ROS, including superoxide anions, free radicals and hydrogen peroxide, are highly reactive molecules generated primarily through mitochondrial electron transport and NADPH oxidase activity (16–19,38,39). Additional sources include peroxisomal metabolism and endoplasmic reticulum stress (40,41). Oxidative stress occurs due to a disruption in the balance between ROS generation and clearance, serving a notable role in the development of cancer (21–23). Cellular protection against ROS involves a multi-level defense system, including enzymatic antioxidants (such as superoxide dismutase, catalase and GSH peroxidase), non-enzymatic scavengers (such as vitamin C, vitamins E and GSH) and repair systems for oxidized biomolecules, which collectively maintain redox homeostasis (39).

Physiological ROS levels regulate essential cellular processes (including proliferation, differentiation, survival and apoptosis). However, supraphysiological ROS levels drive tumorigenesis and progression (42,43). Excessive endogenous or exogenous ROS levels induce direct DNA damage and impair DNA repair mechanisms, causing mutations that inactivate tumor suppressors (such as p53) or activate oncogenes (such as KRAS) (44–46).

ROS further promote malignancy by activating proliferative signaling (including the PI3K/AKT/mTOR and MAPK pathways), and suppressing antitumor immunity via impaired T-cell differentiation/activation, T-cell death, natural killer cell dysfunction and M2 macrophage polarization/recruitment (47,48). ROS facilitate invasion and metastasis through EMT, and induce EMT-associated cytoskeletal rearrangement (Rho GTPase-dependent), extracellular matrix degradation (matrix metalloproteinase-dependent) and angiogenesis [hypoxia-inducible factor (HIF)-dependent] (49).

Although high ROS levels are crucial in promoting tumor initiation and progression, excessive ROS levels also serve an antioncogenic role in cancer (26,50). Excessively accumulated ROS repress cancer cell growth by inhibiting cancer cell proliferation through disrupting nucleotide/ATP synthesis and inducing cell cycle arrest (51). ROS also trigger tumor cell death by activating endoplasmic reticulum stress-mediated, mitochondrial and p53-dependent apoptotic pathways, along with the ferroptosis pathway (26). Therefore, targeting the regulation of ROS levels (for example, using pro-oxidant agents or inhibiting antioxidant pathways) has emerged as a novel therapeutic strategy in cancer treatment, aiming to exploit the ‘dual role’ of oxidative stress to achieve selective elimination of tumor cells.

Mitophagy represents a selective type of autophagy that functions as a protective response to intracellular and extracellular stress signals (32). Mitophagy maintains mitochondrial and cellular homeostasis by eliminating dysfunctional mitochondria, including depolarized, damaged or superfluous organelles, through lysosomal degradation. The core molecular mechanisms can be divided into Ub-dependent pathways and Ub-independent pathways (31). The PTEN-induced kinase 1 (PINK1)/Parkin pathway represents the most well-characterized Ub-dependent mechanism. Upon mitochondrial depolarization or damage, PINK1 stabilizes on the outer mitochondrial membrane (OMM), and phosphorylates Ub and the E3 Ub ligase Parkin, leading to the ubiquitination of OMM proteins. Autophagy receptors such as p62/sequestosome 1 (SQSTM1) and optineurin then recognize ubiquitinated substrates and link them to microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive autophagosomal membranes for engulfment (31). Alternatively, Ub-independent pathways utilize OMM-resident receptors, including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), BNIP3L (also known as NIX) and FUN14 domain-containing protein 1 (FUNDC1), which directly interact with LC3/GABA type A receptor-associated protein via LC3-interacting regions to initiate mitophagy. These coordinated mechanisms ensure the precise elimination of dysfunctional mitochondria, and their dysregulation is broadly implicated in various pathological states, including cancer (30,52,53).

