Research progress and potential therapeutic targets of a novel disulfide stress-driven cell death-disulfidptosis in gynecological tumors and other gynecological disorders

Abstract

Disulfidptosis is a novel Nicotinamide Adenine Dinucleotide Phosphate (NADPH) deficiency-driven cell death pathway characterized by cystine overload and aberrant disulfide bond formation in actin cytoskeletal proteins, distinct from apoptosis, ferroptosis, and other programmed cell death modalities. In gynecological tumors (ovarian, cervical, and endometrial cancers), this process is orchestrated by dysregulated SLC7A11 expression, impaired thioredoxin system function, and Rac-WRC-Arp2/3-mediated actin network collapse. Bioinformatic analyses of The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) datasets have revealed that disulfidptosis-related genes (e.g., SLC7A11, GYS1, NCKAP1) and lncRNAs (e.g., PRDX6-AS1, EMSLR) correlate with patient prognosis, chemoresistance, and tumor immune microenvironment (TME) remodeling. Therapeutic strategies to induce disulfidptosis include glucose deprivation to limit NADPH supply, inhibition of NADPH-generating enzymes (e.g., G6PD inhibition), and nanodelivery systems (e.g., FeOOH@Fe-Ap@Au) that synchronize disulfidptosis with ferroptosis. Preliminary evidence proposes that disulfidptosis inducers may synergize with immune checkpoint inhibitors (ICIs) through TME modulation, though experimental validation remains ongoing. Beyond malignancies, disulfidptosis-related pathways have been implicated in endometriosis, where disulfidptosis-related genes (DRGs; e.g., PDLIM1, ACTB) regulate ectopic lesion progression via immune-metabolic crosstalk. This review comprehensively summarizes the molecular mechanisms, disease associations, and translational potential of disulfidptosis in gynecological disorders, proposing targeted therapeutic paradigms and future research directions.

Introduction

Gynecological malignancies, including ovarian, cervical, and endometrial cancers, represent a major global health burden due to their high incidence, aggressive progression, and frequent recurrence. Among these, ovarian cancer exhibits the highest mortality rate, with a five-year survival rate below 50% in advanced-stage patients [1,2]. Meanwhile, cervical and endometrial cancers collectively account for over 1.2 million new cases worldwide each year [3]. Despite advancements in surgery, chemotherapy, and targeted therapies, intrinsic and acquired drug resistance remains major obstacles to improving patient outcomes [4,5]. Additionally, the immunosuppressive tumor immune microenvironment (TME) further limits the therapeutic efficacy of immunotherapy in gynecological cancers [6]. Therefore, elucidating novel cell death mechanisms to overcome therapeutic resistance is crucial for developing next-generation treatment strategies.

Disulfidptosis, a recently identified form of programmed cell death driven by disulfide stress, has emerged as a promising therapeutic target in cancer biology [7]. First described by Liu et al. in 2023, this process occurs when glucose deprivation induces nicotinamide adenine dinucleotide phosphate (NADPH) depletion, thereby impairing the conversion of cystine to cysteine in solute carrier family 7 member 11 (SLC7A11)-high cells. This results in aberrant disulfide bond formation within actin cytoskeletal proteins and subsequent cytoskeletal collapse [8]. Distinct from apoptosis, ferroptosis, or pyroptosis, disulfidptosis uniquely integrates amino acid metabolism (cystine transport), redox homeostasis (NADPH/thioredoxin system), and cytoskeletal dynamics (Rac-WAVE regulatory complex (WRC)-Actin-Related Protein 2/3 (Arp2/3) pathway) [9]. Notably, gynecological cancers frequently overexpress SLC7A11 to sustain glutathione (GSH) synthesis and maintain redox balance [10,11], rendering them particularly vulnerable to disulfidptosis induction under metabolic stress. Beyond malignancies, dysregulated disulfidptosis has also been implicated in endometriosis (EMs), a benign yet metabolically dysregulated and invasive gynecological disorder [12-14].

This review systematically summarizes the mechanistic basis, pathophysiological roles, and therapeutic implications of disulfidptosis in gynecological diseases, highlighting its potential to reshape precision oncology frameworks and guide innovative combination therapies.

The core mechanisms and regulatory pathways of disulfidptosis

Cystine accumulation induces aberrant disulfide bond formation in cytoskeletal proteins

Disulfidptosis is a newly identified form of programmed cell death triggered by the accumulation of aberrant intracellular disulfide bonds. Its central mechanism centers on cystine overload and subsequent disulfide crosslinking within cytoskeletal proteins.

NADPH depletion and cystine accumulation

Studies have revealed that under specific conditions such as glucose starvation - a major source of cellular NADPH - cells with high SLC7A11 expression exhibit excessive cystine uptake. Cystine serves as a critical precursor for GSH synthesis, aiding in oxidative stress resistance. However, the reduction of cystine to its active form, cysteine, is an NADPH-dependent process. When NADPH levels decline (e.g., during glucose deprivation), cystine reduction becomes impaired, resulting in its intracellular accumulation [8]. Further research has identified thioredoxin-related protein of 14 kDa (TRP14) as a key enzyme catalyzing cystine reduction, which depends on the NADPH-dependent thioredoxin reductase (TrxR) system to maintain its reduced state [15]. Thus, either NADPH deficiency or direct TrxR inhibition disrupts cystine-to-cysteine conversion, promoting cystine accumulation and subsequent disulfidptosis [15,16].

Aberrant disulfide bond formation in cytoskeletal proteins

Accumulated cystine induces “disulfide stress”, characterized by excessive formation of abnormal intra- or inter-protein disulfide bonds in the cytosol. Using bioorthogonal chemical proteomics, Liu et al. demonstrated that in glucose-deprived, SLC7A11-high cells, proteins undergoing aberrant disulfide modifications were predominantly enriched in pathways related to the actin cytoskeleton and cell adhesion [8]. This finding highlights the cytoskeletal system as a primary target of disulfide stress.

