells. It precipitates a state of ER stress, drastically consumes GSH, and underpins the iron-fueled elevation of lipid-derived ROS. At present, a variety of artificially synthesized small molecule inhibitors have shown potential in research. These inhibitors can specifically act on key proteins or enzymes in the ferroptosis signaling pathway, block the endoplasmic reticulum stress and lipid ROS accumulation caused by sorafenib, and offers a clear path forward for translating our understanding of ferroptosis into revolutionary new treatments [ 182 , 265 , 266 ]. In addition, sulfasalazine can also increase the cell’s ability to take up cystine by acting on the PI3K/AKT/ERK1/2 pathway and the TP53/SLC7A11 pathway, maintain the homeostasis of intracellular GSH, and thus enhance the ferroptosis of rheumatoid arthritis. Forefront research has recently delineated the contributions of ferroptosis to a broad array of clinical and biological conditions. First, central to sulfasalazine’s efficacy in rheumatoid arthritis is a complex regulatory network mediating its effects [ 267 ]. Second, in a seminal study, Wu et al. utilized a murine model to show that BBR triggers ferroptosis in nasopharyngeal carcinoma cells, primarily through the System Xc-/GSH/ GPX4 axis [ 268 ]. They also found that restoring GPX4 expression could rescue cells from this form of death, underscoring its importance in BBR’s ability to curb cancer spread. Third, through a direct molecular assault on the KEAP1 , mangiferin successfully blocks ferroptosis, according to dual in vivo and in vitro evidence. This liberates the NRF2 transcription factor, setting off a protective cascade through SLC7A11 and GPX4 that champions bone formation against osteoporosis [ 269 ]. Fourth, icariin has been shown to reduce ferroptosis in chondrocytes, preventing cartilage degradation via the SLC7A11/GPX4 axis. These distinct studies consistently identify the SLC7A11/GPX4 pathway as a critical lever for controlling ferroptosis [ 270 ]. Although System xc- inhibitors have shown good effects in inhibiting diseases, there are no inhibitors of this type applied in the field of gynecological diseases. GPX4 falls under the umbrella of the glutathione peroxidase (GPx) family and exists as a dimeric enzyme consisting of two protein subunits, each containing about 205 amino acids. Its molecular weight is about 19 kDa, composed of about 170 amino acids. In mammals, there are multiple isoforms of the enzyme, which are fundamental to sustaining cellular redox balance and fortifying cells to withstand damage from oxidative stress [ 271–274 ]. In 2014, research on targeted metabolomics revealed that both enhancing and suppressing GPX4 expression effectively mitigated the lethal effects of 12 distinct ferroptosis inducers on cells, characterizing GPX4 as a principal regulator of ferroptosis [ 275 ]. Compounds targeting GPX4 —containing RAS-selective lethal 3 (RSL3) , Fertility inhibition protein (FINO2) , and ML162 —directly or indirectly impede GPX4 function, triggering ferroptosis characterized by elevated ROS production and intracellular peroxide accumulation [ 276–281 ]. Concurrently, endogenous metabolic enzymes contribute to ferroptosis regulation. Notably, cysteine/cystine-metabolizing enzymes deplete serum cysteine/cystine pools, limiting GSH biosynthesis substrates and thereby suppressing GPX4 activity to induce ferroptosis [ 282–285 ]. Statins like simvastatin and fluvastatin similarly promote tumor cell ferroptosis through transcriptional repression of GPX4 [ 286–289 ]. Natural compounds exhibit potent ferroptosis-modulatory effects via GPX4 inhibition. By downregulating GPX4 , Curcumin provokes autophagy-mediated ferroptosis in non-small cell lung cancer cells, ultimately curbing tumor development [ 290 ]. Similarly, boswellia carterii n-hexane extract (BCHE) exerts its cytotoxic effects on tumor cells in breast cancer by enhancing transferrin synthesis and Fe²⁺ accumulation, concomitantly repressing GPX4 to exacerbate ROS-induced lipid peroxidation and ferroptosis [ 291 ]. Emerging evidence highlights botanical agents such as baicalein, salidroside, and quercitrin, which disrupt GPX4 -catalyzed lipid repair pathways to selectively induce cancer cell ferroptosis with negligible toxicity [ 292–297 ]. Currently, it has also been found that vitamin K2 shows its anti-osteoarthritis (OA) efficacy through a dual-target regulation mechanism. On the one hand, it proficiently antagonizes the activation of the MAPK/ NF-κB signaling cascade – triggered by reduced GPX4 expression – thereby delaying the catabolic progression of the extracellular matrix. On the other hand, vitamin K₂ mitigates the inhibitory impact of RSL3 on GPX4 function, allowing the ferroptosis process to proceed smoothly [ 298 ]. Covalent targeting of selenocysteine residues, achieved through alkyl chloride activation, defines the mechanism of existing GPX4 inhibitors, all of which are alkylating agents. However, the prevailing strategy among existing GPX4 inhibitors involves alkylation: reactive alkyl chlorides covalently engage selenocysteine