In 2023, the World Heart Federation released the World Heart Report, which highlighted that cardiovascular diseases (CVDs) will remain the primary cause of death globally for decades (1). In 2023, Liu et al (2) identified a novel form of cell death termed disulfidptosis, which is triggered in cells with high expression of the cystine transporter solute carrier family 7 member 11 (SLC7A11) under glucose deprivation. Elevated SLC7A11 levels increase cystine uptake; however, under glucose-deficient or oxidative stress conditions, the depletion of nicotinamide adenine dinucleotide phosphate (NADPH) impairs the reduction of cystine to cysteine. This leads to disulfide stress (3), causing cytoskeletal dysfunction and, ultimately, cell death.

Since disulfidptosis was first discovered in cancer cells, existing studies have primarily focused on its role in oncology (4,5). Nevertheless, emerging research has suggested a potential link between disulfidptosis and CVDs (6–9). Disulfide stress, a key step in disulfidptosis, promotes antioxidant system collapse and reactive oxygen species (ROS) accumulation, exacerbating oxidative stress and potentially triggering cellular inflammation, autophagy and other pathological processes through cascade signaling pathways, worsening CVD progression (10). Given these findings, the present review aimed to explore the molecular mechanisms of disulfidptosis, emphasizing its pathophysiological impact on CVDs, and discussing novel perspectives for prevention and therapeutic intervention.

The present study is a narrative review, aiming to provide a comprehensive and critical discussion on the current research status, molecular mechanisms and potential implications of the novel cell death modality disulfidptosis in the field of CVDs. The PubMed database (https://pubmed.ncbi.nlm.nih.gov/) was searched using the following search strategy: [‘disulfidptosis’ (Title/Abstract) OR ‘disulfide stress’ (Title/Abstract) OR ‘SLC7A11’ (Title/Abstract) OR ‘xCT’ (Title/Abstract) OR ‘system Xc-’ (Title/Abstract)] AND [‘cardiovascular’ (Title/Abstract) OR ‘heart’ (Title/Abstract) OR ‘myocardial’ (Title/Abstract) OR ‘cardiomyocyte’ (Title/Abstract) OR ‘vascular smooth muscle cell’ (Title/Abstract) OR ‘endothelial cell’ (Title/Abstract) OR ‘fibroblast’ (Title/Abstract) OR ‘atherosclerosis’ (Title/Abstract) OR ‘ischemia’ (Title/Abstract) OR ‘heart failure’ (Title/Abstract)]. The present review primarily focused on original research articles, reviews, commentaries, and letters related to the molecular mechanisms of disulfidptosis and its potential role in CVDs, including myocardial infarction (MI), heart failure, aortic dissection and hypertrophic cardiomyopathy. The search was limited to articles published in English.

In the complex pathology of CVDs, disulfidptosis is likely to form intricate dialogue networks with other cell death modalities, collectively determining cellular fate and tissue outcome. The present review focused primarily on the crosstalk between disulfidptosis and ferroptosis, as disulfidptosis and ferroptosis share the most direct and close relationship. Similar to disulfidptosis, ferroptosis is notably linked to SLC7A11 and GSH (23).

In 2003, Dolma et al (24) discovered a novel compound, erastin, which could selectively eliminate tumor cells that expressed SV40 large T antigen (ST) and mutant Ras. This induced a new non-apoptotic form of cell death. In 2008, Yang and Stockwell (25) discovered two new compounds: RSL5 and RSL3. Similar to erastin, these compounds induced the iron-dependent, non-apoptotic cell death of tumor cells containing mutant Ras, which could be inhibited by the iron chelator deferoxamine and vitamin E. In 2012, the Stockwell laboratory formally named this cell death process ferroptosis (26).

Morphologically, ferroptosis is characterized by the loss of plasma membrane integrity, cell membrane rupture, mitochondrial shrinkage, rupture of the mitochondrial outer membrane, reduction or loss of cristae, and increased membrane thickening (27). At the molecular level, the key cause of ferroptosis is the inactivation of GSH peroxidase 4 (GPX4) (28). This results in failure to clear lipid peroxides promptly, which are subsequently catalyzed by divalent iron ions (Fe²⁺) via the Fenton reaction (29), ultimately damaging the integrity of the cell membrane system.

Initially, the inhibition of xCT on the cell membrane, whose key component is SLC7A11, prevents cystine uptake. This leads to intracellular cysteine depletion and an insufficient amount of raw material for GSH synthesis (30). Consequently, GPX4 becomes functionally stagnant due to the lack of its required cofactor (30). Long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid, are recognized and activated by acyl-CoA synthetase long chain family member 4 (31). Subsequently, under the action of lysophosphatidylcholine acyltransferase 3 (32), they are esterified and incorporated into membrane phospholipids. This results in cellular membranes, especially plasma and mitochondrial membranes, being enriched with PUFA-containing phospholipids (PUFA-PLs), which are notably susceptible to oxidation due to their bis-allylic structures (33). These membrane PUFA-PLs are catalyzed by various oxidase systems, generating phospholipid hydroperoxides (PL-PUFA-OOH) (34). Unstable intracellular Fe²⁺, via the Fenton reaction, convert PL-PUFA-OOH into highly reactive lipid radicals and lipid peroxyl radicals. Ferroptosis occurs when the clearance capacity of GPX4 is overwhelmed by the generation of lipid peroxides. In this process, the inhibition of SLC7A11 is one of the primary causes of GPX4 inactivation (35).