The critical role of the Rac-WRC-actin network in the execution of cell death

Genome-wide CRISPR-Cas9 screening identified NCK-associated protein 1 (NCKAP1) and its associated WAVE regulatory complex (WRC) as essential promoters of disulfidptosis [8]. NCKAP1 is a core component of WRC, which activates the actin-related protein 2/3 (Arp2/3) complex to mediate branched actin polymerization and lamellipodia formation - a process regulated by Rac signaling [17]. Functional studies confirmed that knockout of NCKAP1 or other WRC components significantly alleviated disulfidptosis, whereas overexpression of constitutively active Rac enhanced disulfidptosis in a WRC-dependent manner [8]. It is hypothesized that the Rac-WRC-driven branched actin network forms a structural scaffold, which facilitates abnormal disulfide crosslinking among actin cytoskeletal proteins [8]. These aberrant disulfide bonds disrupt actin cytoskeletal dynamics and functional integrity, ultimately leading to cell death.

Summary of the core mechanism

Under conditions of NADPH deficiency (e.g., glucose starvation) or thioredoxin system inhibition (e.g., via TrxR inhibitors), the reduction of cystine to cysteine is impaired in SLC7A11-high cells, leading to cystine accumulation and disulfide stress. The primary targets of disulfide stress are cytosolic actin networks, particularly the branched actin filaments regulated by Rac-WRC signaling. Aberrant disulfide crosslinking within these cytoskeletal proteins disrupts their structural and functional integrity, executing disulfidptosis (Figure 1).

Figure 1.

Summary of the Core Mechanism in Disulfidptosis. Disulfidptosis is triggered by NADPH depletion under conditions such as glucose starvation or SLC7A11 overexpression, leading to disrupted cellular redox balance. The reduction in cystine-to-cysteine and NADPH regeneration via the pentose phosphate pathway (PPP) are disrupted, resulting in excessive disulfide bond formation in actin cytoskeleton components (e.g., Arp2/3 and actin-associated proteins). The accumulation of aberrant disulfide crosslinks disrupts lamellipodia structure and induces cytoskeletal collapse.

Regulatory pathways governing key signaling networks in disulfidptosis susceptibility

Cellular susceptibility to disulfidptosis is precisely regulated by multiple signaling pathways, primarily involving SLC7A11 expression, NADPH homeostasis, and actin cytoskeletal dynamics.

Regulatory pathways controlling SLC7A11 expression

As the functional subunit of the cystine/glutamate antiporter system xCT, SLC7A11 serves as a pivotal determinant of cellular sensitivity to disulfidptosis. Its expression is tightly controlled by the following key transcription factors:

Activating transcription factor 4 (ATF4)

ATF4 is activated under stress conditions and binds to amino acid response elements (AARE) within target gene promoters. It directly upregulates SLC7A11 and other stress-responsive genes, thereby enhancing cystine uptake and antioxidant capacity. However, this compensatory mechanism paradoxically increases cellular susceptibility to disulfidptosis [18,19].

Nuclear factor erythroid 2-related factor 2 (Nrf2)

Nrf2, a master regulator of antioxidant responses, is normally maintained at low levels through Kelch-like ECH-Associated Protein 1 (KEAP1)-mediated ubiquitination and degradation. Oxidative stress disrupts this process, stabilizing Nrf2 and promoting its binding to antioxidant response elements (ARE), thereby upregulating SLC7A11 and other cytoprotective genes. While this enhances redox resilience, excessive Nrf2 activation may also elevate disulfidptosis vulnerability [20].

Tumor suppressor p53

p53 directly binds to the promoter region of SLC7A11 and suppresses its transcription [21]. This p53-mediated downregulation is a well-established mechanism for inhibiting ferroptosis, while simultaneously reducing disulfidptosis propensity.

Metabolic and energy-sensing pathways

AMP-activated protein kinase (AMPK), a central cellular energy sensor, plays a critical role in maintaining NADPH homeostasis. Under metabolic stress (e.g., glucose deprivation), AMPK activation helps sustain NADPH levels and promotes tumor cell survival [22]. Notably, LKB1-mutant lung cancer cells (e.g., H460) exhibit heightened sensitivity to glucose deprivation-induced cell death, which has been speculated to represent disulfidptosis [23]. These findings suggest that LKB1-AMPK pathway inactivation, by disrupting NADPH homeostasis, significantly enhances disulfidptosis susceptibility. Thus, concurrent targeting of glucose metabolism and AMPK signaling may synergistically induce disulfidptosis, offering a potential therapeutic strategy for cancer treatment.

Redox regulatory pathways

As previously discussed, the Thioredoxin (Trx) system (comprising TrxR and Trx) is essential for reducing cystine to cysteine (via TRP14) and correcting aberrant protein disulfide bonds within cytosolic proteins [15,16,24,25]. Consequently, TrxR inhibition (impairing NADPH-dependent reducing capacity) or direct Trx dysfunction effectively triggers disulfidptosis [16,26,27]. While upstream regulators of the Trx system (e.g., PI3K-AKT [28] or Toll-like receptor signaling [29]) may indirectly modulate disulfidptosis susceptibility, further experimental validation is required.

Actin cytoskeletal regulatory pathways

As outlined in the core mechanism, Rac GTPase activates the WRC, which in turn stimulates the Arp2/3 complex to drive branched actin polymerization and lamellipodia formation. This pathway not only executes disulfidptosis by providing scaffolds for aberrant disulfide crosslinking but also dictates its intensity [8,30]. Thus, upstream pathways regulating Rac activity or WRC assembly/function (e.g., growth factor receptor or integrin signaling) may theoretically influence disulfidptosis progression, representing promising research avenues and therapeutic targets.

Summary of regulatory pathways

Cellular sensitivity to disulfidptosis is governed by a multi-layered regulatory network. The expression level of SLC7A11 is directly modulated by key transcription factors, including ATF4 (which promotes expression) and p53 (which inhibits expression), while Nrf2 indirectly influences its expression through antioxidant programs.

As a sensor of cellular energy and metabolism, the AMPK pathway plays a crucial cytoprotective role by maintaining NADPH homeostasis. Inactivation of this pathway (e.g., through LKB1 mutations) disrupts redox balance and markedly enhances susceptibility to disulfidptosis. Direct inhibition of the Trx system, a core redox-regulating mechanism responsible for cystine reduction and repair of protein disulfide bonds, effectively induces disulfidptosis. Finally, the Rac-WRC-Arp2/3-mediated actin cytoskeleton remodeling pathway determines the efficiency of disulfidptosis execution. This pathway orchestrates actin cytoskeletal remodeling and provides the structural framework for aberrant disulfide bond formation. Collectively, inhibitors targeting these pathways, either alone or in combination with other therapeutic strategies (such as glucose deprivation and TrxR inhibitors), hold promise for inducing disulfidptosis in tumor cells and enhancing antitumor efficacy.