residues, which greatly limits the clinical application of most GPX4 inhibitors. In a pioneering study, Li’s lab reported that treatment with BSA-SeNPs powerfully activates NRF2 , consequently eliciting an increase in the antioxidant enzyme GPX4 across both its mRNA and protein forms, effectively counteracting ROS accumulation during erastin-triggered ferroptosis [ 252 ]. This contributes new perspectives for engineering GPX4 inhibitors. Ferroptosis is initiated and sustained by two core alterations: massive iron accumulation within the cell, which fuels widespread lipid peroxidation. To prevent this, a class of compounds known as ferroptosis inhibitors is used. They work either by capturing free radicals, blocking the production of lipid peroxides, or removing free iron [ 299 , 300 ]. This diversity in their functional approach leads to their main classification into two categories: iron ion chelators and lipid peroxidation regulators. Ferrostatin-1 (Fer-1) is a potent and highly selective blocker of ferroptosis. Data collected from multiple studies validate that Fer-1 blocks iron accumulation in spinal anterior horn neurons by activating the ERK1/2/Specificity Protein 1 (SP1)/GPX4 signaling cascade. This mechanism plays a significant role in improving neural function injury and blood spinal cord barrier (BSCB) damage in rats after spinal ischemia reperfusion injury (SCIRI). Per experimental studies ( in vivo/in vitro ) by He et al. Fer-1 inhibits angiotensin II-induced ferroptosis in vascular smooth muscle cells (VSMCs) via SLC7A11/GPX4 pathway activation, thereby delaying abdominal aortic aneurysm (AAA) formation and preserving vascular wall integrity [ 301 ]. Within a mouse model system simulating LPS-driven lung injury, Fer-1 exhibits inhibitory effects on lipid peroxidation [ 301 ]. Emerging research further reveals that Fer-1 ameliorates neuronal ferroptosis caused by hypoxic-ischemic brain damage (HIBD) by suppressing erastin-driven ROS generation and oxidative stress [ 302 ]. Additionally, selective ferroptosis inhibition has been shown to reverse the cytotoxic effects of isoflurane and other anesthetics on astrocytes, alleviating prolonged isoflurane-induced cognitive impairment and potentially addressing neonatal cognitive dysfunction [ 303 ]. These findings underscore Fer-1’s robust suppression of lipid peroxidation across diverse ferroptotic stimuli. Structural analogs of Fer-1, such as SRS11-92 and SRS11-86 , offer enhanced stability and superior tissue-protective capabilities [ 304 , 305 ]. For instance, SRS11-92 confers neuroprotection by inhibiting NRF2 -mediated oxidative stress and ferroptosis [ 306 ]. Liproxstatin-1 (Lip-1), a spiroquinoxaline amine compound, reduces ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) primarily by targeting EGR1 to suppress ferroptosis and subsequent inflammatory factor release [ 307 ]. Similarly, Lip-1 can also alleviate ischemia-reperfusion injury induced by lung transplantation by inhibiting ferroptosis [ 308 ]. The exacerbation of acute pancreatitis (AP) by hypertriglyceridemia (HTG) is well-documented, particularly through an inflammatory response intrinsically connected to ferroptosis. Targeting this axis, Lip-1 exerts its therapeutic effect via lipid metabolism regulation, which restrains ferroptosis and ultimately preserves pancreatic integrity [ 309 ]. Furthermore, experimental findings demonstrate that Lip-1 downregulates ferroptosis-related proteins such as ACSL4 and TP53 , alongside modulating time-restricted feeding. Concurrently, treatment maintains mitochondrial structural integrity and functional capacity, accompanied by reduced cellular lipid peroxidation and ROS generation [ 310 ]. Supporting its cardioprotective role, Lip-1 has been empirically validated to relieve hypertensive heart damage, fibrotic progression, and adverse cardiac remodeling. This protection operates via augmented GPX4 signal transduction, effective ferroptosis clearance, and constrained lipid peroxidation [ 311 , 312 ]. Collectively, these discoveries provide novel insight into ferroptosis regulatory mechanisms and highlight promising targets for developing therapies against ferroptosis-associated pathologies. Iron chelators exert their primary function by sequestering excess cellular iron. This binding action prevents iron from donating electrons to oxygen species, thereby cutting down on highly reactive hydroxyl radical generation. By curbing this fenton reaction, iron chelators effectively suppress ferroptosis [ 313–315 ]. New research has revealed that iron chelators, by targeting viral iron-dependent mechanisms, modulating host immunity, and influencing cell death pathways, have demonstrated broad-spectrum antiviral potential. With advancements in targeted delivery technologies and deeper mechanistic insights, they are poised to become a novel tool in antivirus therapy, particularly in combating drug-resistant viruses or severe infections, where they could play a unique role [ 316 ]. Iron chelators have demonstrated significant potential in slowing the neurodegenerative progression of Alzheimer’s