Disulfidptosis mechanisms and therapeutic implications in cancer metabolic reprogramming and future perspectives

Abstract

Regulatory cell death exhibits distinctive advantages in cancer therapy. Among such mechanisms, disulfidptosis effectively inhibits tumor growth by inducing disulfide bond stress and subsequent rupture under particular conditions, thus demonstrating substantial potential for cancer treatment. Genes associated with disulfidptosis contribute to the survival and proliferation of various cancer cell types. They significantly impact the tumor microenvironment (TME) by modulating cancer’s metabolic reprogramming and antioxidant response, achieving anti-tumor effects. This review explores the recently identified regulatory cell death mechanism, disulfidptosis, through an examination of its mechanisms, the relationship between relevant genes and cancer, analyses of the TME, and the prospects of emerging therapeutics, offering fresh insights for disulfidptosis research in oncology.

Introduction

Programmed Cell Death (PCD) is a cellular metabolic process controlled by specific molecular mechanisms and signaling pathways [1]. Recently, novel forms of PCD, such as pyroptosis, ferroptosis, and cuproptosis, have garnered significant attention. These mechanisms involve DNA and chromatin fragmentation, mitochondrial dysfunction, and plasma membrane rupture, making them highly relevant to cancer research [2, 3]. By delineating the metabolic wiring of programmed cell death (PCD), researchers aim to clarify mechanisms of disease progression and rationally design next-generation cancer therapies. These strategies focus on tuning cancer cell–intrinsic targets and pathways, reconditioning the tumor microenvironment (TME), and circumventing the apoptosis resistance that limits conventional treatments [4–6]. For example, the ferroptosis inhibitor sorafenib has shown efficacy in inducing lipid peroxidation-mediated ferroptosis in cancer cells expressing ACSL4 [7]. Recent studies have expanded the understanding of PCD forms and their potential therapeutic applications. Wang et al. [8] demonstrated that sorafenib, combined with elesclomol, a copper ion carrier, significantly enhanced cuproptosis in hepatocellular carcinoma (HCC) cells, and the findings were validated in xenograft models. Emerging evidence suggests that PCD impacts TME by regulating immune cell sensitivity to specific cell death forms, thus amplifying the efficacy of immunotherapies [9]. Ferroptosis inhibitors have been reported to activate immune cells by delivering chemotactic signals, thereby playing an active role in immunotherapy [10]. A groundbreaking study by Liu et al. [11] identified disulfidptosis, a new PCD form triggered under glucose starvation conditions. It involves SLC7A11-mediated suppression of NADPH regeneration, leading to disulfide bond stress, actin cytoskeleton collapse, and subsequent cell death. GLUT inhibitors can significantly enhance disulfidptosis in SLC7A11-overexpressing cancer cells, further validating its therapeutic potential in tumor suppression. Cuproptosis is triggered by excessive copper binding to mitochondrial lipoylated enzymes, leading to protein aggregation and metabolic enzyme inactivation [12]. Ferroptosis, in contrast, primarily results from iron-catalyzed lipid peroxidation that causes cell membrane damage [13]. Distinct from these metal ion-mediated mechanisms, disulfidptosis arises under glucose starvation, where high expression of SLC7A11 leads to NADPH depletion and disulfide stress imbalance. This results in intracellular accumulation of aberrant disulfide bonds, causing protein misfolding and collapse of the actin cytoskeleton [11]. In oncology, unconventional metabolic forms of PCD, such as ferroptosis, cuproptosis, and more recently disulfidptosis, have emerged as pivotal research frontiers. These modalities expand beyond classical apoptosis and necroptosis, underscoring that cancer cells exploit diverse metabolic dependencies to evade death and sustain malignant progression. Their importance lies in the fact that metabolic vulnerabilities are often tumor-specific, thereby offering opportunities to design therapies that selectively eradicate cancer cells while sparing normal tissues [6]. Methodologically, new PCDs are typically mapped through a triad of biochemical phenotyping, genetic perturbation, and preclinical validation. Positioning disulfidptosis within this arc clarifies why redox-metabolic vulnerabilities are clinically relevant and how they might translate to patient benefit. The discovery and validation of novel PCD pathways typically follow a systematic framework: the initial identification of distinct biochemical phenotypes, subsequent confirmation through genetic perturbation, and preclinical validation in tumor models. For instance, ferroptosis is characterized by lipid peroxide accumulation, whereas cuproptosis is associated with lipoylated enzyme aggregation. Similarly, disulfidptosis has been defined as an NADPH-limiting, disulfide stress–induced collapse of the actin cytoskeleton in SLC7A11^high tumors. Positioning disulfidptosis within this broader continuum not only underscores its mechanistic distinctiveness but also situates it as a potentially exploitable vulnerability in cancer therapy. In this review, we explore the underlying mechanisms of disulfidptosis and its association with cancer, aiming to provide new perspectives and theoretical foundations for future cancer diagnosis and therapy.

