Mechanistic Role of Disulfidptosis in Type 2 Diabetes Mellitus

ABSTRACT

Disulfidptosis is a newly identified form of regulated cell death. It occurs under glucose‐starvation conditions and is characterized by metabolic dysregulation in cells with high expression of SLC7A11. Increased cystine uptake under these conditions leads to depletion of NADPH, ultimately triggering cell death. Current research on disulfidptosis has mainly focused on malignant tumors. However, the critical factors involved in disulfidptosis, including high SLC7A11 expression and NADPH depletion, may have potential relevance to type 2 diabetes mellitus (T2DM). Both insulin secretion and insulin resistance are regulated by NADPH levels, and SLC7A11 also plays a key role in glucose metabolism through maintaining redox homeostasis. Although the direct connection between disulfidptosis and T2DM remains to be experimentally verified, this review integrates existing studies to systematically examine their theoretical relationship from both mechanistic and therapeutic perspectives. It focuses on the roles of SLC7A11, NADPH, and other related factors in T2DM and its complications, aiming to provide a theoretical basis for developing new treatment strategies for diabetes.

This study elucidates the potential link between disulfidptosis and type 2 diabetes mellitus (T2DM). We propose that high SLC7A11 expression combined with glucose starvation triggers rapid NADPH depletion and severe disulfide stress. This leads to aberrant disulfide cross‐linking of actin cytoskeletal proteins and F‐actin network collapse, inducing disulfidptosis. This mechanism contributes to β‐cell injury and insulin resistance through redox imbalance and cytoskeletal dysfunction, offering a novel perspective on T2DM pathogenesis.

1. Introduction

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia and is closely related to genetic factors. According to the IDF Diabetes Atlas published by the International Diabetes Federation in 2021, the global number of people living with diabetes has reached 537 million and continues to rise [1]. In China, the prevalence of diabetes shows significant variation by age and gender. Among adults aged 18 years and older, the overall prevalence is 11.2%, while it increases to 31.8% in people aged over 70 years, with elderly women showing particularly high rates [2]. Despite the availability of various glycemic control methods and therapeutic approaches, both macrovascular and microvascular complications remain largely unavoidable. The pathophysiological mechanisms of diabetes are not only influenced by genetic predisposition but are also closely associated with cellular metabolism and epigenetic regulation. In particular, cell death, especially regulated cell death, plays a significant role in the pathogenesis and therapeutic strategies of diabetes.

In 2023, Professor Gan Boyi's team identified a novel form of cell death known as disulfidptosis [3]. This mechanism is triggered by the intracellular accumulation of disulfides (such as cystine), which induces disulfide stress, disrupts the cellular redox balance, and compromises cell survival. The process is dependent on NADPH generated through the pentose phosphate pathway (PPP), which neutralizes disulfide stress and helps maintain redox homeostasis. In cancer cells with high SLC7A11 expression, glucose deprivation leads to rapid NADPH depletion, resulting in disulfide accumulation and consequent cell death. Given the potential molecular links between disulfidptosis and type 2 diabetes mellitus (T2DM) and its complications, a comprehensive investigation of its mechanisms could not only deepen our understanding of diabetes pathogenesis but also provide a theoretical foundation for innovative therapeutic strategies. This review focuses on the translational potential of disulfidptosis in the pathophysiology and treatment of T2DM, aiming to open new avenues for metabolic intervention.

2. Disulfidptosis

2.1. Comparison of Disulfidptosis With Other Forms of Regulated Cell Death

Disulfidptosis is a newly discovered form of regulated cell death (RCD) that is mechanistically distinct from other types of cell death [3, 4]. This process is driven by high expression of the cystine transporter SLC7A11 (also known as xCT), which leads to excessive uptake of cystine (the oxidized dimer form of cysteine). Under glucose starvation, intracellular NADPH is rapidly depleted, resulting in abnormal accumulation of disulfides (mainly cystine), which subsequently induces collapse of the F‐actin cytoskeleton, ultimately leading to a characteristic cell death phenotype marked by cytoskeletal disintegration and cell contraction [3]. Compared with other types of RCD, disulfidptosis operates via a unique mechanism. Ferroptosis is triggered by iron‐dependent lipid peroxidation, characterized by glutathione (GSH) depletion, GPX4 inactivation, and mitochondrial shrinkage, along with a reduction or loss of mitochondrial cristae [5, 6]. Cuproptosis results from the binding of copper ions to lipoylated proteins in the tricarboxylic acid (TCA) cycle, which disrupts iron–sulfur cluster proteins and interferes with mitochondrial respiration [7]. Apoptosis is initiated via extrinsic or mitochondrial pathways that rely on caspase cascades, and is characterized by nuclear condensation and the formation of apoptotic bodies [8]. Necroptosis is mediated by RIPK3‐dependent phosphorylation of MLKL, leading to swelling and rupture of the plasma membrane and an inflammatory response [9]. Pyroptosis is a caspase‐1‐dependent form of inflammatory cell death triggered by inflammasome activation and mediated by gasdermin D (GSDMD), characterized by membrane pore formation, massive release of proinflammatory cytokines, and a potent inflammatory response [10]. These mechanistic comparisons underscore disulfidptosis as a unique form of cell death driven by a specific metabolic context involving massive disulfide bond accumulation and actin cytoskeleton collapse, uniquely dependent on the combined effects of glucose deprivation and elevated SLC7A11 expression [3, 4].