Mitophagy is widely reported to exhibit aberrant activity levels in various cancer types compared with under normal physiological conditions (54,55). Current research has revealed its dual role in cancer biology, demonstrating both tumor-promoting and tumor-suppressive functions depending on the cellular context (56,57). In its pro-tumorigenic capacity, mitophagy is known to enable cancer cell survival under stress and facilitates malignant progression by clearing dysfunctional mitochondria (58). Under hypoxia, mitophagy mediated by BNIP3 and NIX is known to enhance tumor aggressiveness by lowering mitochondrial ROS levels, stabilizing HIF-1α, promoting glycolytic shift and inducing EMT, which collectively increase invasiveness and metastatic potential (59). Chemotherapy- or radiotherapy-induced mitochondrial damage can activate the PINK1/Parkin pathway, which ubiquitinates damaged mitochondria to block cytochrome c release, thereby potentially enabling cancer cells to evade apoptosis and develop therapeutic resistance (60). During metastasis, FUNDC1-dependent mitophagy is suggested to optimize energy metabolism to fuel ATP production, supporting cancer cell migration and invasion (61). Additionally, mitophagy may suppress NLR family pyrin domain containing 3 (NLRP3) inflammasome activation by removing mitochondrial damage-associated molecular patterns [mitochondrial DNA (mtDNA) and cardiolipin], thereby reducing secretion of the pro-inflammatory cytokine IL-1β and impairing antitumor immunity to promote immune evasion (62).

Conversely, mitophagy also exerts tumor-suppressive effects, as supported by multiple lines of evidence (59,63). In precancerous or early-stage tumors, mitophagy impedes malignant transformation by eliminating mitochondria harboring oncogenic damage. For example, mtDNA mutations, which drive early carcinogenesis, are selectively cleared via NIX/BNIP3-dependent mitophagy, thereby mitigating ROS-induced nuclear genomic instability and delaying tumor initiation (64). The tumor suppressor p53 has been shown to enhance mitophagy by transcriptionally activating DNA damage-regulated autophagy modulator 1, facilitating the removal of dysfunctional mitochondria and inducing apoptosis in premalignant cells, as validated in colorectal precancerous models (65,66). Furthermore, excessive mitochondrial damage can trigger ‘autosis’, a form of autophagic cell death, via mitochondrial membrane potential collapse and ATP depletion, irreversibly eliminating premalignant cells. In inflammation-associated carcinogenesis, mitophagy is proposed to block chronic inflammation-driven tumorigenesis by clearing mitochondrial damage-associated molecular patterns (such as cardiolipin and mtDNA), thereby inhibiting NLRP3 inflammasome activation and IL-1β secretion (67). Critically, the tumor-suppressive effects of mitophagy are context- and stage-dependent: Activation of mitophagy in PTEN-deficient or KRAS-mutant precancerous models reduces hyperproliferative lesions, whereas the same intervention in advanced tumors may paradoxically promote malignancy due to metabolic rewiring and survival adaptation. This spatiotemporal duality underscores the necessity of stage-specific targeting of mitophagy pathways in cancer therapy (68,69).

Emerging evidence highlights stage- and molecular context-specific regulation of mitophagy in EC, although research in this field remains sparse (70). Dysregulation of the PTEN/PI3K/AKT pathway, observed in >80% of EC cases, impairs PINK1/Parkin-mediated mitophagy, resulting in the accumulation of dysfunctional mitochondria, increased ROS levels, heightened genomic instability and estrogen-driven proliferation (71). However, evidence has revealed that PTEN-deficient EC cells activate an alternative mitophagy pathway mediated by the autophagy and beclin 1 regulator 1-autophagy-related protein 5 complex, which bypasses Unc-51 like autophagy activating kinase 1 (ULK1) inhibition and maintains mitochondrial quality control under mTORC1 hyperactivation (13). In type I EC, hyperactivated mTORC1 phosphorylates ULK1 at Ser757, disrupting the ULK1-AMP-activated protein kinase (AMPK) complex essential for mitophagy initiation and promoting tumor cell survival (34). Notably, advanced TP53-mutant ECs exhibit hypoxia-driven compensatory upregulation of BNIP3L/NIX-mediated mitophagy, which is transcriptionally activated by HIF-1α under hypoxic conditions to sustain mitochondrial metabolism and chemoresistance, thereby contributing to the poor prognosis of p53-aberrant tumors (33). This dual regulatory role, tumor-suppressive in early stages and pro-tumorigenic in advanced disease, underscores the need for stage-specific therapeutic strategies. Restoring PINK1/Parkin signaling in PTEN-deficient models may improve mitochondrial quality control, while targeting BNIP3L/NIX in TP53-mutant tumors could enhance chemosensitivity. However, the molecular mechanisms underlying these context-dependent effects require further elucidation.