Mechanism and triggering conditions of disulfidptosis

Liu et al. [11] conducted proteomics research and discovered that actin cytoskeleton molecules are highly enriched in the modified components. The enrichment of actin targets indicates that disulfide bond formation requires cortical actin at the plasma membrane or actin filaments [14]. The formation of the actin cytoskeleton is considered part of the PCD process, occurring in both animals and plants. In plants, actin reorganization triggered by self-recognition can induce cell death to prevent self-fertilization. In animal cells, actin filaments undergo severing by gelsolin, activating myosin kinase ROCK. This activation leads to intense contractile activity of myosin, promoting apoptosis. Disulfide bonds are formed through the oxidation of two cysteine residues within actin [15, 16]. In cancer cells with high SLC7A11 expression, glucose depletion fosters an environment conducive to disulfide bond formation, resulting in high-molecular-weight species on non-reducing gels. Under conditions reliant entirely on SLC7A11-mediated cystine uptake, abnormalities in actin cytoskeleton morphology manifest, including cell edgecontraction and lamellipodia collapse, ultimately leading to cell death. Notably, cells with high SLC7A11 expression undergo thioaptosis when thioredoxin 1 is inhibited or upon hydrogen peroxide treatment, which catalyzes cystine to cysteine [17, 18].

Disulfidptosis exhibits selective disulfide bond formation that is gated by cytosolic redox chemistry. Under high SLC7A11 activity, sustained cystine import increases the demand for NADPH to reduce cystine to cysteine; when glucose starvation or GLUT inhibition limits pentose phosphate pathway (PPP) output, the thioredoxin/glutaredoxin and GSH systems become NADPH-limited, shifting the intracellular redox potential toward disulfide formation [11, 19–21]. In this context, thiol–disulfide exchange reactions preferentially modify solvent-exposed, low-pK_a cysteine residues, a process whose kinetics and reversibility are determined by local microenvironment and electron-donor availability [19, 22]. These features mechanistically explain why disulfide accumulation is tightly coupled to NADPH depletion rather than indiscriminate oxidation. This provides additional verifiable hypotheses regarding the mechanism underlying disulfide-induced cell death (Fig. 1).

Fig. 1.

Schematic diagram of the conditions and mechanisms triggering disulfidptosis.In SLC7A11low cells, intracellular glucose uptake occurs via GLUT transporters, leading to the production of glucose-6-phosphate (G6P). This supports the pentose phosphate pathway (PPP), which generates NADPH, a crucial cofactor for reducing cystine to cysteine. Pyruvate production through glycolysis, followed by its metabolism via the TCA cycle and mitochondrial oxidative phosphorylation, ensures adequate energy supply and cellular homeostasis. The sufficient availability of NADPH prevents the accumulation of disulfides and avoids disulfide stress, maintaining the integrity of the actin cytoskeleton and promoting cell survival. Conversely, in SLC7A11high cells, glucose starvation or inhibition of glucose uptake leads to reduced intracellular glucose levels, decreased G6P production, and impaired PPP activity. This results in the depletion of NADPH, especially under conditions of excessive cystine uptake via System Xc-. The inability to reduce cystine to cysteine leads to disulfide accumulation and disulfide stress, which causes the formation of aberrant disulfide bonds in actin cytoskeletal proteins. This process activates the Rac–WAVE regulatory complex (WRC)–Arp2/3 signaling pathway, disrupting the F-actin network and triggering lamellipodia formation, ultimately leading to the collapse of the actin cytoskeleton and disulfidptosis. Abbreviations: GLUT, glucose transporter; SLC7A11, solute carrier family 7 member 11; PPP, pentose phosphate pathway; NADPH, nicotinamide adenine dinucleotide phosphate; G6P, glucose-6-phosphate; TCA, tricarboxylic acid cycle; Rac, Rac family small GTPase; WRC, WAVE regulatory complex; Arp2/3, actin-related protein 2/3

Disulfides play a crucial role in maintaining the physical and chemical stability of proteins by acting as cross-linking mediators between subunits [23, 24]. Zheng et al. [25], based on existing experimental data related to disulfide-induced cell death, proposed that several conditions must be met to trigger disulfidptosis. First, the high expression of SLC7A11 leads to continuous intracellular cysteine uptake and glutamate efflux, thereby promoting disulfide stress [14, 26]; Second, glucose depletion blocks the pentose phosphate pathway, preventing the generation of sufficient NADPH to counteract disulfide bond stress and maintain cellular homeostasis, resulting in disulfide bond accumulation [27]༛Third, abnormal disulfide bond formation occurs within the actin cytoskeleton. When these conditions coexist, disulfide stress activates the Rac-WRC-Arp2/3 signaling pathway, leading to the accumulation of disulfide bonds within the actin cytoskeleton. Notably, genetic or pharmacologic interference with thioredoxin/thioredoxin reductase (e.g., TXNRD1 inhibition) further accelerates this process in SLC7A11-high cells, underscoring the dependence of cytoskeletal integrity on NADPH-supported reductive systems [17, 18]. This accumulation causes actin contraction and detachment from the plasma membrane, ultimately resulting in cell shrinkage and death.