2.2. Disulfidptosis and the Pathogenesis of T2DM

Professor Gan Boyi's research team conducted a mechanistic investigation of disulfidptosis in tumor cells from six perspectives. Glucose starvation and high expression of SLC7A11 serve as essential preconditions. Proteomic analyses confirmed that these conditions induce aberrant disulfide bond cross‐linking in actin cytoskeletal proteins, triggering severe disulfide stress. This promotes abnormal disulfide bonding within cytoskeletal actin, leading to impaired F‐actin contractility and plasma membrane detachment. Activation of Rac promotes lamellipodia formation via the WAVE regulatory complex (WRC), and overexpression of a constitutively active form of Rac1 (Rac1 Q61L mutant) enhances lamellipodia formation and disulfidptosis in cells with high SLC7A11 expression. Moreover, GLUT inhibitors can specifically induce disulfidptosis in tumors with elevated SLC7A11 expression. This mechanism may be potentially associated with the pathogenesis of diabetes, as SLC7A11‐mediated redox imbalance, glucose metabolism dysregulation, and cytoskeletal dysfunction may collectively contribute to β‐cell injury and insulin resistance. These findings offer new insights into the pathological mechanisms underlying diabetes. Figure 1 illustrates the proposed mechanistic links between disulfidptosis and T2DM.

FIGURE 1.

Proposed mechanistic links between disulfidptosis and type 2 diabetes mellitus.

2.2.1. SLC7A11 And Diabetes Mellitus

Under glucose‐starved conditions, cell death in SLC7A11‐overexpressing cells is distinct from other forms of regulated cell death. Although ATP levels decrease under glucose deprivation, SLC7A11 overexpression slightly restores ATP levels but paradoxically accelerates cell death, indicating that this death mechanism is not due to ATP depletion. Treatment with thiol oxidants exacerbates cell death, whereas inhibition of disulfide accumulation prevents cell death in SLC7A11‐overexpressing cells. In contrast, knockout of SLC7A11 abolishes this effect. Therefore, cell death induced by the combination of SLC7A11 overexpression and glucose starvation is primarily driven by disulfide stress, and is independent of ATP depletion or cystine crystal formation. This unique form of cell death has been termed “disulfidptosis” [3].

As a key subfamily of genes encoding amino acid transporters, members of the solute carrier family 7 (SLC7), particularly SLC7A11—which encodes the xCT protein—form the System xc⁻ transporter in conjunction with its partner protein SLC3A2, which encodes 4F2hc. This transporter mediates a 1:1 stoichiometric exchange of extracellular cystine and intracellular glutamate [11]. Within this system, xCT is responsible for the transmembrane transport activity, while 4F2hc regulates the trafficking of SLC7A11 to the plasma membrane. The core function of System xc⁻ transporter lies in the import of cystine, which serves as a rate‐limiting substrate for the biosynthesis of GSH, the major endogenous antioxidant. Additionally, the system controls extracellular glutamate levels. GSH maintains redox homeostasis by scavenging reactive oxygen species [12]. Dysfunction of this system increases cellular sensitivity to oxidative stress and contributes to the progression of neurodegenerative diseases, positioning xCT as a critical node in cellular pathophysiology and a potential therapeutic target [11].

In patients with type 2 diabetes mellitus (T2DM), GSH deficiency is closely associated with impaired protein turnover efficiency [13]. GSH levels are significantly reduced in the erythrocytes of diabetic individuals [14], and elevating GSH concentrations plays a pivotal role in improving metabolic control. This is achieved by enhancing glucose metabolism and insulin sensitivity, lowering levels of free fatty acids and reactive oxygen species (ROS), and suppressing the acute hyperglycemia‐induced elevation of plasma cytokines. Individuals with impaired GSH synthesis capacity are not only more susceptible to T2DM and its complications, but also exhibit more severe GSH depletion in the presence of complications. Ferroptosis plays a key role in the pathogenesis of diabetes; both glucose‐stimulated insulin secretion (GSIS) defects and arsenic‐induced β‐cell injury are implicated in this process, and abnormal serum iron levels are directly linked to increased T2DM risk [15]. At the molecular level, SLC7A11‐mediated cystine uptake is critical for cell survival. Inhibition of this transporter leads to GSH depletion, oxidative stress, and activation of ferroptosis. Conversely, glutathione peroxidase 4 (GPX4) suppresses lipid peroxidation by utilizing reduced GSH, while overexpression of SLC7A11 promotes GSH synthesis and confers resistance to ferroptosis [16]. These findings highlight the central regulatory role of SLC7A11‐mediated cystine uptake in maintaining cellular homeostasis under oxidative stress conditions.