In conclusion, mitophagy serves as both a ‘metabolic accomplice’ and a ‘genomic custodian’ in EC, with its dualistic role underscoring the therapeutic conundrum in targeting mitochondrial quality control. The transition from tumor-suppressive to pro-survival functions is intricately linked to disease stage, molecular subtypes (such as POLE-mutated and TP53-aberrant) and metabolic rewiring driven by PTEN/PI3K dysregulation or obesity-associated stress (33). Future endeavors must prioritize stage-adaptive strategies, activating mitophagy to enforce genomic fidelity in precancerous lesions while inhibiting FUNDC1/PINK1/Parkin-driven pathways to disrupt metabolic plasticity in advanced tumors. Integrating multi-omics profiling (such as mitophagic flux mapping and spatial metabolomics) with clinical staging will unlock context-specific vulnerabilities, enabling the design of precision therapies that convert mitophagy from a foe to an ally in the battle against EC, as illustrated in Fig. 1.

Ferroptosis is an iron-dependent RCD pathway that is driven by lipid peroxidation, originating from redox imbalance, dysregulated lipid metabolism and disrupted iron homeostasis (72); however, cellular adaptation to these stressors hinges on dynamic modifications of core regulatory pathways, which paradoxically form the molecular basis of ferroptosis resistance (29). The GPX4/GSH axis is a central defense system: System Xc⁻ [composed of solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2] imports cystine for GSH synthesis and GPX4 utilizes GSH to reduce lipid peroxides. Resistance often arises from GPX4 or System Xc⁻ upregulation (73). Alternatively, the ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) axis has been identified as a key GPX4-independent pathway wherein FSP1 reduces ubiquinone to ubiquinol, which quenches lipid radicals (28). Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a well-established promoter of ferroptosis that enriches membranes with polyunsaturated fatty acids; its suppression diminishes ferroptosis sensitivity (74). Iron metabolism serves a dual role: Iron overload amplifies lipid peroxidation, while iron storage proteins [such as ferritin heavy chain 1 (FTH1)] buffer toxicity. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a recognized suppressor of ferroptosis, primarily by activating antioxidant genes (such as GPX4 and FTH1) (29,75). p53 exerts context-dependent effects, which may include inhibiting SLC7A11 or activating spermidine/spermine N1-acetyltransferase 1 (65–67).