Associated genes in tumor metabolic reprogramming

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to counteract oxidative stress induced by metabolic imbalance during growth and metastasis, thereby supporting rapid proliferation [28, 29]. Genes associated with disulfidptosis represent critical targets in tumor metabolic reprogramming, influencing cancer progression.

SLC7A11 (also known as xCT), a member of the solute carrier family 7, is a key protein regulating cancer cell metabolism. SLC7A11 mediates tumor cell death under glucose-depleted conditions. Experiments have shown that disulfidptosis induced by high SLC7A11 expression can be reversed by reducing agents, but this effect is absent in SLC7A11-knockdown or knockout tumor cells. Most cancer cells import cystine via SLC7A11, reducing it to cysteine for glutathione (GSH) synthesis, which acts as an antioxidant [17, 30]. Furthermore, SLC7A11 inhibits ferroptosis by mediating GPX4, a defense mechanism against ferroptosis [26]. Zhang et al. [31] found that amino acid transport in primary chronic lymphocytic leukemia cells depends on cysteine supplied by SLC7A11-related proteins secreted by stromal cells in the TME. This suggests that SLC7A11 may play a role in transporting key metabolites during cancer progression, affecting the TME. Overexpression of SLC7A11 in cancer cells leads to excessive cystine uptake, resulting in cytoplasmic accumulation and toxicity. This process relies heavily on glucose to supply NADPH, facilitating cystine-to-cysteine conversion. Disruption of this supply induces cystine and disulfide stress, supporting the theoretical basis for microenvironmental influence [11]. SLC7A11 overexpression is widely believed to promote tumor growth by protecting cells from oxidative stress-induced death and is elevated in cancer patients [26]. However, research by Yan et al. [17] indicates that SLC7A11 overexpression inhibits tumor metastasis, potentially due to increased sensitivity to oxidative stress in metastatic cancer cells, rendering them vulnerable to new microenvironments. SLC7A11 has demonstrated prognostic value in various solid tumors, including colorectal cancer [32], oral squamous cell carcinoma [33], and gliomas [34]. Chen et al. [35], using an esophageal squamous cell carcinoma mouse model, revealed that SLC7A11 may serve as a potential target for blocking cancer metastasis. Investigating the relationship between SLC7A11 expression levels, cell death, and solid tumor progression could offer new insights into cancer regulatory mechanisms.

SLC3A2 is often mentioned alongside SLC7A11, as the two form the Xc- cystine/glutamate antiporter, inhibiting ferroptosis. SLC3A2 typically forms heterodimers with L-type amino acid transporters (LAT), facilitating amino acid transport. By regulating LAT subunits, SLC3A2 promotes glutamate and leucine uptake, modulating the mTORC1 pathway and influencing cell growth and metabolism [36, 37]. SLC3A2 exhibits moderate to high expression in malignancies such as lung cancer, breast cancer, and gliomas [38, 39]. Hansen et al. [40] confirmed that SLC3A2 is a major risk factor in lung adenocarcinoma. Knockdown of SLC3A2 not only affects lung adenocarcinoma cell proliferation and migration but also indirectly influences macrophage polarization by mediating metabolic reprogramming. Similar conclusions were drawn from studies on oral squamous cell carcinoma by Sun et al. [41]. In summary, SLC7A11 and SLC3A2 are closely associated with disulfidptosis and exhibit potentialas pan-cancer prognostic markers, profoundly impacting tumor proliferation and metastasis.

RPN1 is a type I transmembrane protein in the endoplasmic reticulum (ER) and a subunit of oligosaccharyltransferase (OST), regulating N-glycosylation in coordination with ribophorin [42]. During ubiquitination, RPN1, as a proteasome subunit, recognizes ubiquitin and substrate domains, facilitating substrate binding and deubiquitination [43]. Abnormal OST subunits can lead to hypoglycosylation, protein misfolding, and ER stress, ultimately resulting in protein folding imbalance and overload [38, 40]. Studies have demonstrated a significant correlation between ER stress and cancer prognosis, particularly in breast cancer [44, 45]. Ding et al. [45] confirmed through in vitro experiments that RPN1 is strongly associated with cell proliferation and migration.

NCKAP1 was initially discovered in Alzheimer’s disease, where its expression is relatively low [46]. Inhibition of NCKAP1 can induce neuronal apoptosis [47]. As a subunit of the multi-protein Scar/WAVE complex (WAVE regulatory complex, WRC), NCKAP1 was identified by Liu et al. [11] through genome-wide CRISPR/Cas9 screening as a key target. Their study also confirmed that actin networks generated by the WRC may be involved in disulfidptosis. Further studies revealed that upstream activators such as RAC1 and other WRC subunits also participate in disulfidptosis. This was the first time that branched actin pseudopodia generated by WRC were implicated in this novel form of regulated cell death (RCD) [14]. NCKAP1, acting as a scaffold protein, binds RAC1 and activates WASF1. Once activated, the NCKAP1 complex ensures the functionality and invasive regulation of WASF1. WASF1 expression has been linked to the invasiveness of prostate, colorectal, pancreatic, and breast cancers [48]. In breast and liver cancers, high NCKAP1 expression correlates with prognosis, acting as a tumor suppressor by regulating the p53 pathway [48, 49]. However, some studies suggest that NCKAP1 may promote malignancy by destabilizing WASF1, enhancing cancer progression [50].