Comparing disulfidptosis with other programmed cell death pathways

The discovery of disulfidptosis introduces a novel form of metabolic stress-induced programmed cell death that is mechanistically distinct from classical pathways such as apoptosis and pyroptosis. The following sections systematically compare disulfidptosis with other well-established cell death modalities, focusing on definitions, molecular mechanisms, morphological hallmarks, and potential crosstalk.

Apoptosis

Apoptosis, first described in 1972, represents the earliest recognized form of genetically regulated cell death responsible for eliminating superfluous cells to maintain tissue homeostasis [31,32].

The process can be initiated via extrinsic (death receptor) or intrinsic (mitochondrial) pathways, ultimately leading to the activation of a caspase cascade and DNA fragmentation [33,34].

Morphologically, apoptotic cells exhibit characteristic features such as cell shrinkage, chromatin condensation, and apoptotic body formation without provoking inflammation [35].

In contrast, disulfidptosis is driven by cytoskeletal disulfide crosslinking under metabolic stress, without caspase involvement [8,34]. Their regulatory networks are independent, though oxidative stress (e.g., NADPH depletion) may intersect both pathways by simultaneously impairing apoptosis repair while promoting disulfidptosis [8,36]. Although both apoptosis and disulfidptosis can be initiated under cellular stress, apoptosis is caspase-dependent and nuclear-centered, whereas disulfidptosis is caspase-independent and primarily cytoskeleton-centered.

Ferroptosis

Ferroptosis, first defined in 2012, is an iron-dependent form of regulated cell death triggered by lipid peroxide accumulation [37].

The process is initiated by inhibition of SLC7A11, leading to GSH depletion, subsequent inactivation of Glutathione Peroxidase 4 (GPX4), and iron-catalyzed lipid peroxidation via Fenton reactions [38,39].

Morphologically, ferroptotic cells exhibit reduced mitochondrial cristae, increased membrane density, while lacking classical apoptotic/necrotic features [40].

Notably, while both ferroptosis and disulfidptosis are closely linked to SLC7A11 regulation, they exhibit opposing dependencies. SLC7A11 downregulation promotes ferroptosis but suppresses disulfidptosis, whereas its upregulation inhibits ferroptosis while sensitizing cells to disulfidptosis [18]. Mechanistically, ferroptosis is characterized by lipid peroxidation-driven membrane damage, while disulfidptosis is defined by cytoskeletal disulfide crosslinking and structural collapse [8,40].

Despite these distinctions, both processes share common upstream regulators associated with oxidative stress and metabolic imbalance. For instance, both modalities are influenced by intracellular NADPH levels and the redox status of SLC7A11-high tumor cells. Under glucose deprivation, NADPH depletion not only enhances cell susceptibility to disulfidptosis but also indirectly amplifies lipid peroxidation and ferroptotic responses [18]. Furthermore, recent studies suggest that therapeutic interventions targeting SLC7A11 or NADPH-generating metabolism may simultaneously modulate ferroptosis and disulfidptosis, highlighting their functional interconnection [41]. Therefore, among all known programmed cell death types, ferroptosis represents the most biologically and therapeutically relevant pathway for comparison with disulfidptosis (Figure 2).

Figure 2.

Comparison between disulfidptosis and ferroptosis. Both ferroptosis and disulfidptosis are NADPH-dependent forms of cell death but act through distinct molecular mechanisms. Ferroptosis is characterized by lipid peroxidation and ROS accumulation, leading to plasma membrane rupture. In contrast, disulfidptosis is caused by glucose starvation - induced NADPH depletion, which causes abnormal disulfide crosslinking of actin mcytoskeletal proteins, resulting in actin network collapse and subsequent plasma membrane disruption.

Pyroptosis

Pyroptosis is an inflammatory form of programmed death activated by pathogens or damage signals, leading to the release of pro-inflammatory cytokines [42].

The molecular mechanism involves caspase-1 (canonical) or caspase-4/5/11 (non-canonical) cleaving Gasdermin D (GSDMD) to form plasma membrane pores, thereby facilitating the release of interleukin (IL)-1β/IL-18 [42,43].

Morphologically, pyroptosis is characterized by cell swelling, membrane rupture, and massive cytokine release [42]. In contrast to pyroptosis which is immunologically triggered and highly inflammatory [44], disulfidptosis occurs independently of inflammasome activation or GSDMD cleavage. The two processes are morphologically distinct - pyroptosis features membrane pores formation, whereas disulfidptosis features cytoskeletal collapse. Despite their shared rapid kinetics [41], pyroptosis represents an immunogenic, cytokine-releasing death mode, while disulfidptosis proceeds in a non-inflammatory and metabolically driven manner.

Necroptosis

Necroptosis is a form of regulated necrotic death mediated by the tumor necrosis factor (TNF)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) signaling [45]. Its execution mechanism involves RIPK1/RIPK3-mediated phosphorylation of MLKL to form membrane pores, while phosphoglycerate mutase family member 5 (PGAM5) simultaneously promotes mitochondrial fragmentation [46-48].

Morphologically, necroptosis is characterized by organelle swelling, loss of membrane integrity, and subsequent release of inflammatory intracellular contents [49]. Unlike necroptosis, which depends on kinase cascades (RIPK1-RIPK3-MLKL), disulfidptosis occurs independently of this pathway. Although both death modalities lead to cellular structural collapse, disulfidptosis distinctly lacks MLKL-mediated membrane perforation [50]. Necroptosis and disulfidptosis both culminate in structural collapse of the cell, but necroptosis is kinase-driven (RIPK1-RIPK3-MLKL), whereas disulfidptosis bypasses kinase cascades and relies on disulfide stress.

Autophagy

Autophagy is a lysosomal-dependent degradation pathway (officially classified in 2013) essential for maintaining cellular homeostasis [51]. The process is initiated by activation of the Unc-51-like autophagy activating kinase 1 (ULK1) complex, which triggers autophagosome formation. During this process, microtubule-associated protein 1A/1B light chain 3 (LC3)-II-labeled membranes encapsulate cytoplasmic components, which are subsequently degraded following fusion with lysosomes [52,53].