Ferroptosis exhibits a dynamically regulated dual role in EC progression: Its suppressed state drives tumor invasion, metastasis and therapy resistance through multifaceted molecular mechanisms, while ferroptosis-inducing strategies have the potential to reverse drug resistance and inhibit metastasis (16,76–78). The core regulatory hubs GPX4 and Nrf2 are upregulated in EC and are functionally synergistic. GPX4 maintains membrane stability by reducing toxic lipid peroxides (such as phosphatidylethanolamine hydroperoxide), whereas Nrf2 enhances antioxidant defense via transcriptional activation of SLC7A11 (cystine/glutamate antiporter) and FTH1 (iron storage protein) (79–81). A multivariate analysis of the TCGA-uterine corpus endometrial carcinoma cohort revealed that GPX4/Nrf2 co-upregulation was independently associated with lymph node metastasis risk [odds ratio (OR), 3.21; 95% confidence interval (CI), 1.38–7.45; P=0.007] and International Federation of Gynecology and Obstetrics III/IV staging (OR, 2.94; P=0.012) (82,83). EC cells evade ferroptosis through epigenetic reprogramming, including the microRNA (miR)-424-5p-mediated destabilization of ACSL4 mRNA via 3′untranslated region binding (validated by dual-luciferase assays) and hypermethylation of the ACSL4 promoter CpG island (methylation β-value >0.6; P<0.001), collectively suppressing pro-ferroptotic lipid peroxidation (83). Iron metabolism dysregulation exacerbates malignant phenotypes: FTH1 upregulation reduces the labile iron pool by enhancing iron storage, thereby inhibiting Fenton reaction-driven lipid peroxidation, while divalent metal transporter 1 mediates lysosomal iron efflux to amplify ferroptosis sensitivity in metastatic niches. Concurrently, transferrin receptor 1 (TFR1)-mediated iron overload activates pro-angiogenic factors (such as VEGF) via the mitochondrial ROS/HIF-1α axis (84). Clinical translational studies have highlighted the therapeutic potential of combining erastin with cisplatin: Cisplatin-resistant EC cells (Ishikawa-CR line) acquire ferroptosis resistance via GPX4/FSP1 dual-pathway upregulation, whereas erastin/cisplatin co-treatment induces caspase-3-independent cell death (4.2-fold apoptosis increase; P<0.001) (11,85). Metformin suppresses SLC7A11 transcription via the AMPK/p53 axis (chromatin immunoprecipitation-quantitative PCR-validated), reducing peritoneal metastases by 68% in patient-derived xenograft (PDX) models (P=0.002) (86,87). Interim analysis of the NCT04817332 phase II trial demonstrated improved objective response rates with erastin/carboplatin-paclitaxel combination therapy in recurrent EC (51 vs. 32% for monotherapy; P=0.039), albeit with increased ferroptosis-related toxicity (grade 3 anemia, 28 vs. 12%) (88). Parallel preclinical investigations provided complementary insights: To further elucidate the cellular diversity underlying treatment responses, single-cell RNA sequencing of patient-derived EC samples revealed significant heterogeneity in ferroptosis-related gene expression profiles. Meanwhile, leveraging nanodelivery systems to encapsulate ferroptosis inducers has been established as a promising strategy in preclinical models to enhance tumor selectivity and reduce systemic toxicity (89). These findings systematically elucidate the pivotal role of ferroptosis dysregulation in EC progression and provide novel directions for developing redox metabolism-targeted precision therapies (16).

ROS serve as key signaling molecules that dynamically coordinate the balance between mitophagy and ferroptosis. Mitochondrial ROS promote PINK1/Parkin-mediated mitophagy, which clears damaged mitochondria and limits lipid peroxidation (31,52). Conversely, endoplasmic reticulum-derived ROS activate the inositol-requiring enzyme 1α/c-Jun N-terminal kinase pathway, upregulating ACSL4 to enhance membrane polyunsaturated fatty acid incorporation and ferroptosis sensitivity (90). Lipid peroxidation products [such as phospholipid hydroperoxides (PLOOH)] further amplify mitochondrial damage, establishing a feedforward loop (91). This interplay exhibits concentration dependence in EC: Physiological ROS levels promote cytoprotective mitophagy via AMPK-ULK1 signaling to suppress early malignant transformation (92), whereas chemotherapy (such as cisplatin)-induced ROS trigger ferroptosis-dominated cell death by depleting GSH and inhibiting GPX4 (93). A previous study has revealed that estrogen receptor α (ERα) activation in EC cells simultaneously upregulates mitochondrial ROS production and autophagy-related genes (such as BNIP3), driving dynamic imbalances between mitophagy and ferroptosis to fuel tumor progression (94).