GYS1 encodes glycogen synthase, a key enzyme in glycogen biosynthesis that incorporates glucose residues into glycogen chains via glycosidic bonds [51]. Its activity varies with conformation: under low-glucose conditions, GYS1 remains inactive, but it can transition into an ordered complex that forms tetramers to extend glycogen primers [52]. Fully activated GYS1 catalyzes glycogen synthesis at multiple checkpoints. Hypoxia, a hallmark of the TME, modulates GYS1 expression at the transcriptional level [53]. GYS1 is detected across all breast cancer subtypes, particularly in triple-negative and Ki-67-high tumors. Knockdown of GYS1 inhibits breast cancer proliferation in vitro and in vivo, sensitizing cells to mitochondrial destabilization, making it a potential therapeutic target [54]. In some patients, GYS1 overexpression correlates with poor outcomes in acute myeloid leukemia and non-small cell lung cancer [55, 56]. Chen et al. [57] demonstrated that silencing GYS1 enhances sunitinib lethality in renal clear cell carcinoma, highlighting its therapeutic potential.

NDUFS1, one of seven nuclear-encoded core subunits of mitochondrial respiratory complex I, plays a vital role in mitochondrial function. Mutations in complex I genes are associated with various mitochondrial disorders and cancers [58]. Complex I dysfunction or hyperactivity can alter NAD+/NADH balance, promoting or inhibiting cancer progression depending on the context [59, 60]. NDUFS1, the largest subunit, can experience up to 80% activity loss due to mutations [61]. Clinical evidence indicates that NDUFS1 is a prognostic marker, with low expression reflecting metabolic shifts and poor outcomes in lung cancer [62]. Additionally, NDUFS1 promotes ROS production, facilitating HIF1α accumulation and nuclear translocation, driving gastric cancer progression [63]. In colorectal cancer, PHB2 directly interacts with NDUFS1 to activate the oncogenic OXPHOS pathway, underscoring its role in tumor metabolism [64]. NDUFA11, another nuclear-encoded complex I subunit, also exhibits mutations that disrupt enzyme stability, leading to complex I deficiency [65]. Mao et al. [66] found that suppressing NDUFA11 reduces ROS production, positioning it as a key target for oxidative stress regulation in breast cancer. NDUFA11 downregulation has been linked to amyloidosis in breast cancer cells, offering novel insights into cancer metabolism [67]. NUBPL is a complex I assembly factor whose depletion impairs mitochondrial function and has been implicated in complex I deficiency through exome sequencing studies [68, 69]. NUBPL amplification has been observed in colorectal cancer. Wang et al. [70] showed that NUBPL activates the ERK pathway, inducing epithelial-mesenchymal transition (EMT) and promoting metastasis. NUBPL also plays a role in melanoma metastasis [71]. Targeting NUBPL offers potential avenues for suppressing tumor reprogramming and metastasis.

LRPPRC is an RNA-binding protein characterized by 35-residue repeats [72]. It plays a crucial role in maintaining mitochondrial homeostasis by directly interacting with Beclin 1 and Bcl-2 to prevent reactive oxygen species (ROS) formation and preserve mitochondrial membrane potential [73, 74]. LRPPRC has been extensively studied in tumor progression. In diethylnitrosamine-induced HCC mouse models, LRPPRC expression is significantly reduced, and its depletion further increases the incidence of HCC [75]. However, in human HCC tissues, LRPPRC is significantly upregulated and correlates with poor patient survival [76]. In lung adenocarcinoma, LRPPRC expression is markedly lower in tumor tissues compared to adjacent non-tumor tissues. Knockdown or depletion of LRPPRC in bladder and lung cancer cells suppresses tumor growth both in vitro and in vivo [77]. In triple-negative breast cancer, overexpression of the LRPPRC protein enhances the expression of mitochondrial-encoded subunits involved in OXPHOS, thereby promoting tumor cell proliferation and metastasis. The commonly used gynecological drug gossypol acetate exhibits significant anti-tumor properties by binding to LRPPRC [78]. Although the prognostic role of LRPPRC in cancer remains inconclusive, its heterogeneous effects on tumors and enhanced sensitivity to chemotherapeutic agents highlight its significant research potential.

OXSM is a mitochondrial protein involved in the elongation of fatty acid chains [79]. Transcription factors, which bind to specific DNA sequences to regulate gene expression, play a critical role in the cis-regulatory action of enhancers on target genes. OXSM expression is closely associated with the key transcription factor CBFB [80, 81]. In colorectal cancer, CBFB deficiency may affect OXSM expression, potentially inducing resistance to mitogen-activated protein kinase (MAPK) pathway inhibitors [82]. In ovarian cancer, OXSM interacts with HSP60 to maintain its stability; knockdown of HSP60 significantly reduces OXSM expression, which is essential for lipoic acid synthesis, and promotes ovarian cancer cell progression [83]. OXSM functions as a central regulatory hub in cancer, triggering diverse biological effects [84].