Under glucose starvation conditions, high SLC7A11 expression steers cells toward disulfidptosis, whereas if SLC7A11 is inhibited, cells tend to undergo ferroptosis. Thus, SLC7A11 acts as a common molecular switch for disulfidptosis and ferroptosis. In this way, cell fate depends on SLC7A11 activity and glucose availability (36). Simultaneously, the depletion of GSH during disulfidptosis creates a reduced cellular environment that is prone to ferroptosis. Furthermore, the disruption of cell membrane integrity caused by disulfidptosis might accelerate the diffusion of lipid peroxides and, thus, the process of ferroptosis (37).

The heart comprises intricately coordinated cell types, including contractile cardiomyocytes, pacemaker cells, supporting cells, immune cells and neural cells (38). Understanding the characteristics and interaction mechanisms of disulfidptosis in these cells is important for investigating CVD pathogenesis and developing targeted therapies. The following section discusses the effects of disulfidptosis on cardiomyocytes, vascular smooth muscle cells (VSMCs), endothelial cells (ECs), fibroblasts and macrophages (Fig. 2).

In a recent study, a natural resin extracted from Dracaena cochinchinensis demonstrated anti-inflammatory and neuroprotective properties against ischemic brain injury. Molecular docking analysis suggested that this resin may downregulate genes associated with disulfidptosis, including Flna, Iqgap1, Tln1 and Myh9. This indicates that its neuroprotective effects may be achieved through modulating these genes and thereby potentially influencing the disulfidptosis pathway. However, whether disulfidptosis is directly involved in mediating the resin's effects requires further experimental confirmation (75).

In the context of type A aortic dissection (TAAD), a recent study utilized machine learning to analyze disulfidptosis-related genes. Compared with healthy controls, CAPZB, PDLIM1, and MYH10 were identified as three hub genes, all of which exhibited lower expression levels in TAAD samples. This study also revealed marked differences in immune cell infiltration in TAAD tissues. These associative findings suggested that alterations in the expression of disulfidptosis-related genes may have been linked to changes in the immune microenvironment of TAAD; however, the specific causal mechanisms underlying this association warrant further investigation (8).

Regarding ischemic cardiomyopathy (IC), Tan et al (7) utilized bioinformatics and machine learning approaches to identify MYH9, NUBPL, MYL6, MYH10 and NCKAP1 as potential diagnostic biomarkers. These genes were associated with processes such as myocardial structure and immune cell infiltration. A diagnostic model based on these five genes demonstrated high predictive accuracy across multiple datasets, which was supported by preliminary validation in a mouse model of IC. Notably, this study primarily provided associative evidence at the gene expression level and has not directly confirmed the occurrence of disulfidptosis as a cell death event in IC models (7). Furthermore, studies on other CVDs, such as heart failure and hypertrophic cardiomyopathy, have observed changes in the expression of disulfidptosis-related genes, implying a potential association between disulfidptosis and CVDs (6,9,76).

In summary, thus far, research has predominantly focused on bioinformatics analyses and associative validation of expression changes in disulfidptosis-related genes across various CVDs. These findings offer important evidence and hypotheses that disulfidptosis may be involved in the pathological processes of CVDs. However, it must be emphasized that the association between these pathologies at the gene expression level does not equate to the functional activation of this cell death program. There is still a lack of key experimental evidence that directly confirms the occurrence of disulfidptosis, such as by detecting characteristic protein disulfide cross-linking and cytoskeletal collapse, in CVD models, both in vivo and in vitro. Therefore, future research should move beyond associative analyses and focus on verifying the specific mechanistic role of disulfidptosis in CVDs through direct molecular and functional experiments (Table I) (6–9,75).

Directly inhibiting SLC7A11 activity may be an effective approach for ameliorating disulfidptosis. SLC7A11 is the specific subunit of the xCT transporter on the cell membrane that is responsible for exchanging extracellular cystine for intracellular glutamate. Sulfasalazine, which is similar to the known xCT inhibitor erastin, effectively inhibits the expression and transport function of xCT, leading to GSH depletion in MDA-MB-231 and MDA-MB-468 cells (triple-negative breast cancer cell lines) (77). This mechanism has been shown to improve heart failure (78).

Furthermore, supplementing NAD⁺ represents another therapeutic strategy. NAD is a notable coenzyme required for cellular energy metabolism and redox homeostasis (79). Supplementation with NAD precursors can markedly increase myocardial NAD levels, improving cardiac function (80–82). Also, activators of malic enzyme can promote NADPH generation (83), which has been shown to alleviate pulmonary hypertension (84,85).