Mitophagy and ferroptosis are interconnected through shared molecular nodes, forming a bidirectional regulatory network (95). On the one hand, mitophagy suppresses ferroptosis by degrading ACSL4, a key enzyme that catalyzes polyunsaturated fatty acid-phospholipid synthesis, and removing lipid peroxidation precursors (96). On the other hand, ferroptosis-derived lipid peroxides (such as PLOOH) activate PINK1/Parkin or NIX/BNIP3L-dependent mitophagy via mitochondrial membrane oxidation (97). Emerging evidence demonstrates that ACSL4, a ferroptosis-specific regulator, induces mitochondrial Ca²⁺ overload, leading to membrane depolarization and subsequent mitophagy initiation (98). Additionally, labile iron released during ferroptosis exacerbates mitochondrial oxidative damage through Fenton reactions, creating an ‘iron-ROS-mitophagy’ cycle. In EC, PTEN loss-induced dysregulation of the PI3K/AKT/mTOR pathway disrupts redox homeostasis via dual mechanisms: Impairing ULK1 phosphorylation to block protective mitophagy and downregulating GPX4 to heighten ferroptosis susceptibility (33). Combined targeting of both pathways (for example, using mitophagy inducer urolithin A + ferroptosis activator RSL3) synergistically inhibits tumor growth in preclinical models, highlighting the therapeutic potential of modulating the ROS-mitophagy-ferroptosis axis (16,71), as illustrated in Fig. 2.

EC is characterized by alterations in redox homeostasis that is driven by hormonal imbalances and somatic mutations. Estrogen dominance, a hallmark of type I EC, activates ERα-mediated mitochondrial biogenesis, amplifying superoxide generation while epigenetically suppressing Nrf2-dependent antioxidant defenses through promoter hypermethylation of NFE2 like bZIP transcription factor 2 (NFE2L2) (99). Conversely, progesterone exerts protective effects by binding to the progesterone receptor-B isoform, upregulating thioredoxin reductase and GSH synthetase through cAMP-response element binding protein phosphorylation, a mechanism disrupted in obesity-associated progesterone resistance (100). PTEN loss (occurring in 40–80% of cases) exacerbates this imbalance via dual pathways: i) Hyperactivation of PI3K/AKT/mTORC1 inhibits ULK1-driven mitophagy, allowing the accumulation of ROS-generated damaged mitochondria; and ii) transcriptional repression of the FSP1/CoQ10 axis through yes-associated protein and transcriptional coactivator with PDZ-binding motif nuclear translocation, sensitizing cells to ferroptosis (101,102). Single-cell multi-omics has identified PTEN-null CD44-positive aldehyde dehydrogenase 1 family member A1-high cancer stem cells (CSCs) that evade ferroptosis via aldehyde detoxification and CoQ10 recycling, establishing a redox-buffered niche resistant to oxidative stress (103).

Redox adaptations exhibit temporal evolution during disease progression: i) Premalignant lesions exhibit compensatory upregulation of mitophagic machinery (elevated Parkin RBR E3 ubiquitin-protein ligase and BNIP3 levels) with concomitant suppression of ferroptosis drivers (low ACSL4 expression); ii) early invasive tumors activate the FSP1/CoQ10 antioxidant system and suppress mitophagy through mTORC1-mediated transcription factor EB phosphorylation, resulting in lipid peroxide accumulation; and iii) advanced tumors undergo metabolic rewiring (glutamine-driven oxidative phosphorylation and HIF-1α signaling) to enforce mitophagy dependency and ferroptosis resistance (104–106). These stage-specific adaptations inform rational therapeutic targeting: mTOR inhibition with rapamycin restores protective mitophagy in premalignant states, while FSP1 inhibitors combined with ferroptosis inducers (such as imidazole ketone erastin) overcome therapy resistance in advanced disease.