In non‐pregnant populations, hypomethylation at the cross‐ancestry CpG site cg06690548 of the SLC7A11 gene in peripheral blood leukocytes is significantly associated with elevated fasting insulin levels, suggesting its involvement in the genetic regulation of insulin resistance [17]. Transcriptomic analyses of mouse macrophages and dendritic cells revealed that SLC7A11 negatively regulates the wound healing process—its inhibition accelerates the kinetics of cutaneous wound closure and significantly reduces the accumulation of apoptotic cells at wound sites [18]. Notably, SLC7A11 functions as a negative regulator of erythrocytosis, and its targeted inhibition holds potential as a therapeutic strategy for improving the management of diabetes and chronic inflammation‐related skin wounds. Figure 2 illustrates the regulatory network linking SLC7A11 to diabetes and its complications.

FIGURE 2.

Core regulatory network of SLC7A11 in diabetes and its complications.

2.2.2. Disulfide Bonds and Diabetes Mellitus

Under glucose‐starved conditions, cells with high SLC7A11 expression experience disulfide stress induced by NADPH depletion, which promotes the formation of aberrant disulfide bonds on cysteine residues of proteins and significantly impairs cellular functions. Glucose deprivation induces an increase in disulfide bonds, with actin cytoskeletal proteins being the major targets of disulfide bond formation under such conditions. These proteins typically contain multiple cysteine residues, which readily form disulfide bonds during glucose starvation. Furthermore, cells with high SLC7A11 expression are particularly sensitive to disulfide stress, affecting the stability of the actin cytoskeleton. Notably, disulfide bonds in actin cytoskeletal proteins are significantly increased in SLC7A11‐high cells under glucose‐deprived conditions [3].

Disulfide bonds are covalent linkages formed by the oxidation of two thiol groups, typically occurring between two cysteine residues within a polypeptide chain. These bonds contribute to the stabilization of protein structures, prevent undesired side reactions involving cysteine, and participate in the regulation of protein activity [19]. Intracellularly, the formation of disulfide bonds plays a role in sensing and transducing oxidative stress signals, whereas extracellularly, the reduction or isomerization of disulfide bonds is involved in signal transduction or effector functions and plays a critical role in platelet function.

In both rodent and human β‐cells, alterations in the disulfide bond pattern of proinsulin can affect insulin production and secretion. Studies using Akita and Munich mouse models have demonstrated that cysteine mutations in proinsulin disrupt proper disulfide bond formation. This disruption exacerbates endoplasmic reticulum (ER) stress, leading to insulin‐deficient diabetes and ultimately resulting in β‐cell dysfunction. In addition, intracellular oxidative or reductive stress may impair the native disulfide pairing in proinsulin, thereby triggering the onset or progression of type 2 diabetes [20, 21]. Figure 3 illustrates the relationship between disulfide bonds and the pathogenesis of diabetes.

FIGURE 3.

The relationship between disulfide bonds and the pathogenesis of diabetes.

2.2.3. Disulfide Bonds in Cytoskeletal Proteins Under Disulfidptosis

Under glucose‐starved conditions, NADPH depletion occurs in cells with high SLC7A11 expression, leading to the formation of disulfide bonds within actin cytoskeletal proteins. In these SLC7A11‐overexpressing cells, non‐reducing protein blotting reveals a decreased migration rate of actin cytoskeletal proteins, suggesting the presence of disulfide bond formation. This migration delay is abolished by CRISPR‐Cas9‐mediated knockout of SLC7A11, indicating that SLC7A11‐mediated cystine uptake is critical to this process. Treatment with 2‐deoxy‐d‐glucose (2DG) can prevent cell death under these conditions, whereas reactive oxygen species (ROS) scavengers are ineffective. Immunoprecipitation combined with non‐reducing SDS‐PAGE further confirms the formation of intermolecular disulfide bonds between actin cytoskeletal proteins under glucose deprivation. The combination of elevated cystine uptake due to SLC7A11 overexpression and glucose starvation induces severe disulfide stress, thereby promoting aberrant disulfide bond formation within the actin cytoskeleton through a ROS‐independent mechanism [3].