Multiple experimental studies have validated the impact of key disulfidptosis-related genes on tumor growth in both in vitro and in vivo models. For instance, tumor cells with high SLC7A11 expression undergo disulfidptosis under glucose-deprived conditions, resulting in significant suppression of tumor proliferation, whereas SLC7A11 knockout abolishes this form of cell death [43]. Similarly, silencing GYS1 inhibits the proliferation and tumorigenicity of triple-negative breast cancer cells [54]. Moreover, RPN1 knockdown triggers severeendoplasmic reticulum stress and induces apoptosis in breast cancer cells, suggesting a critical role of RPN1 in tumor cell survival [44, 45]. NCKAP1, a core component of the WAVE signaling complex, is not only an essential gene in the disulfidptosis pathway but also modulates the invasive and metastatic potential of various cancer cells depending on its expression level [48]. These fundamental experimental findings collectively demonstrate the functional significance of disulfidptosis-associated genes in cancer progression and support their potential as therapeutic targets in oncology. In order to systematically summarize the roles of major disulfidptosis-associated genes, their proposed functions, representative cancer types, and therapeutic implications are presented in Table 1.

Table 1.

Cancer relevance and therapeutic effects of disulfidptosis-related genes

Representative cancer types	Therapeutic implications/effects
Esophageal squamous carcinoma, colorectal cancer, oral squamous carcinoma, gliomas [27–30]	Tumors with high SLC7A11 are more sensitive to GLUT inhibitors (e.g., BAY-876, KL-11743); potential prognostic biomarker and therapeutic target [10, 94–95].
Lung adenocarcinoma, breast cancer, gliomas, oral squamous carcinoma [33–36]	Knockdown suppresses proliferation/migration and reprograms immune metabolism; potential prognostic marker and metabolic target [35–36].
Breast cancer [39–40]	Silencing induces ER-stress-dependent apoptosis; potential synthetic lethal and protein-folding stress target [39–40].
Hepatocellular carcinoma, breast cancer [43–44]	WRC-targeting stapled peptides inhibit metastasis; NCKAP1 status may influence disulfidptosis-based therapeutic strategies [10, 43–45].
Breast cancer, AML/MDS, NSCLC, renal clear cell carcinoma [49–52]	GYS1 knockdown suppresses TNBC growth in vitro and in vivo, sensitizing cells to mitochondrial destabilization; silencing enhances sunitinib efficacy [49, 52].
Lung cancer, gastric cancer, colorectal cancer [57–58]	Low expression indicates poor prognosis; promotes ROS–HIF1α signaling in gastric cancer; targeting NDUFS1 may improve therapeutic responses [57–58].
Breast cancer [60–61]	Suppression reduces ROS production; potential oxidative stress regulator and metabolic vulnerability [60–61].
Colorectal cancer, melanoma [64–65]	Promotes metastasis via ERK/EMT signaling; potential target for blocking tumor progression and metastatic spread [64–65].
Hepatocellular carcinoma, bladder cancer, lung adenocarcinoma, triple-negative breast cancer [69–72]	Overexpression enhances OXPHOS and tumor proliferation; gossypol acetate binds LRPPRC with therapeutic potential; heterogeneous prognostic roles [69–72].
Colorectal cancer, ovarian cancer [76–77]	HSP60 stabilizes OXSM, promoting ovarian cancer progression; potential central metabolic regulator and therapeutic target [76–78].

Immune infiltration and drug sensitivity

TME is a micro-ecosystem composed of tumor cells, immune cells, and secreted small molecules [85]. Immune cells in the TME can suppress tumor growth by eliminating tumor cells or protect tumor cell subpopulations from immune therapies, leading to resistance [86–88]. Tumorigenic processes such as angiogenesis, invasion, immune evasion, and immunosuppression are closely linked to the TME [89, 90]. Growing evidence suggests that disulfidptosis may influence immune cell infiltration and the efficacy of immunotherapy by remodeling the tumor microenvironment. Guo et al. [91] identified PRN1 and GYS1 as key disulfidptosis-related genes and potential risk factors in gliomas. Their study established a correlation between disulfidptosis genes and the anti-inflammatory mechanisms of M2 macrophages. M2 macrophages secrete chemokines, including CCL-22 and CCL-24, to recruit Th2 cells and Tregs, exerting immunosuppressive effects. Additionally, IL4 and TGF-β secreted by M2 macrophages promote tumor growth, angiogenesis, and inhibition of T-cell-mediated anti-tumor responses [92]. Wang et al. [93], using unsupervised clustering machine learning algorithms, classified disulfidptosis-related transcriptional data in lung adenocarcinoma, identifying clusters with high disulfidptosis activity. Their findings confirmed that higher CD8 + T-cell infiltration correlates with favorable survival outcomes in lung adenocarcinoma patients [94], enhancing sensitivity to immunotherapy. Notably, Zhao et al. [95] applied disulfidptosis gene signatures to cluster bladder cancer cases, enabling risk stratification and personalized immunotherapy prediction. Interestingly, clusters with lower immune infiltration levels exhibited better prognoses, indicating that immune infiltration and disulfidptosis-related outcomes may vary across cancer types, necessitating further clinical validation. Existing cancer-related models, such as those for lung cancer [96], breast cancer [97], colorectal cancer [98], bladder cancer [95], and kidney cancer [99], leverage transcriptomic and clinical data to develop predictive frameworks. These models highlight the potential of disulfidptosis in cancer classification and drug prediction. However, most studies lack specific pharmacological data, underscoring the need for additional preclinical and clinical research to validate disulfidptosis-related mechanisms and gene roles in cancer prognosis and therapeutic prediction.