Fe-S cluster biogenesis acts as a critical node linking mitochondrial integrity and ferroptosis sensitivity. Deficiencies in mitochondrial Fe-S assembly systems [such as iron-sulfur cluster assembly enzyme (ISCU) and frataxin] disrupt electron transport chain function, causing superoxide accumulation and PINK1/Parkin-mediated mitophagy, while cytosolic labile iron pool expansion exacerbates lipid peroxidation via Fenton reactions, increasing ferroptosis susceptibility (109). In EC, ISCU promoter hypermethylation and miR-214 upregulation synergistically impair Fe-S cluster synthesis, whereas cancer-associated fibroblasts rescue redox homeostasis by delivering Fe-S complementation factors (such as cysteine desulfurase) via exosomes (110,111). Therapeutic Fe-S cluster donors (such as Fe₄S₄) restore mitochondrial function while inducing ferroptosis, exhibiting synergistic efficacy in PTEN-deficient organoid models and offering a novel strategy to overcome therapy resistance (103).

The spatiotemporal dynamics of oxidative stress critically influence therapeutic responses in EC. Chemotherapy (e.g., cisplatin) induces biphasic ROS generation (112): Acute-phase mitochondrial ROS activate AMPK-ULK1-mediated protective mitophagy, promoting cell survival, while chronic-phase ROS accumulation triggers ferroptosis via GSH depletion and GPX4 inactivation. The circadian regulators BMAL1 and CLOCK rhythmically control the expression of autophagy genes like LC3B. This regulation drives a peak in autophagic activity at night, which helps to counteract the oxidative damage that accumulates during the day (113). Chronotherapy strategies leveraging these rhythms [e.g., administering ferroptosis inducers (such as erastin) during active circadian phases] synergize with endogenous ROS fluctuations, enhancing treatment efficacy (114,115).

Spatial heterogeneity further shapes oxidative stress regulation: Hypoxic tumor cores suppress ferroptosis via HIF-1α-mediated downregulation of ACSL4 and TFR1, while upregulating BNIP3-driven mitophagy to maintain CSC stemness. By contrast, high-ROS microenvironments at invasive fronts activate NF-κB/STAT3 signaling to promote EMT and FSP1/CoQ10-dependent ferroptosis resistance (112,116). CSCs remodel stromal niches via exosomal transfer of antioxidants (such as glutathione S-transferase P1) and iron chelators, creating localized ‘oxidative sanctuaries’ (117). Nanotherapeutic strategies exploiting this heterogeneity, such as ROS-responsive carriers delivering autophagy inhibitors to cores and ferroptosis inducers to invasive fronts, exhibit potent antitumor effects in preclinical models (118).

In summary, the spatiotemporal regulation of oxidative stress defines distinct therapeutic vulnerabilities, enabling chronotherapeutic and microenvironment-targeted interventions.

The oxidative stress network offers novel biomarkers and therapeutic strategies (119). Combined evaluation of mitophagy (for example, mtDNA copy number) and ferroptosis markers (for example, lipid peroxidation products) enables real-time monitoring of tumor redox status (120). CD8⁺ T cell-derived IFNγ enhances ferroptosis susceptibility via STAT1/interferon regulatory factor 1/ACSL4 signaling, suggesting synergies between immune checkpoint inhibitors and ferroptosis inducers (121). Advanced imaging technologies (such as nanoprobe-based iron tracking) integrated with artificial intelligence (AI) algorithms accurately predict ferroptosis sensitivity (122).

Spatiotemporally optimized combinations, such as sequential autophagy inhibition followed by ferroptosis induction, overcome compensatory resistance (123,124). ROS-responsive nanocarriers achieve precise drug release by exploiting microenvironmental features (such as low pH and high GSH levels), effectively targeting both hypoxic cores and invasive fronts. Additionally, targeting PTEN-null vulnerabilities with mTOR and glutaminase inhibitors synergistically blocks mitophagy and induces ferroptosis, achieving remarkable responses in patient-derived models (101).

These advances highlight the clinical potential of targeting oxidative stress dynamics for precision therapy in EC.