Disease (AD) by chelating abnormally deposited iron ions in the brain, inhibiting oxidative stress responses, and reducing pathological protein accumulation, thereby offering a novel therapeutic strategy for AD intervention [ 317–321 ]. Cutting-edge research has shown that polydopamine nanoparticles (PDA NPs) offer a promising therapeutic strategy against intervertebral disc degeneration. They combat ferroptosis through a multifaceted approach: they chelate iron ions, scavenge ROS, and inhibit the ubiquitination of GPX4 . This action leads to the upregulation of cellular antioxidant pathways [ 322 ]. Deferoxamine (DFO), an iron chelator with poor membrane permeability, accumulates in lysosomes via endocytosis and interacts with them, intercepting iron ions that should be transported to other parts, thereby preventing the generation of lipid active oxygen species [ 323–325 ]. Nevertheless, the abbreviated plasma half-life of deferoxamine necessitates repeated dosing regimens, thereby predisposing patients to side effects. To address this issue, a team from Harvard Medical School developed a novel DFO nano chelator that provides sustained release over two weeks [ 326 , 327 ]. Deferiprone (DFP) combats oxidative stress by chelating intracellular iron, promoting disease regression in various pathologies [ 328–332 ]. Notably, Ye et al. employed a mouse model to demonstrate DFP’s capacity to inhibit retinal ferroptosis, preserve retinal structure/function, and provide therapy for retinal detachment [ 333 ]. Additionally, studies have found that DFP reduces neuronal ferroptosis and alleviates neurological dysfunction through the N-myc downstream regulates gene-1 (NDRG1)/YAP signaling pathway, offering a potential non-invasive treatment for patients with brain injury following intracranial hemorrhage [ 334 ].

Recent years have seen a growing recognition of ferroptosis as a clinically significant player in the complex processes underlying numerous diseases. Its role in the development, worsening, and treatment of conditions ranging from neurodegenerative diseases and cancers to strokes, brain trauma, organ injury, and liver and kidney failure is now becoming increasingly clear [ 335–341 ]. As research progresses, the important role of ferroptosis in gynecological diseases has increasingly attracted the attention of scientists ( Figure 2 ). However, compared to other diseases, the crucial mechanisms linking ferroptosis to gynecological disorders are not yet well elucidated. This might be limited by the scarcity of in situ animal models for gynecological diseases and the relatively weak foundational research in this area. Ferroptosis research in gynecology is currently at an early but promising stage. Unraveling the complex mechanisms and identifying the core regulatory nodes of ferroptosis during the development and advancement of gynecological diseases presents a significant opportunity for both theoretical advancement and clinical innovation. State-of-the-art methodologies, including single-cell RNA sequencing, open chromatin sequencing at the single-cell level, and spatial transcriptomic analysis, are now available to propel this field forward. These technologies help us better understand the ferroptosis related changes at the single cell level in gynecological diseases, thereby accelerating the resolution of key mechanisms of ferroptosis in these conditions [ 342–348 ]. The primary signaling pathways of ferroptosis: System Xc-, a heterodimer consisting of SLC7A11 and SLC3A2 , performs a cystine/glutamate antiport function across the plasma membrane. Cystine is vital for GSH synthesis. Inhibiting GPX4 or having low GSH leads to lipid peroxide buildup, membrane damage, and ferroptosis, releasing ROS and increasing oxidative stress. Genes like TP53 and RBM3 inhibit SLC7A11 expression, promoting ferroptosis. Although many basic studies have reported that ferroptosis regulators show certain effects at the cellular and animal levels, these compounds mainly face several problems, such as poor physical and chemical properties, suboptimal pharmacokinetics, characterized by systemic exposure and associated toxicity, rapid clearance from the body, insufficient distribution to target areas, and an inability to exert strong ferroptosis induction or modulation ( Table 6 ). These compounds often have poor draggability, leading to subpar clinical applications. Presently, a significant emphasis in clinical translation lies on the development of agents capable of specifically targeting ferroptosis. In recent years, advances in nanotechnology and related targeted drug delivery modalities have emerged as potent enablers for creating novel ferroptosis regulators. Notably, nano-drug delivery systems effectively overcome pharmacokinetic hurdles, including limited aqueous solubility and impaired membrane penetration, to facilitate site-specific accumulation [ 349–354 ]. The strides made hold substantial promise for the eventual clinical deployment of ferroptosis-modulating compounds to combat gynecological disorders. Research progress on ferroptosis in gynecological diseases.