Disulfidptosis inducers and inhibitors

In recent years, a series of studies have focused on the regulatory network and therapeutic interventions of disulfidptosis, rapidly advancing our understanding of its underlying mechanisms and druggable potential. Comparisons between cancer cells with high SLC7A11 expression and low-expression control groups have demonstrated that high SLC7A11 expression correlates with heightened sensitivity to glucose transporter (GLUT) inhibitors [11, 100, 101]. This suggests that disulfidptosis may regulate cancer cell growth and death by targeting key genes. The development of inducers holds significant therapeutic value, while inhibitors are equally crucial. Inhibitors of cell death pathways are applicable not only to cancer immunotherapy but also to non-cancer conditions such as stroke [102]. Liu et al. [11] demonstrated the anti-cancer effects of disulfidptosis by inducing it in renal cancer cells using GLUT inhibitors. Mechanistically, UMRC6 renal cancer cells treated with BAY-876 (a GLUT1 inhibitor) and KL-11,743 (a combined GLUT-1 and 3 inhibitor) exhibited suppressed intracellular glucose uptake, which impaired the supply of glucose-6-phosphate to the PPP. This depletion markedly reduces NADPH generation, which is essential for cystine-to-cysteine reduction mediated by SLC7A11. As a result, cystine accumulates, generating abnormal disulfide bonds that disrupt actin cytoskeleton stability and trigger disulfidptosis in vivo. In xenograft models, administration of BAY-876 successfully reproduced this metabolic vulnerability, validating that GLUT inhibition acts as an upstream metabolic blockade directly promoting disulfide stress in tumor tissues. The efficacy of BAY-876 was validated in xenograft mouse models and patient-derived organoid models under conditions favoring disulfidptosis. Of note, lung cancer with KEAP1 mutations sustains NRF2 homeostasis, promoting SLC7A11 transcription and overexpression. KEAP1-mutated lung cancer cells exhibit glucose dependency; under glucose-depleted conditions, SLC7A11 mediates excessive cystine uptake, resulting in disulfide accumulation and subsequent disulfidptosis [103, 104]. Inducing disulfidptosis in lung cancer cells by aberrantly activating SLC7A11 through modulation of the KEAP1/NRF2 pathway offers a novel and precise therapeutic strategy for targeting treatment-refractory tumors. Itsuki et al. [105] found that Merlin, a key gene implicated in neurofibromatosis type 2, regulates SLC7A11 in high-density glioblastoma cells. Merlin downregulates SLC7A11 expression, inhibiting glucose deprivation-induced disulfidptosis. Additionally, ferroptosis inhibitors such as Ferrostatin-1 suppress p53 hyperactivation, preventing embryonic lethality caused by System Xc- activation. This suggests that targeting System Xc- to modulate disulfidptosis could provide new therapeutic insights. When β-mercaptoethanol interacts with cystine during cystine uptake through System Xc-, mixed disulfides enter the cell via System L, rapidly converting to cysteine. This highlights β-mercaptoethanol as a potential modulator of disulfidptosis through System Xc- [106].

Non-coding RNAs, such as long non-coding RNAs (lncRNAs), play regulatory roles in cellular processes by modulating cell death pathways through multiple targets [107]. Wu et al. [108] demonstrated that NEAT1, an lncRNA, regulates ferroptosis-related proteins, influencing ferroptosis sensitivity in lung cancer cells. Similarly, Guo et al. [91] validated through bioinformatics analysis the association between LNC02525 and disulfidptosis in glioma cells. Mechanistically, LNC02525 interacts with transcriptional regulators to upregulate SLC7A11 expression and preserve redox homeostasis, thereby attenuating disulfide stress-induced cell death. Silencing LNC02525 accelerates disulfidptosis, whereas its overexpression enhances tumor cell migration and invasion. Collectively, these findings indicate that LNC02525 functions not only as a molecular switch regulating disulfide stress but also as a promising therapeutic target. Targeted inhibition of LNC02525 may sensitize tumors to disulfidptosis-inducing agents, offering translational potential for precision oncology. LNC02525 knockdown promoted disulfidptosis, while overexpression enhanced glioma cell migration and invasion. Proteins also play crucial roles in immune responses during cancer immunotherapy. CD8 + T cells secrete interferon-γ, downregulating the expression of SLC7A11 and SLC3A2, subunits of System Xc-, both key genes in disulfidptosis. Tumor cells with reduced subunit expression exhibit decreased cystine uptake, potentially leading to disulfidptosis.