The cytoskeleton is a complex and dynamic network that plays a crucial role in maintaining cell shape, mechanical strength, adhesion, division, migration, as well as in cellular responses to stress and environmental adaptation. It is primarily composed of four structural elements: actin filaments, microtubules, intermediate filaments, and septins, each of which performs distinct and essential functions within the cell [22]. The cytoskeleton not only serves as a target for numerous intracellular signaling pathways but also provides an organized platform for the transport and regulation of cellular components, bridging the nucleus with the extracellular environment. As such, the cytoskeleton acts as an effective stress sensor and integrator, mediating adaptive cellular responses [23].

Actin is a major component of the cytoskeleton and is involved in various cellular functions, including proliferation, adhesion, motility, growth, and cytokinesis. In β‐actin molecules, cysteine residues play a role in actin polymerization and filament formation. During this process, β‐actin undergoes intracellular oxidation, leading to the formation of a disulfide bond between its thiol group at Cys 374 and GSH. This oxidative modification of β‐actin is critical for the formation of GSH disulfides following integrin engagement and cell spreading [24]. During cell adhesion, glutathionylation of actin leads to the disassembly of myosin filaments. Additionally, oxidation of β‐actin can promote the formation of intermolecular disulfide bonds between Cys 374 residues of adjacent β‐actin molecules, thereby facilitating cytoskeletal reorganization. In the context of disulfidptosis, excessive accumulation of intracellular disulfide‐containing molecules induces disulfide stress, which interacts with actin cytoskeletal proteins and ultimately results in actin network collapse and cell death. NADPH can inhibit disulfidptosis by reducing disulfide bonds in actin cytoskeletal proteins [25].

In studies on cell‐based therapies for diabetes [26], manipulation of cell–biomaterial interactions and the actin cytoskeletal state altered the timing of endocrine transcription factor expression and the ability of pancreatic progenitor cells to differentiate into SC‐β cells. This approach was able to stimulate glucose‐stimulated insulin secretion (GSIS) and reverse diabetes more rapidly in mouse models, demonstrating its therapeutic potential. The polymerization state of the actin cytoskeleton in pancreatic progenitor cells is a key regulatory factor determining pancreatic cell fate. This state is associated with the expression of crucial pancreatic transcription factors, including NEUROG3 and NKX6‐1. The impact of cytoskeletal protein alterations on diabetes is shown in Figure 4.

FIGURE 4.

Effects of cytoskeletal protein changes on diabetes.

2.2.4. F‐Actin Contraction and Diabetes Mellitus

Under glucose starvation conditions, cells with high SLC7A11 expression exhibit pronounced alterations in the actin cytoskeleton, including cell contraction and actin filament condensation. This actin cytoskeletal remodeling leads to the detachment of actin from the cell membrane [3]. The morphological changes of the intracellular actin cytoskeleton are SLC7A11‐dependent. These alterations can be alleviated by cystine starvation, 2‐deoxyglucose (2DG), or the reducing agent 2‐mercaptoethanol (2ME), but not by the antioxidants Tempol or Trolox. Abnormal disulfide bond formation induced by glucose deprivation in cells with high SLC7A11 expression is the primary driver of actin contraction and detachment.

Actin is responsible for forming the filamentous network within cells, providing both mechanical support and motility. The cytoskeleton formed by polymerized actin plays a critical role in maintaining cell morphology and function, and its mesh‐like structure can remain intact even after the plasma membrane is disrupted [27]. Actin filaments offer structural support and mobility to both amoebae and animal cells. The interactions among actin filaments, microtubules, and intermediate filaments further enhance the mechanical strength of the cytoskeleton [28].

In streptozotocin (STZ)‐induced diabetic mouse models, diabetes has been shown to disrupt the cellular cytoskeleton. Fluorescence‐based quantification of F‐actin revealed that the structure of F‐actin in the striated muscle of diabetic animals was more disorganized and significantly reduced in content [29, 30]. This disruption and discontinuity of F‐actin filaments compromise intercellular communication and muscle cell signal transduction. Consequently, the structural integrity of muscle fibers is altered, potentially leading to impaired muscle function, such as reduced cellular differentiation, muscle weakness, and diminished regenerative capacity following injury [29]. The relationship between F‐actin contraction and diabetes is illustrated in Figure 5.

FIGURE 5.

The relationship between F‐actin contraction and diabetes.