Morphologically, autophagy is characterized by the formation of double-membrane autophagosomes without evidence of acute membrane damage [54]. Unlike disulfidptosis, autophagy exhibits context-dependent dual functionality, serving either pro-survival or pro-death roles. While autophagy requires lysosomal function and the participation of autophagy-related gene (ATG) products, disulfidptosis is driven by disulfide stress. Notably, under glucose starvation, these pathways may compete - autophagy attempts metabolic rescue to counteract the lethal effects of disulfidptosis [55]. Autophagy may act as a survival attempt under glucose starvation, counteracting metabolic stress, while disulfidptosis represents an irreversible cytoskeletal collapse under the same conditions.

Alkaliptosis

Alkaliptosis, first characterized in 2018, is a pH-dependent death triggered by intracellular alkalinization [56]. The underlying mechanism involves JTC801-mediated activation of the IKBKB-NF-κB pathway, leading to downregulation of carbonic anhydrase IX (CA9) and consequent sustained alkaline conditions [57].

Morphologically, alkaliptotic cells exhibit plasma membrane damage associated with prolonged intracellular alkalinization [58]. Distinct from disulfidptosis, which is characterized by redox imbalance, alkaliptosis primarily results from dysregulation of pH homeostasis. Although both represent metabolic stress-induced cell death, they operate through fundamentally different mechanisms: alkaliptosis is driven by CA9 downregulation and intracellular alkalinization, whereas disulfidptosis arises from the SLC7A11-NADPH axis leading to aberrant disulfide bond accumulation.

Oxeiptosis

Oxeiptosis, first described in 2018, is a reactive oxygen Species (ROS)-induced apoptosis-like death [59]. The process is initiated when elevated ROS levels trigger KEAP1 mitochondrial translocation, which subsequently activates the PGAM5-Apoptosis-Inducing factor mitochondrial associated 1 (AIFM1) axis, leading to nuclear condensation and cell death [60].

Morphologically, oxeiptotic cells exhibit chromatin condensation without fragmentation and prominent mitochondrial swelling [61]. Unlike disulfidptosis, oxeiptosis specifically depends on the KEAP1-PGAM5-AIFM1 signaling cascade and mitochondrial dysfunction [62]. Although both pathways are associated with oxidative stress, they target distinct cellular components: oxeiptosis primarily affects DNA and mitochondria, whereas disulfidptosis specifically disrupts the actin cytoskeleton.

In summary, both oxeiptosis and disulfidptosis are ROS-associated forms of programmed cell death; however, oxeiptosis is mediated by the KEAP1-PGAM5-AIFM1 axis and targets mitochondria, while disulfidptosis specifically disrupts cytoskeletal integrity.

NETosis

NETosis, first described in 2004, is a neutrophil-specific form of cell death characterized by the release of neutrophil extracellular traps (NETs) that entrap and neutralize pathogens [63]. The underlying mechanism depends on ROS generated by nicotinamide adenine dinucleotide phosphate oxidase (NOX), which activates peptidylarginine deiminase 4 (PAD4) to decondense chromatin and facilitate NETs release [64].

Morphologically, NETosis is defined by nuclear membrane dissolution with subsequent chromatin extrusion [65]. In contrast to disulfidptosis, NETosis serves as an immune defense mechanism with distinct biological functions. Interestingly, both processes involve NADPH metabolism but in opposing ways: NETosis utilizes NADPH to fuel ROS production via NOX for antimicrobial defense, whereas disulfidptosis requires NADPH for disulfide reduction. While NETosis and disulfidptosis both engage NADPH-dependent metabolism, NETosis uses NADPH oxidase to generate ROS for antimicrobial defense, whereas disulfidptosis depends on NADPH for maintaining cystine reduction and redox balance.

Lysosome-dependent cell death

Lysosomal-dependent cell death, first characterized in 2000, is a cell death initiated by lysosomal membrane rupture [66]. The molecular mechanism involves ROS accumulation and calcium (Ca²⁺) overload, which induce lysosomal membrane permeabilization (LMP). This event leads to the release of cathepsins that either activate caspase cascades or directly degrade cellular membranes [66].

Morphologically, this process is characterized by lysosomal enzyme leakage that ultimately leads to complete membrane collapse [31]. Unlike disulfidptosis, lysosomal cell death specifically requires cathepsin release and caspase activation [67]. While both pathways culminate in cellular structural failure, they target distinct cellular components: lysosomal cell death primarily affects membrane systems, whereas disulfidptosis specifically disrupts the cytoskeleton. Both lysosome-dependent cell death and disulfidptosis are stress-induced, but the former is executed by lysosomal enzyme release, while the latter depends on actin cytoskeleton disulfide crosslinking.

Parthanatos

Parthanatos, first identified in 2009, is a Poly (ADP-Ribose) polymerase-1 (PARP-1)-mediated, DNA damage-dependent cell death [68]. The molecular mechanism involves PARP-1 overactivation in response to severe DNA damage, leading to depletion of cellular NAD+ levels, leading to nuclear translocation of apoptosis-inducing factor (AIF) and subsequent DNA degradation [69].

Morphologically, parthanatos is characterized by chromatin dispersion and mitochondrial vacuolization [70]. Distinct from disulfidptosis, parthanatos specifically centers on PARP-1/AIF-mediated nuclear damage. Although both cell death pathways deplete cellular NADPH pools, they target different molecular forms: parthanatos primarily consumes NAD+ [71], whereas disulfidptosis specifically requires NADPH reduction.

Crosstalk and integration

Despite their distinct molecular mechanisms, disulfidptosis intersect with other forms of regulated cell death under specific conditions:

The SLC7A11 transporter acts as a critical molecular switch governing cell fate: its downregulation predisposes cells to ferroptosis, whereas its upregulation under glucose deprivation conditions promotes disulfidptosis [72,73]. Under metabolic stress, glucose starvation not only triggers disulfidptosis but also suppresses ATP production, thereby activating compensatory autophagy or necroptosis pathways and establishing an integrated metabolic stress-response network [74,75].

Oxidative stress also functions as a central regulatory hub: ROS accumulation can drive disulfidptosis (via disulfide formation) [76] while also activating apoptosis, autophagy, or ferroptosis [77], suggesting ROS as a common upstream regulator.