Recent advancements in nanoscale metal-organic frameworks (MOFs) for drug delivery, TME modulation, and cancer treatment have garnered attention [109, 110]. For example, Fe-based MOFs activate the TME in breast cancer, enhancing chemotherapy sensitivity through ferroptosis mechanisms and generating anti-tumor responses [111]. Similarly, Cu-based MOFs disrupt mitochondrial metabolism, lowering tumor tolerance and enhancing chemosensitivity [112]. Despite promising disulfidptosis-related model predictions in chemotherapy and immunotherapy, experimental drug validation remains limited. Further research on disulfidptosis mechanisms and metabolic pathways is needed to identify critical targets. Torin1 inhibits mTOR, limiting tumor cell growth and proliferation, and reduces System Xc- levels, protecting cells from disulfidptosis [113]. MG132, a proteasome inhibitor, stabilizes System Xc- through OTUB1 deubiquitination in a proteasome-dependent manner, inhibiting disulfidptosis [113, 114]. Targeting disulfidptosis through Torin1, MG132, or nanoscale materials holds promise as a novel direction for cancer and disease treatment.

Integration of disulfidptosis with current cancer therapies

Disulfidptosis can be pharmacologically exploited in combination with established anticancer modalities to exacerbate metabolic and redox crises in tumors. Inhibition of GLUT1/3 (e.g., BAY-876 or KL-11,743) reduces glucose influx and pentose phosphate pathway–derived NADPH, thereby intensifying SLC7A11-dependent disulfide stress and destabilizing the actin cytoskeleton [11]. Preclinical studies have demonstrated antitumor activity across multiple models, including head-and-neck squamous cell carcinoma and colorectal cancer, and recent reports have extended disulfidptosis induction to ovarian cancer models [115, 116]. A 2025 nanomedicine study introduced a disulfidptosis “nano-inducer” that disrupted tumor metabolism and reduced cell viability by approximately 80%, highlighting opportunities for combination with chemotherapy to broaden the therapeutic window [117]. Collectively, these findings support combining disulfidptosis inducers with cytotoxic or targeted agents to overcome metabolic plasticity and therapeutic resistance.

Emerging evidence also supports the rational integration of disulfidptosis with immunotherapy. Interferon-γ secreted by activated CD8⁺ T cells downregulates SLC7A11 and SLC3A2 (System Xc-), restricting cystine import and promoting disulfide accumulation [118]. This mechanism may synergize with pharmacological disulfidptosis induction during PD-1/PD-L1 blockade. Recent reviews and translational studies converge on this concept, suggesting that tumors with high SLC7A11 expression and strong glucose addiction may be particularly sensitive when immune pressure suppresses System Xc- [119]. In practice, actionable biomarkers to guide such therapeutic combinations include SLC7A11/SLC3A2 expression, GLUT1 levels, and interferon-γ–related gene signatures predictive of immune checkpoint inhibitor (ICI) benefit. Early multi-omics analyses incorporating disulfidptosis gene sets further support the use of these biomarkers for immunotherapy stratification across cancer types. In parallel, Generative Adversarial Network (GAN)–based gene-expression frameworks can improve feature representation and patient stratification under data-scarce conditions, complementing consensus clustering and penalized regression while keeping the pipeline transparent and reproducible [120].

Finally, concept-driven frameworks propose pairing disulfidptosis induction with radiotherapy or DNA-damaging chemotherapy to overwhelm antioxidant defenses and lower cell death thresholds, thereby enhancing cytotoxic efficacy. Reviews specifically argue that regimens designed to intensify metabolic stress could improve tumor control [121]. However, these studies also cautionthat therapeutic outcomes will depend on treatment schedule, dosing, and tumor genotype, underscoring the need for rigorously designed preclinical investigations and early-phase clinical trials.

Taken together, disulfidptosis is mechanistically distinct from iron- or copper-driven deaths because it hinges on NADPH-limited, disulfide stress–mediated actin destabilization, rather than lipid peroxidation or lipoylated-enzyme aggregation. This mechanistic signature links glucose addiction to drug screening with GLUT inhibitors and to immune rewiring: interferon-γ released by activated CD8⁺ T cells can transcriptionally repress SLC7A11/SLC3A2, curtail cystine import, and thereby create a redox context that synergizes with pharmacologic induction of disulfidptosis during PD-1/PD-L1 blockade [118, 119]. Strategically, tumor types with SLC7A11 upregulation and strong glucose dependence are plausible early candidates, with biomarkers including SLC7A11/SLC3A2 expression and GLUT1 levels.

Looking forward, an integrative therapeutic framework is warranted: pairing GLUT1/3 inhibition with cytotoxics, targeted agents, or immunotherapy, and—where appropriate—layering in radiation or DNA-damaging chemotherapy to overwhelm antioxidant buffering and lower death thresholds. Early reports even suggest that nanomedicine-based “disulfidptosis inducers” can disrupt tumor metabolism and enhance chemosensitivity, highlighting opportunities to broaden the therapeutic window. Notably, recent perspectives emphasize that these emerging therapeutic approaches suggest a promising future for cancer treatment, particularly through strategies centered on the SLC7A11–NADPH axis [122].