As disulfide bond formation is central to disulfidptosis, reducing the formation of aberrant disulfide bonds is important for disease mitigation. For example, the disulfide reductant dithiothreitol can reduce abnormal disulfide bonds, but its application is limited because of its strong odor and toxicity (86). Thioredoxin-interacting protein (TXNIP) is a novel molecular target that enhances endogenous disulfide reductase capacity (87). A single study has shown that cardiomyocyte-specific TXNIP C247S mutation knock-in mice exhibit higher survival rates and smaller infarct sizes following MI than control mice. Inhibition of thioredoxin by TXNIP promotes mitochondrial antioxidant capacity in cardiomyocytes, protecting the heart from MI-induced oxidative damage. This protective mechanism involves potent regulation of the thioredoxin system via a disulfide bond exchange mechanism in adult mouse cardiomyocytes (87).

Additionally, inhibiting actin cross-linking to protect the cytoskeleton represents another strategy to suppress disulfidptosis. Reportedly, in HL-1 murine atrial cardiomyocytes exposed to 2% ethanol, the cytoskeleton was markedly disrupted during apoptosis and the anti-apoptotic transcriptional coactivator Yes-associated protein (YAP) was inactivated. Conversely, the retrovirus-induced expression of constitutively active YAP and jasplakinolide-mediated stabilization of the actomyosin cytoskeleton prevented cardiomyocyte cell death (88).

The present review systematically elaborated on the core molecular mechanisms of disulfidptosis, a novel form of regulated cell death, and explored its potential role in CVDs from the perspective of different cell types within the cardiovascular system. The core of disulfidptosis lies in the lethal imbalance between SLC7A11-mediated cystine metabolism and glucose-dependent NADPH regeneration. The resulting disulfide stress directly affects the cytoskeletal system, which maintains cell morphology and function, and ultimately leads to cellular collapse. For example, disulfidptosis can: i) Impair cardiomyocyte contractility; ii) exacerbate inflammatory responses; iii) promote the synthetic phenotype switch, proliferation and migration of VSMCs; iv) aggravate vascular wall thickening; v) disrupt endothelial barrier function; vi) activate platelets and the coagulation cascade, triggering thrombosis and worsening tissue ischemia; and vii) induce myofibroblast generation, leading to excessive ECM deposition and accelerated fibrosis. Given that glucose starvation is a primary trigger for disulfidptosis and pathological scenarios such as myocardial ischemia-reperfusion injury, the hypoglycemic environment within atherosclerotic plaques and diabetic cardiomyopathy represent typical glucose starvation conditions; as such, the present review hypothesized a close relationship between CVDs and disulfidptosis.

Particularly noteworthy is the mirror-image crosstalk between disulfidptosis and ferroptosis. These cell death modalities share SLC7A11 as a common molecular switch, yet their outcomes diverge based on the cellular metabolic environment; high SLC7A11 expression under glucose starvation steers cells toward disulfidptosis, whereas its inhibition directs cells toward ferroptosis. This nuanced relationship suggests that in pathological contexts with marked metabolic fluctuations, such as myocardial ischemia-reperfusion injury, these two death modalities may coexist or occur sequentially, collectively amplifying tissue damage. To definitively establish the role of disulfidptosis in CVDs, future research should focus on the development and application of direct experimental biomarkers. Key approaches should include, but are not limited to: i) Employing non-reducing gel electrophoresis to detect aberrant disulfide crosslinking in cytoskeletal proteins, such as actin; ii) monitoring the NADPH:GSH ratio to confirm reductive power collapse; iii) assessing SLC7A11 protein levels and cystine transport activity; and iv) rigorously distinguishing disulfidptosis from ferroptosis through morphological observations, for example F-actin staining, combined with specific inhibitors. Establishing and standardizing these detection criteria should be a notable research priority for the next phase in this field.

Although bioinformatics analyses have revealed notable alterations in key disulfidptosis-related genes in CVDs, such as IC and TAAD, providing preliminary evidence for their association with disulfidptosis, it is important to recognize the apparent limitations of current studies. The primary challenge is that the majority of evidence remains indirect, lacking definitive proof of disulfidptosis occurrence in CVD models, such as in vivo animal models or clinical samples, including the direct detection of aberrant disulfide bonds in cytoskeletal proteins (for example, actin), within myocardial or vascular tissues.

However, studies suggest that small molecule inhibitors directly targeting SLC7A11 activity or NAD⁺ supplementation could be potential therapeutic strategies for mitigating disulfidptosis in CVDs. Their combined use may alleviate the adverse effects of NADPH depletion. Additionally, disulfide reductants, such as TXNIP, and the inhibition of actin cross-linking have shown potential in ameliorating the progression of CVDs. Therefore, this strategy represents a promising research topic.

Future investigations should explore the interaction mechanisms between disulfidptosis and ferroptosis by utilizing single-cell sequencing and multi-omics integration to identify novel therapeutic targets, providing novel options for the diagnosis and treatment of CVDs. Furthermore, it is important to precisely evaluate the contribution of disulfidptosis across a broader range of CVD models, such as hypertensive heart disease, myocarditis and heart failure, to clarify whether it acts as a primary driver or synergistic disruptor.