In summary, the discovery of disulfidptosis expands the current landscape of regulated cell death. Comparative analyses reveal that cells employ context-dependent signaling hierarchies to determine death modality in response to diverse stressors (e.g., metabolic, inflammatory, and oxidative stimuli), offering novel therapeutic avenues.

Disulfidptosis in gynecological cancers

Current research landscape of disulfidptosis in gynecological malignancies

Cervical cancer

Compelling in vitro evidence supports the existence of disulfidptosis in cervical cancer. Jin et al. demonstrated that among various cell death inhibitors tested (e.g., ferroptosis inhibitor ferrostatin-1, apoptosis inhibitor Z-VAD-fmk, necroptosis inhibitor necrostatin-1, autophagy inhibitor chloroquine, antioxidant Trolox, and reducing agent Dithiothreitol (DTT)), only DTT completely rescued glucose deprivation-induced cell death in SiHa and HeLa cells. Notably, SLC7A11 knockout abolished this effect, confirming disulfidptosis as the dominant death mechanism under glucose starvation [78].

Bioinformatic analyses of The Cancer Genome Atlas (TCGA) Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) cohort and Gene Expression Omnibus (GEO) datasets have revealed that several disulfidptosis-related genes (DRGs; e.g., SLC7A11, NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11 (NDUFA11), BRICK1 subunit of SCAR/WAVE actin nucleating complex (BRK1), Ras-related C3 botulinum toxin substrate 1 (RAC1), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG)) are dysregulated in cervical cancer and correlate with patient survival. Among these, SLC7A11 promotes cell proliferation, migration, and invasion, with high expression levels associated with poor prognosis and altered immune cell infiltration (e.g., NK cells, macrophages) in the TME [79]. YWHAG, an oncogenic scaffold protein, is overexpressed in cervical cancer, enhancing tumor progression by facilitating proliferative and migratory capacities [78].

Prognostic models incorporating DRGs or disulfidptosis-related lncRNAs have demonstrated strong predictive value in stratifying patients into high- and low-risk groups with distinct responses to chemotherapy (e.g., cisplatin) and immunotherapy. Machine learning identified BRK1, NDUFA11, RAC1, and NADH dehydrogenase (ubiquinone) Fe-S Protein 1 (NDUFS1) as hub genes, with derived models achieving high diagnostic accuracy (AUC > 0.85) [80]. Drug repurposing analyses suggest that metformin and coenzyme I may serve as potential therapeutics [80]. Tumor Immune Dysfunction and Exclusion (TIDE) algorithm-based predictions indicate high-risk patients may benefit more from programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, whereas low-risk patients could respond more favorably to metabolic interventions [81].

Consensus clustering delineates cervical cancer subtypes with differential outcomes. For instance, Cluster B exhibits enhanced immune infiltration (CD8⁺ T cells, M1 macrophages) and superior survival [78]. Immune checkpoints like C-X-C motif chemokine ligand 1 (CXCL1) are upregulated in specific subtypes, implicating disulfidptosis in the modulation of immune evasion [82]. High SLC7A11 expression correlates with elevated tumor mutational burden (TMB), potentially influencing the efficacy immune checkpoint inhibitors (ICIs) [83]. Metabolically, low-risk patients exhibit enrichment of energy metabolism-related pathways (e.g., oxidative phosphorylation), while high-risk patients show activation of pro-inflammatory signaling cascades (e.g., IL-17, NF-κB), suggesting disulfidptosis modulates tumor progression via metabolic-immune crosstalk [81,82].

Endometrial cancer

The involvement of disulfidptosis in endometrial cancer had been validated through both in vitro and clinical studies. Solute carrier family 3 member 2 (SLC3A2) (heterodimer partner of SLC7A11) has been shown to drive endometrial cancer progression by enhancing cell proliferation and invasion, with its knockdown suppressing tumor growth [84]. Similarly, leucine-rich PPR motif-containing protein (LRPPRC), a mitochondrial protein overexpressed in uterine corpus endometrial cancer (UCEC), facilitates metastasis via disulfidptosis-related pathways, as demonstrated by functional assays (Transwell, CCK-8) [85]. SLC7A11 overexpression also predicts increased sensitivity to glucose starvation-induced cell death, highlighting metabolic stress (e.g., cystine accumulation) as a trigger of disulfidptosis [86].

Machine learning-derived prognostic models (e.g., LASSO-Cox, random forest) based on DRGs have demonstrated robust predictive power. Li et al. [87] classified UCEC patients into three subtypes using non-negative matrix factorization (NMF) (23 DRGs), identifying Cluster B as the subtype with superior overall survival (OS; 5-year AUC = 0.71) and enhanced immune infiltration (CD8⁺ T cells). Huang et al. [88] integrated disulfidptosis-ferroptosis genes (DFRGs), identifying cyclin-dependent kinase inhibitor 2A (CDKN2A), frizzled class receptor 7 (FZD7), and lipocalin 2 (LCN2) as prognostic predictors; high-risk patients exhibited shorter OS (HR = 0.38) and reduced immune infiltration. Other studies constructed lncRNA-based models (e.g., PRDX6-AS1, EMSLR) with 1-/3-/5-year AUCs of 0.676-0.722 [89], linking high-risk groups to extracellular matrix (ECM) remodeling and metastasis [86].

Disulfidptosis-associated molecular subtypes also correlate with TME heterogeneity: low-risk tumors exhibit immunostimulatory infiltration profiles (M1 macrophages, resting NK cells), whereas high-risk tumors are enriched with immunosuppressive cells (Tregs) [87,88]. Han et al. [85] noted that patients with high disulfidptosis scores demonstrated enhanced responses to PD-1/PD-L1 inhibitors, possibly due to CXCL1 upregulation. TIDE analysis further suggests that low-risk patients may benefit more from chemotherapy (e.g., cisplatin) [90], while patients with high TMB/MSI are more likely to respond favorably to immunotherapy [91].