Conclusion

The discovery of disulfidptosis marks a significant advancement in the exploration of cell death. Disulfidptosis introduces new perspectives in tumor metabolic reprogramming, providing novel avenues for cancer treatment. Decoupling the SLC7A11 gene from the established paradigm of ferroptosis broadens our understanding of gene interactions and underlying mechanisms. Although unresolved questions remain—such as the induction of disulfide bonds during tumor metabolism, variations in immune cell infiltration across different cancers, and unidentified key targets and pathways—these gaps present opportunities for deeper investigation into the mechanisms and clinical applications of disulfidptosis. We anticipate the development of more targeted disulfidptosis inducers or inhibitors, potentially advancing cancer treatment and patient outcomes.

Figure 1. Schematic diagram of the conditions and mechanisms triggering disulfidptosis.In SLC7A11low cells, intracellular glucose uptake occurs via GLUT transporters, leading to the production of glucose-6-phosphate (G6P). This supports the pentose phosphate pathway (PPP), which generates NADPH, a crucial cofactor for reducing cystine to cysteine. Pyruvate production through glycolysis, followed by its metabolism via the TCA cycle and mitochondrial oxidative phosphorylation, ensures adequate energy supply and cellular homeostasis. The sufficient availability of NADPH prevents the accumulation of disulfides and avoids disulfide stress, maintaining the integrity of the actin cytoskeleton and promoting cell survival. Conversely, in SLC7A11high cells, glucose starvation or inhibition of glucose uptake leads to reduced intracellular glucose levels, decreased G6P production, and impaired PPP activity. This results in the depletion of NADPH, especially under conditions of excessive cystine uptake via System Xc-. The inability to reduce cystine to cysteine leads to disulfide accumulation and disulfide stress, which causes the formation of aberrant disulfide bonds in actin cytoskeletal proteins. This process activates the Rac–WAVE regulatory complex (WRC)–Arp2/3 signaling pathway, disrupting the F-actin network and triggering lamellipodia formation, ultimately leading to the collapse of the actin cytoskeleton and disulfidptosis. Abbreviations: GLUT, glucose transporter; SLC7A11, solute carrier family 7 member 11; PPP, pentose phosphate pathway; NADPH, nicotinamide adenine dinucleotide phosphate; G6P, glucose-6-phosphate; TCA, tricarboxylic acid cycle; Rac, Rac family small GTPase; WRC, WAVE regulatory complex; Arp2/3, actin-related protein 2/3.

Abbreviations

Bcl-2

B-cell lymphoma 2

CBFB

Core Binding Factor Beta

CCL-22

C-C Motif Chemokine Ligand 22

CCL-24

C-C Motif Chemokine Ligand 24

CD8+

Cluster of Differentiation 8 Positive

GSH

Glutathione

ER

Endoplasmic Reticulum

EMT

Epithelial-Mesenchymal Transition

GAN

Generative Adversarial Network

GPX4

Glutathione Peroxidase 4

GLUT

Glucose Transporter

GYS1

Glycogen Synthase 1

HCC

Hepatocellular Carcinoma

IL4

Interleukin 4

KEAP1

Kelch-Like ECH-Associated Protein1

LAT

L-type Amino Acid Transporters

lncRNAs

Long Non-Coding RNAs

LRPPRC

Leucine-Rich Pentatricopeptide Repeat-Containing Protein

MAPK

Mitogen-Activated Protein Kinase

MOFs

Metal-Organic Frameworks

NAD+/NADH

Nicotinamide Adenine Dinucleotide/Nicotinamide Adenine Dinucleotide Hydrogen

NADPH

Nicotinamide Adenine Dinucleotide Phosphate

NCKAP1

NCK-Associated Protein 1

NDUFS1

NADH Dehydrogenase (Ubiquinone) Fe-S Protein 1

NUBPL

Nucleotide Binding Protein-Like

OXPHOS

Oxidative Phosphorylation

OXSM

Oxysterol-binding Protein (OSBP)-Related Protein 2

OTUB1

OTU Deubiquitinase 1

p53

Tumor Protein p53

PCD

Programmed Cell Death

RCD

Regulated Cell Death

RPN1

Ribophorin I

SLC3A2

Solute Carrier Family 3 Member 2

SLC7A11

Solute Carrier Family 7 Member 11

Th2

T-helper 2

TGF-β

Transforming Growth Factor Beta

TME

Tumor Microenvironment

WRC

WAVE Regulatory Complex

ROS

Reactive Oxygen Species

Author contributions

R.C.: Conceptualization and original draft. J.Y. prepared Fig. 1. S.W. and T.Z.: Review and edit drafts. All authors reviewed the manuscript.

Funding

This work was supported by Health Science and Technology Innovation Team Construction Project of Shandong Province (Tao Zhao), Young experts of Taishan Scholars (tsqn202211380), and the China Postdoctoral Science Foundation (2023M741864).

Data availability.

No datasets were generated or analysed during the current study.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have read and approved the final version of the manuscript and agree to its publication.

Competing interests

The authors declare no competing interests.