2.3. The WAVE Regulatory Complex and Rac

A suppressor hit screen identified SLC7A11, SLC3A2, RPN1, and NCKAP1 as essential genes involved in the process of disulfidoptosis [3]. Among these, NCKAP1 is a core component of the WRC. Loss of NCKAP1 suppresses disulfidoptosis without affecting SLC7A11 protein levels, cystine uptake capacity, or the NADP⁺/NADPH ratio. Instead, NCKAP1 deficiency significantly reduces glucose starvation‐induced disulfide bond formation between actin cytoskeletal proteins, F‐actin contraction, and its detachment from the plasma membrane. Conversely, NCKAP1 overexpression induces disulfidoptosis. The WRC promotes actin polymerization and lamellipodia formation by generating a branched cortical actin network beneath the plasma membrane. Deletion of other WRC components similarly suppresses disulfidoptosis. Rac promotes lamellipodia formation by activating the WRC; overexpression of a constitutively active form of Rac1 enhances lamellipodia formation in SLC7A11‐high cells and accelerates disulfidoptosis. Thus, the Rac‐WRC pathway serves as a key regulator of disulfide bond formation between actin cytoskeletal proteins during disulfidoptosis.

The WRC is composed of five key proteins: CYFIP (also known as Sra1), NAP (Nckap1), ABI, HSPC300 (Brk1), and WAVE [31]. The interaction within the WRC is involved in the regulation of membrane protrusion and cell migration, which plays a critical role in disease progression. As a key cellular regulator, WRC is essential for actin dynamics and membrane remodeling. Aberrant WRC function has been associated with a variety of diseases, as mutations or altered expression levels may contribute to disease development. The core aspect of WRC regulation lies in its activation. Rac1, a member of the Rho family of GTPases, is a common activator of the WRC. In its resting state, the WRC remains autoinhibited, and binding of Rac1 allosterically activates it by releasing the WCA (WAVE homology domain) motif.

Suppressing the expression of human Nap1 (NCKAP1) can induce neuronal apoptosis [32]. NCKAP1 is involved in a broad range of cytoskeletal functions and regulates various intracellular processes such as apoptosis, migration, invasion, and neuronal differentiation. It also plays a crucial role in the pathogenesis of several diseases [33]. The polymerization of actin and the extension of lamellipodia require the involvement of WAVE1. Nap1 directly interacts with Rac1 and other components of the WRC, including Cyfip1 and Abi1, to regulate WAVE1 activity [33]. Nap1 localizes along the lamellipodial edge and mediates not only cell migration and layer‐specific neuronal differentiation in the developing neocortex but also remodeling of motility and adhesion mechanisms [34].

Rac plays a pivotal role in the formation of lamellipodia. By activating the downstream effector WAVE, Rac reorganizes the actin cytoskeleton, thereby promoting changes in cell morphology and migration. Rac is essential for the formation of membrane ruffles, cell migration, and axon extension [35]. Even in the absence of the WRC, cells can still form lamellipodia‐like structures (LLS) through Rac activity [36]. A Rac‐dependent but WRC‐independent actin remodeling pathway has also been demonstrated in fibroblasts, suggesting the generalizability of this mechanism across different cell types.

Extracellular vesicles (EVs) are nanoscale particles that circulate in the bloodstream and carry molecular cargo. EVs derived from individuals with diabetes enhance lamellipodia formation and cell migration. Lamellipodia promote cell migration by driving the protrusion of the leading edge through actin polymerization and remodeling. EVs from diabetic patients carry cargo that promotes endothelial cell migration, thereby facilitating angiogenesis. Compared to EVs from normoglycemic individuals, EVs from diabetic subjects significantly increase endothelial cell motility [37]. Figure 6 illustrates the effects of WAVE complex‐ and Rac‐mediated lamellipodia on diabetes.

FIGURE 6.

The effects of WAVE complex‐ and Rac‐mediated lamellipodia on diabetes.

2.3.1. Effects of GLUT Inhibitors on Diabetes Mellitus

Glucose transporter inhibitors, such as BAY‐876 and KL‐11743, induce death in cells with high SLC7A11 expression by inhibiting glucose uptake. This leads to an increased NADP/NADPH ratio, the formation of disulfide bonds in actin cytoskeletal proteins, and the collapse of the F‐actin network. This effect resembles conditions of glucose starvation and does not cause significant changes in body weight or pathological alterations in major organs of animals [3].

Facilitative glucose transporters (GLUTs) are transmembrane proteins that passively transport glucose or other substrates across the cell membrane along their concentration gradients. GLUTs exhibit distinct expression patterns throughout the human body and play important and unique roles in glucose homeostasis [38]. GLUT1 maintains the basal glucose supply in all normal tissues, GLUT2 is involved in insulin secretion in the pancreas, GLUT3 mediates glucose uptake in neurons, and GLUT4 regulates insulin‐dependent glucose transport in muscle and adipose cells [39]. GLUT inhibitors can specifically block glucose metabolism, resulting in a rapid collapse of the NADH pool and a significant increase in aspartate levels, indicating a dramatic shift in mitochondrial oxidative phosphorylation [40].