Ovarian cancer

In ovarian cancer, SLC7A11 overexpression confers susceptibility to disulfidptosis under glucose deprivation [72,92]. Liang et al. [93] revealed a critical link between disulfidptosis and glycogen metabolism in ovarian clear cell carcinoma (OCCC): glycogen synthase 1 (GYS1) stabilizes p53 via ubiquitin-dpecific peptidase 14 (USP14)-mediated deubiquitination, forming a p53-GYS1 feedback loop that boosts NADPH production, thereby counteracting disulfidptosis and contributing to platinum resistance. Other players include LRPPRC (mitochondrial protein) and Alpha-Actinin-4 (ACTN4) (actin-binding protein), which regulate cytoskeletal stability during disulfidptosis [92,94]. Zhang et al. [72] proposed that simultaneous induction of disulfidptosis and ferroptosis via glucose oxidase-mediated NADPH/GSH depletion could sensitize ovarian tumors to oxidative stress.

Prognostic models leveraging DRGs (e.g., Myosin Light Chain 6 (MYL6), PDZ and LIM Domain Protein 1 (PDLIM1), ACTN4) effectively stratify patients into distinct survival risk groups [92]. Jin et al. [95] developed a 14-gene prognostic signatures (e.g., interferon beta 1 (IFNB1), insulin-like growth factor 2 (IGF2)), where low-risk groups showed prolonged survival and heightened immune infiltration. Similarly, lncRNA-based models (e.g., PRDX6-AS1, HLA Complex P5 (HCP5)) achieved 1-/3-/5-year AUCs of 0.676-0.863 [96,97], with high-risk tumors predominantly associated with Hedgehog signaling [96] and ECM pathways [98].

Furthermore, disulfidptosis-associated molecular subtypes correlate with distinct immune landscape shifts: low-risk tumors harbor cytotoxic CD8⁺ T cells and M1 macrophages, while high-risk tumors display increased infiltration of M2 macrophages and Tregs [92,99].

Studies have proposed multiple targeting strategies through bioinformatics analyses and experimental validations (Figure 3). Liang et al. [93] demonstrated that inhibition of GYS1 or disruption of the p53-GYS1 loop could reverse platinum resistance. The FeOOH@Fe-Ap@Au nanosystem designed by Zhang et al. [72] synchronously activates disulfidptosis and ferroptosis by depleting glucose and delivering iron ions, exhibiting significant therapeutic efficacy in ovarian cancer models. Zhou et al. [99] and Jin et al. [95] suggested that disulfidptosis-related biomarkers might be used to screen patient subsets suitable for immunotherapy (e.g., PD-1 inhibitors) or chemotherapy (e.g., platinum-based agents).

Figure 3.

Strategies for targeting disulfidptosis. Potential therapeutic strategies for regulating disulfidptosis include: (1) cystine overload via SLC7A11 upregulation or exogenous cystine supplementation; (2) NADPH depletion through inhibition of glucose uptake, G6PD, or the PPP; (3) inhibition of thioredoxin/thioredoxin reductase (Trx/TrxR) by compounds such as auranofin; (4) nanodelivery systems inducing redox imbalance; and (5) modulation of regulatory lncRNAs or combination therapies integrating immune checkpoint inhibitors (PD-1/PD-L1 blockade).

In conclusion, as a novel form of programmed cell death, disulfidptosis is closely associated with tumor progression, therapeutic resistance, and immune microenvironment regulation acorss gynecological malignancies such as cervical, endometrial, and ovarian cancers. Prognostic models constructed based on disulfidptosis-related biomarkers offer promising tools for risk stratification and treatment optimization. Furthermore, therapeutic strategies (e.g., combination with immunotherapy or metabolic intervention) represent a novel direction for precision therapy in gynecological tumors.

Inducing disulfidptosis in gynecological cancers

In recent years, disulfidptosis has demonstrated significant potential in the treatment of gynecological malignancies, including ovarian, cervical, and endometrial cancers. Current evidence indicates that inducing disulfidptosis should fullfill three key conditions [9]: (1) Excessive cystine uptake: The core determinant lies in cystine overload rather than merely high SLC7A11 expression. Even in tumor cells with relatively low SLC7A11 expression, exogenous cystine can similarly induce disulfidptosis; (2) NADPH deficiency or impaired utilization: Insufficient NADPH availability prevents the effective reduction of cystine to cysteine, leading to the accumulation of oxidized disulfides and subsequent redox imbalance; (3) Formation of abnormal disulfide bonds within the actin cytoskeleton: The buildup of cystine induces excessive disulfide crosslinking among actin-associated proteins, disrupting cytoskeletal stability and ultimately executing disulfidptosis.

However, current evidence suggests that directly inducing disulfidptosis by upregulation of Rac-WRC-cytoskeletal proteins (condition 3) is not feasible. These proteins are typically expressed at high basal levels in tumor cells [100], and further upregulation is unlikely to enhance disulfidptosis; instead, it may inadvertently promote tumor proliferation and invasion [101]. Therefore, based on conditions (1) and (2), researchers have summarized the main strategic directions for inducing disulfidptosis in gynecological cancers.

Targeting glucose metabolic deprivation

Currently, disulfidptosis is primarily triggered by the glucose starvation or inhibition of glucose transporters, which restricts NADPH production in tumor cells with high SLC7A11 expression [8]. Studies have shown that systemic glucose deprivation can simultaneously activate disulfidptosis and ferroptosis in ovarian cancer by suppressing the SLC7A11/GSH/GPX4 antioxidant axis [72]. In cervical cancer cell lines (SiHa and HeLa), glucose deprivation significantly promotes disulfidptosis [78].

Reducing cytoplasmic NADPH production

Another effective approach to trigger disulfidptosis involves directly reducing intracellular NADPH availability, thereby impairing the conversion of cystine to cysteine. NADPH serves as a crucial electron donor that provides reducing power for biosynthetic reactions and the maintenance of redox balance [102]. Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the dehydrogenation of glucose-6-phosphate to 6-phosphogluconolactone, while reducing nicotinamide adenine dinucleotide phosphate (NADP⁺) to NADPH. Inhibition of G6PD effectively lowers intracellular NADPH levels [103]. Recent studies by Meng et al. reported that G6PD K45A increases intracellular NADPH concentrations in cervical cancer cells [104], suggesting that G6PD inhibitors could serve as a potential strategy to induce disulfidptosis in cervical cancer. In OCCC, GYS1 maintains NADPH supply through a p53-GYS1 positive feedback loop, thereby conferring resistance to disulfidptosis, which also provides a potential strategy for inducing disulfidptosis [93].