Key challenges remain in modeling oxidative stress dynamics. Current organoid systems lack spatiotemporal resolution for tumor-microenvironment crosstalk (for example, immune cell interactions and hormone gradients) (125). Integrating single-cell transcriptomics with spatial metabolomics is essential to resolve redox heterogeneity and niche-specific adaptations (126,127). Mechanistic gaps persist regarding the subcellular localization of ferroptosis regulators (such as FSP1) and the crosstalk between Nrf2 and circadian pathways (96–99). Compensatory activation, such as GPX4 inhibition upregulating FSP1/CoQ10, requires sequential targeting strategies tailored to tumor heterogeneity (128–131). AI-driven drug discovery (for example, using deep generative models) predicts synergistic combinations (such as mTOR inhibitors with ferroptosis inducers), validated in PDX models (132).

Future studies must integrate computational biology and high-resolution omics to map the oxidative stress landscape, enabling personalized therapeutic strategies.

A primary unresolved question is the spatiotemporal dynamics of this interplay within the tumor microenvironment (TME). The precise thresholds of oxidative stress that dictate a switch from pro-survival mitophagy to lethal ferroptosis across different molecular subtypes and disease stages remain unmapped (120). This context-dependent duality necessitates a deeper understanding of how metabolic and hormonal cues influence this balance. Concurrently, the immunological consequences of targeting this axis constitute a critical knowledge gap. It is not known whether ferroptosis induction or mitophagy modulation can enhance antitumor immunity by, for example, triggering immunogenic cell death or reversing immunosuppressive niches, which would create a rationale for combinations with immunotherapy.

The compelling preclinical evidence stands in stark contrast to the current clinical trial landscape, highlighting a significant translation gap. To definitively assess the clinical translation of these mechanisms, a systematic search of the ClinicalTrials.gov registry (https://clinicaltrials.gov/) was conducted on September 10, 2025. The search strategy utilized keywords including ‘endometrial cancer’, ‘ferroptosis’, ‘mitophagy’ and related terms. Crucially, the following exclusion criteria were applied: i) Trials not focused on EC; ii) non-interventional studies; and iii) trials where direct targeting of mitophagy or induction of ferroptosis was not an explicit primary strategy. It is important to note that this search constituted a systematic search of trial registries and not a systematic review; as such, a formal quality assessment of the identified trials or a synthesis of data from existing publications was not performed, which is a limitation of this methodological approach.

This rigorous search confirmed a complete absence of clinical trials specifically designed to directly target mitophagy or induce ferroptosis as a primary therapeutic strategy in EC. However, the search identified several interventional trials investigating agents with indirect mechanistic links to these pathways: i) mTOR inhibitors: Active and completed trials investigating everolimus (such as NCT01797523 and NCT00870337) are relevant due to the established role of mTOR signaling in regulating the mitophagic flux and cellular stress responses; and ii) AMPK activators: Multiple trials involving metformin (such as NCT04576104, NCT07145827 and NCT01205672) are of interest based on preclinical evidence suggesting its potential to modulate AMPK activity and sensitize cells to ferroptosis.

The absence of direct-targeting trials underscores the nascent stage of translating these concepts into clinical applications. Conversely, the prevalence of trials involving mTOR inhibitors and AMPK activators suggests a growing clinical recognition of the importance of targeting broader metabolic and stress-response pathways in EC, which may indirectly influence mitophagy and ferroptosis (134,135).

Translation of these insights faces significant barriers. The lack of robust, dynamic biomarkers (such as circulating lipid peroxidation products) beyond static molecular classification severely hinders patient stratification. Furthermore, managing systemic toxicity, particularly of potent ferroptosis inducers, is a paramount concern. Overcoming this requires the development of advanced nano-theranostic platforms engineered for EC-specific targeting [e.g., against folate receptor α (FRα)] and TME-responsive drug release (e.g., triggered by high ROS levels) to maximize efficacy and minimize off-target effects. The inherent compensatory activation of parallel pathways (such as upregulation of the FSP1/CoQ10 axis upon GPX4 inhibition) further necessitates the rational design of combination therapies.