GLUT1 and GLUT3 are the primary glucose transporters in human pancreatic islets and β cells [41]. GLUT4‐mediated glucose transport is essential for adipose tissue, muscle, and cardiac tissues, and a reduction in its signaling leads to insulin resistance. In diabetic transgenic mouse models, increased expression of GLUT4 in skeletal muscle improves overall glucose homeostasis [42]. However, since glucose uptake is crucial for all cells, reducing GLUT activity is generally not feasible [43]. The expression of GLUT2 is necessary for the physiological regulation of glucose‐sensitive genes, and its inactivation in the liver impairs glucose‐stimulated insulin secretion, revealing a liver–β cell axis that may depend on bile acid regulation of β cell secretory capacity [44]. In the nervous system, GLUT2‐dependent glucose sensing is vital for β cell mass and function. Techniques, such as electrophysiology and optogenetics, have shown that hypoglycemia activates neurons expressing GLUT2 in the nucleus tractus solitarius, thereby stimulating glucagon secretion. In humans, mutations in the GLUT2 gene cause transient neonatal diabetes and increase the risk of fasting hyperglycemia and type 2 diabetes [44]. Experimental studies combining GLUT inhibitors with insulin indicate that the insulin molecules in these analogs elicit glucose responses through conjugation with GLUT inhibitors, and their binding affinity to endogenous GLUTs is regulated by plasma and tissue glucose levels [45]. Figure 7 illustrates the connection between GLUT inhibitors and the pathogenesis of diabetes.

FIGURE 7.

The relationship between GLUT inhibitors and the pathogenesis of diabetes.

3. The Potential of Disulfidptosis for the Treatment of Diabetes Mellitus Type 2

3.1. Therapeutic Potential of Disulfidptosis

NADPH and SLC7A11 are two critical components in disulfide stress‐induced cell death [3], regulated by cystine uptake and glucose metabolism pathways. When the supply of NADPH is insufficient to reduce cystine to cysteine, disulfide stress occurs, inducing the formation of disulfide bonds in actin cytoskeletal proteins, cytoskeletal contraction, detachment from the plasma membrane, and ultimately leading to cell death. Under glucose starvation conditions, cells with high SLC7A11 expression promote the formation of disulfide bonds in actin cytoskeletal proteins and F‐actin contraction, triggering effective cell death. Treatment with reducing agents that prevent disulfide stress, such as DTT, 2ME, and TCEP, completely inhibits cell death.

Currently, there is no direct evidence establishing a definitive link between disulfide stress‐induced cell death and T2DM. However, the potential role of the disulfide stress mechanism in the prevention and treatment of T2DM warrants attention. Oxidative stress is a key factor in the pathological process of T2DM, impairing pancreatic β‐cell function, exacerbating insulin resistance, and disrupting glucose regulation, thereby promoting disease progression [46]. The function of SLC7A11 is as a cystine/glutamate antiporter that maintains intracellular redox balance by facilitating glutamate synthesis and reducing oxidative stress‐induced cellular damage. This transporter is a critical component of the cellular antioxidant defense system [16]. The primary role of NADPH is to scavenge reactive oxygen species (ROS), and targeting NADPH‐related pathways may offer novel therapeutic strategies for insulin resistance. The disulfide stress‐induced cell death mechanism may intersect with T2DM by regulating SLC7A11‐mediated cystine metabolism, enhancing NADPH‐dependent antioxidant capacity, and counteracting disulfide bond stress, thereby indirectly affecting diabetes‐related cellular dysfunction [31]. Although the direct relationship between disulfide bond dysregulation and T2DM remains to be confirmed, in‐depth research into its molecular mechanisms—such as the SLC7A11‐cystine metabolic axis and NADPH redox regulation—could provide a theoretical foundation for elucidating novel pathogenic mechanisms and experimental intervention strategies for diabetes.

Significant differences exist in the pathway activities of various cell death modes across different renal cell types. Pathway activity analysis indicates that CTI exhibits high pathway activity in intracellular death, copper toxicity, disulfide stress‐induced cell death, alkalosis, and apoptosis. The activity of programmed cell death (PCD) pathways correlates with the glomerular filtration rate (GFR), with disulfide stress‐induced cell death showing a negative correlation with GFR [47]. Four key genes associated with diabetic nephropathy—CXCL6, CD48, C1QB, and COL6A3—may be related to the deterioration of renal function in patients with diabetic nephropathy. Blocking the expression of these key genes could potentially delay disease progression [48]. Furthermore, these four genes, which have high diagnostic value, are associated with disulfide stress‐induced cell death, and their expression levels may be closely linked to the decline of renal function in diabetic nephropathy. Disulfide stress‐induced cell death is expected to become a novel therapeutic target for patients with diabetic nephropathy, as inhibiting this form of cell death may slow the deterioration of renal function. The impact of disulfide stress‐induced cell death regulatory pathways on diabetes is illustrated in Figure 8.