Targeting the lncRNA pathway

LncRNAs are transcripts longer than 200 nucleotides that lack protein-coding potential. They regulate RNA, DNA, and proteins, thereby influencing the differentiation, proliferation, and migration of cancer cells [105]. Recent studies have revealed that lncRNAs play critical roles in regulating disulfidptosis, primarily through their modulation of downstream key DRGs (e.g., Glucose Transporter 1 (GLUT1) and SLC7A11) [106]. Numerous disulfidptosis-associated lncRNAs have been identified in gynecological diseases [98]. In endometrial cancer, lncRNAs including PRDX6-AS1, EMSLR, and SEC24B-AS1 have been identified, and prognostic models incorporating these lncRNAs have demonstrated strong predictive power for patient survival [86,89,90]. Similar analyses have been conducted in ovarian cancer [96-98] and cervical cancer [83]. However, whether these lncRNAs can induce disulfidptosis in gynecological cancers requires further investigation.

Nanodelivery systems

Nanodelivery systems have emerged as a promising strategy for inducing programmed cell death by precisely delivering effector molecules to tumor sites, preserving drug stability, and overcoming physiological barriers. Recent studies have demonstrated that rationally designed nanodelivery platforms can effectively enhance the induction of disulfidptosis [107]. For example, researchers have developed multifunctional FeOOH nanoshuttles (FeOOH@Fe-Ap@Au NSs), which co-load gold nanodots and iron-apigenin complexes (Fe-Ap). A major advantage of this system lies in its ability to precisely regulate the SLC7A11/GSH/GPX4 signaling axis through the properties of nanocarriers. This targeted regulation not only effectively triggers disulfidptosis but also simultaneously induces ferroptosis, achieving synergistic activation of dual death pathways [72]. This innovative design exemplifies the immense potential of nanoscale therapeutics in overcoming the limitations of single-agent therapies.

Disulfidptosis and ICIs

In recent years, disulfidptosis has been increasingly recognized as a factor influencing TME remodeling and therapeutic efficacy of ICIs. Despite major advances in cancer immunotherapy, the clinical response rate to ICIs remains modest, with fewer than 30% of patients demonstrating durable benefit. A major challenge in current cancer immunotherapy is converting “cold tumors” (tumors with low clinical response rates) into “hot tumors” that are more sensitive to immunotherapies. Accumulating evidence suggests that combining ICIs with additional therapeutic approaches can not only enhance clinical response rates but also mitigate tumor resistance to ICIs [108]. This is particularly relevant in malignancies exhibiting high SLC7A11 expression, as SLC7A11 promotes tumor immune evasion through its roles in sustaining cell survival and antioxidant defense [109]. Given that disulfidptosis represents a unique form of cell death occurring predominantly in SLC7A11-high tumors, therapeutic strategies that integrate disulfidptosis induction with ICIs may provide a novel and synergistic approach for improving treatment efficacy in these cancer types [110].

Cross-regulation between disulfidptosis metabolic pathways and immune checkpoints

SLC7A11 plays a pivotal role in mediating disulfidptosis. Previous studies have shown that SLC7A11 expression positively correlates with the therapeutic efficacy of PD-1/PD-L1 inhibitors in melanoma [111], although this finding has not yet been widely validated in other cancer types. As a key determinant of NADPH levels, its metabolic imbalance is directly linked to disulfidptosis: NADPH depletion triggers disulfidptosis [112], whereas elevated NADPH levels downregulate PD-L1 expression by inhibiting the ataxia telangiectasia mutated (ATM)/ataxia telangiectasia and Rad3-telated (ATR)/checkpoint kinase 1 (Chk1) signaling pathway [113,114]. In a high-glucose environment, hexokinase 2 (HK2) phosphorylates IκBα, activating NF-κB and upregulating PD-L1 expression [115,116]. Pharmacologic inhibition of HK2 has been shown to reverse immunosuppression and enhance ICIs efficacy [117]. In the Rac1-WRC pathway, the Rac1 P29S mutation has been found to selectively upregulate PD-L1, and patients harboring this mutation exhibit better responses to ICI therapy [118]. Targeting cyclin-dependent kinase 9 (CDK9), a downstream regulator of Rac1, can inhibit tumor proliferation while upregulating PD-L1 and major histocompatibility complex (MHC) I expression, producing a synergistic antitumor effect when combined with PD-1 inhibitors [119]. Notably, the Arp2/3 complex (a downstream effector of WRC) activated during disulfidptosis may serve as a novel link between cytoskeletal dynamics and immune checkpoint regulation. Recent findings show that PD-1 can inhibit T-cell actin remodeling independently of its canonical signaling motifs, leading to Arp2/3 complex deficiency [120], suggesting that cytoskeletal dynamics may represent a novel mechanism underlying crosstalk between disulfidptosis and ICIs.

Predictive value of disulfidptosis for ICIs efficacy

Prognostic models based on DRGs or disulfidptosis-related lncRNAs have demonstrated considerable potential in predicting patient response to ICIs in gynecological cancers. Lin et al. constructed a prognostic model comprising seven disulfidptosis-related lncRNAs, whose expression signatures showed strong correlations with key immune checkpoints - including PD-1, PD-L1, and cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) - thereby enabling identification of ovarian cancer patients likely to benefit from immunotherapy [96]. Similarly, Liu et al. developed a disulfidptosis-related lncRNA index (DLI) for cervical cancer and found that patients in the high-DLI group might respond more favorably to immunotherapeutic strategies involving CTLA4 blockers and PD-L1 blockers [83]. Through systematic analysis of DRGs and consensus clustering, Yao et al. successfully stratified cervical cancer patients into distinct molecular subtypes. Their study revealed marked inter-subtype differences in the expression of the immune checkpoint-related gene CXCL1, suggesting that CXCL1 may serve as a key molecular hub connecting the disulfidptosis regulatory network with the TME remodeling [82].

Potential biomarkers and challenges in clinical translation

Despite the promising potential of disulfidptosis-related markers in predicting ICIs efficacy, their clinical translation faces several challenges. Glucose deprivation is a critical environmental trigger of disulfidptosis in tumor cells with high SLC7A11 expression. Although this condition can be experimentally induced in vitro by inhibiting glucose transporters (e.g., GLUT) or establishing glucose-free culture environments, achieving selective induction in vivo is far more complex. Effective therapeutic strategies must specifically target SLC7A11-high tumor cells while sparing normal tissues to avoid systemic metabolic toxicity. Notably, the elevated metabolic demand of tumor cells may lead to glucose starvation within the TME, potentially inducing a nutrient-restricted state for infiltrating immune cells. This raises an important question: could glucose starvation trigger disulfidptosis in immune cells expressing high levels of SLC7A11, thereby dampening immune activation and contributing to the formation of “cold tumors” with reduced immunotherapeutic responsiveness? Addressing this uncertainty will be essential for translating disulfidptosis-based strategies into clinical practice and optimizing their integration with immunotherapy.

Disulfidptosis and other gynecological diseases

To date, endometriosis (EMs) is the only gynecological disease other than malignancies that has been mechanistically linked to disulfidptosis. EMs is a common, chronic, estrogen-dependent gynecological disorder characterized by dysmenorrhea, pelvic pain, infertility, and depression. Although benign, EMs exhibits several cancer-like features, including metastatic dissemination, progressive and invasive growth, and hormone-dependent proliferation [121].

Multiple studies employing bioinformatics, machine learning, and animal experiments have demonstrated a significant association between DRGs and the pathogenesis of EMs. Through differential expression analysis, protein-protein interaction network construction, and immune infiltration analysis, researchers have identified a wide array of differentially expressed DRGs between ectopic versus eutopic endometrial tissues. These include beta-actin (ACTB), GYS1, IQ motif containing GTPase activating protein 1 (IQGAP1), myosin heavy chain 10 (MYH10), nucleotide binding protein-like (NUBPL), SLC7A11, and talin 1 (TLN1) (in eutopic tissues), as well as capping actin protein zeta beta (CAPZB), CD2-associated protein (CD2AP), MYH10, 3-Oxoacyl-ACP synthase mitochondrial (OXSM), and PDLIM1 (in ectopic tissues). These genes are implicated in biological processes such as cytoskeletal remodeling, oxidative stress, and immune modulation, processes that collectively contribute to the pathophysiology of EMs [121]. For instance, immune cell infiltration analysis further revealed that NK cells play a critical role in EMs, with DRGs such as PDLIM1, F-box protein 45 (FBXO45), and TSC22 domain family member 4 (TSC22D4) exhibiting significant correlations with immune checkpoint molecules and the HLA gene family, suggesting that disulfidptosis may contribute to EMs progression by regulating immune evasion [13,14].

In the exploration of diagnostic markers, the integration of multimodal machine learning algorithms has significantly improved model predictive performance [121]. Studies have identified a panel of signature genes including ACTB, SLC7A11, CD2AP, and MYH10, whose diagnostic efficacy has been validated across independent datasets, achieving a maximum AUC of 0.865 [14]. Notably, PDLIM1 has emerged as a core hub gene, consistently validated across multiple studies. Immunohistochemical analyses of clinical samples confirmed elevated PDLIM1 expression in endometriotic tissues, while in vitro experiments demonstrated its ability to regulate the proliferation of primary EMs cells, further reinforcing its potential as a therapeutic target [13]. Additionally, drug screening based on DRGs has identified 12 potential compounds, among which tretinoin exhibited regulatory effects on the expression of key signature genes in animal models, providing experimental evidence for the development of drugs targeting disulfidptosis [121].

Current research still has certain limitations. The specific molecular mechanisms by which DRGs contribute to the pathogenesis of EMs remain incompletely elucidated, and most existing diagnostic models primarily rely on retrospective data [13,121]. Future studies should integrate single-cell sequencing and functional experiments to clarify how disulfidptosis regulates the initiation and progression of EMs through metabolic reprogramming and its crosstalk with the immune microenvironment. Nevertheless, the current findings have opened new avenues for molecular subtyping, non-invasive diagnosis, and targeted therapy of EMs. In particular, the intersection of disulfidptosis and immune regulation represents a promising direction to overcome existing therapeutic bottlenecks in Ems.

Conclusion and perspective

This review provides a comprehensive overview of the core mechanisms and translational value of disulfidptosis in gynecological diseases (Table 1). As a distinct form of cytoskeletal disulfide stress-induced cell death triggered by cystine accumulation and NADPH deficiency, disulfidptosis promotes the progression of gynecological malignancies (ovarian, cervical, and endometrial cancers) through the SLC7A11/cystine metabolic axis, AMPK-mediated NADPH homeostasis regulation, and Rac-WRC-Arp2/3-dependent actin network collapse. Beyond malignancy, disulfidptosis has also been implicated in benign proliferative disorders such as EMs. Prognostic models based on DRGs and lncRNAs have demonstrated reliable performance in predicting patient survival and responsiveness to immunotherapy. Moreover, intervention strategies targeting glucose metabolic deprivation, rate-limiting enzymes in NADPH synthesis (e.g., G6PD), or nanodelivery systems have shown significant therapeutic potential, particularly when combined with immune checkpoint inhibitors, which can exert synergistic antitumor effects by remodeling the tumor immune microenvironment.

Table 1.

Key aspects of disulfidptosis: mechanisms, regulation, comparison, disease relevance, and therapeutic strategies

Section	Content
Core Mechanism	Triggers: High SLC7A11 → cystine accumulation; NADPH↓/TrxR inhibition → blocked cystine reduction
	Pathway: Rac → WRC → Arp2/3 → branched actin cytoskeleton
	Outcome: Aberrant disulfide bond formation in actin cytoskeleton → lamellipodia disruption → cytoskeletal collapse
Regulatory Network	SLC7A11 regulation: ATF4↑, Nrf2↑, p53↓
	Metabolic: AMPK maintains NADPH; LKB1 loss ↑ sensitivity
	Redox: Trx/TrxR system
	Cytoskeleton: Rac/WRC/Arp2/3
PCD Comparison	Ferroptosis: lipid peroxidation/GPX4 loss
	Apoptosis: caspase-dependent
	Pyroptosis: inflammasome/GSDMD pores
	Necroptosis: RIPK1-RIPK3-MLKL
Disease Relevance	Tumors: cervical, endometrial, ovarian; associated with progression, drug resistance, TME remodeling
	Endometriosis: DRGs regulate immune - metabolic crosstalk
Induction Strategies	Limit glucose metabolism
	Inhibit NADPH synthesis
	Target lncRNAs
	Nanodelivery: co-induce disulfidptosis + ferroptosis

Disclosure of conflict of interest

None.