FIGURE 8.

The influence of disulfidptosis‐regulating pathways on the pathogenesis and progression of diabetes.

3.2. NADPH

Cellular production of NADPH is promoted through multiple pathways, including the pentose phosphate pathway, the citric acid cycle, and fatty acid metabolism. NADPH is primarily known for its role in biosynthetic reactions and for maintaining redox balance by regenerating reduced glutathione. It regulates oxidative stress, inflammatory responses, and also participates in lipid metabolism [49]. Oxidative stress, inflammatory responses, lipotoxicity, and NADPH oxidases (NOX), which produce ROS using NADPH as a substrate, are all associated with insulin resistance. Insulin resistance refers to the disruption of insulin signaling pathways, leading to impaired glucose uptake and metabolism, and is a key pathological mechanism in the development of diabetes. In diabetes, alterations occur in glucose, amino acids, and fatty acids. Elevated blood glucose levels in diabetic patients can increase NADPH production via the pentose phosphate pathway, which affects the redox reactions and metabolic signaling networks controlling insulin secretion in pancreatic β cells. Prolonged hyperglycemia induces oxidative stress that may deplete NADPH necessary for antioxidant defenses, such as the regeneration of reduced glutathione. Elevated glucose and pro‐inflammatory cytokines activate various signaling pathways, ultimately causing pancreatic β cell death through mechanisms, including necroptosis, apoptosis, ferroptosis, and necrosis. NADPH plays a dual role in the ferroptosis of pancreatic β cells, both promoting ferroptosis and maintaining cellular antioxidant defense.

NADPH oxidase (NOX), which uses NADPH as a substrate to produce ROS, is closely associated with the development of insulin resistance. Excessive activation of NOX enzymes not only intensifies oxidative stress but also depletes cellular NADPH reserves, thereby impairing the antioxidant capacity of cells. This forms a vicious cycle that perpetuates insulin resistance. In diabetes, the NADPH oxidase system is activated, particularly the NOX4 isoform, leading to increased ROS generation and oxidative stress, ultimately resulting in damage to multiple organs such as the liver and kidneys. NOX4 is a key pathogenic factor in oxidative stress‐related complications of diabetes. Inhibiting NOX4 can alleviate diabetes‐related tissue damage, suggesting its potential as a therapeutic target. For example, sitagliptin may exert hypoglycemic effects and improve liver function parameters by modulating NOX4 enzyme activity. These findings indicate that the NADPH‐NOX4 axis serves as a critical bridge connecting diabetes and its complications [50].

3.3. SLC7A11

SLC7A11 is a key subunit of the cystine/glutamate antiporter known as system Xc⁻, responsible for transporting extracellular cystine into the cell while exporting intracellular glutamate. Once inside the cell, cystine is reduced to cysteine, which is subsequently used for the synthesis of GSH to maintain redox homeostasis. However, under glucose‐deprived conditions, cells with high SLC7A11 expression suffer from insufficient NADPH supply, which is essential for cystine reduction. This leads to abnormal accumulation of cystine and the induction of disulfide stress. Excess cystine forms aberrant disulfide bonds with thiol groups (–SH) on cytoskeletal proteins such as actin, disrupting the structural integrity of the cytoskeleton and ultimately triggering disulfidoptosis.

3.3.1. Metabolic Regulation by SLC7A11

As a cystine–glutamate antiporter, SLC7A11 maintains redox homeostasis by facilitating the uptake of cystine for GSH synthesis. Inhibition of SLC7A11 reduces GSH production and increases lipid peroxidation in the cell membrane. Regulating the expression of SLC7A11 or enhancing its protein activity helps alleviate oxidative stress (OS), maintain intracellular redox balance, and control the onset and progression of endocrine and metabolic disorders such as diabetes. SLC7A11 is involved in glucose metabolism [51] and affects diabetic wound healing by modulating glucose metabolism in dendritic cells (DCs) [49]. In diabetic wounds, high SLC7A11 expression in DCs impairs their ability to clear apoptotic cells, thereby hindering tissue repair. In contrast, SLC7A11‐deficient DCs utilize glycogen stores to enhance aerobic glycolysis, improve phagocytic capacity, and accelerate wound healing. Tumor cells with high SLC7A11 expression rely heavily on glucose metabolism to maintain redox balance; glucose supports cystine metabolism and redox homeostasis via glycolysis (providing ATP) and the pentose phosphate pathway (generating NADPH). Glucose deprivation exacerbates cell death in SLC7A11‐overexpressing tumor cells. Upregulation of SLC7A11 enhances cell death under glucose‐limited conditions by increasing mitochondrial activity, while upregulation of its antagonists promotes cell death by disrupting glutamine metabolism. These findings identify SLC7A11 as a critical target for regulating the metabolic vulnerability of cancer cells. Therefore, SLC7A11 enhances the glucose dependence of cancer cells, thereby promoting their survival and proliferation [52].

T2DM is characterized by insulin resistance and β‐cell dysfunction, and its pathogenesis is associated with the accumulation of pancreatic islet amyloid and the infiltration and activation of macrophages. During this process, the upregulation of SLC7A11 is promoted to ensure cystine supply for the inflammatory response, maintain redox homeostasis (by reducing ROS), and protect islet function [53]. According to Baat et al. [54], deletion of SLC7A11 reduces GSH levels in islets and upregulates γ‐glutamyl cyclotransferase (CHAC1), which degrades GSH and releases cysteine, leading to decreased cystine levels, aggravated endoplasmic reticulum (ER) stress, and impaired insulin secretion. SLC7A11 is thus essential for maintaining GSH levels in islet β‐cells and insulin production. In diabetic kidney disease (DKD), the expression of SLC7A11 and GPX4 in renal tubules is reduced, leading to ferroptosis. However, SGLT2 inhibitors (such as empagliflozin) [55] and quercetin (QCT) [56] can upregulate SLC7A11 and GPX4, thereby synergistically alleviating ferroptosis and renal injury. Ankylosing spondylitis (AS), a cardiovascular complication of T2DM, can also be improved by the natural flavonoid hydroxysafflor yellow A (HSYA) [57], which suppresses miR‐429 expression, upregulates SLC7A11 and GPX4, reduces ROS and malondialdehyde (MDA) levels, and inhibits cardiac ferroptosis. In addition, HSYA reduces the expression of vascular adhesion molecules (VCAM‐1 and ICAM‐1) and improves endothelial dysfunction, providing a potential therapeutic target for the co‐treatment of T2DM and AS.

3.3.2. SLC7A11 Agonists and Inhibitors

Several natural bioactive compounds, such as quercetin (QCT), hydroxysafflor yellow A (HSYA), arbutin (ARB), epigallocatechin gallate (EGCG), and mangiferin, along with pharmaceutical agents like empagliflozin and metformin, have demonstrated the potential to upregulate the expression of SLC7A11 [51]. SLC7A11 has been closely associated with tumor progression, metastasis, chemoresistance, and poor prognosis.

S‐(4)‐CPG and sulfasalazine have been identified as effective inhibitors of SLC7A11, capable of suppressing GSH production and attenuating tumor growth in vivo. In glioma cells, SLC7A11 is associated with cellular infiltration, and both sulfasalazine and (S)‐4‐CPG can inhibit glioma invasion by blocking SLC7A11 activity [58]. Hu [59] developed a potent SLC7A11 inhibitor, HG106, through function‐based chemical screening. In KRAS‐mutant lung adenocarcinoma, HG106 induces oxidative stress (OS) and endoplasmic reticulum (ER) stress‐mediated apoptosis, significantly reducing cystine uptake and intracellular GSH synthesis, thereby downregulating SLC7A11 expression, suppressing tumor growth, and prolonging patient survival. TP53 and BAP1 regulate the transcription of tumor suppressor genes. The expression of SLC7A11 is suppressed as promoted by BAP1 [60], which has been shown to reduce cystine uptake and glutathione synthesis. Other SLC7A11 inhibitors with anticancer properties include sorafenib, erastin, and imidazole ketone erastin (IKE), which promote iron accumulation by restricting cystine uptake. Currently, only sulfasalazine and sorafenib have been applied in clinical practice [51].

3.3.3. Potential of SLC7A11 for Diabetes Treatment

In a study on breast cancer suppression [61], metformin was found to downregulate the expression of the key ferroptosis pathway protein SLC7A11, thereby inducing ferroptosis to inhibit breast cancer. Ginsenoside Rg5, known for its hypoglycemic effects, improves insulin resistance in diabetic mice. It promotes diabetic wound healing by suppressing the expression and activity of SLC7A11, thereby inhibiting glycolysis‐induced dendritic cell activation [62]. Type 2 diabetes is associated with the formation of islet amyloid and the infiltration and activation of macrophages in pancreatic islets [54]. During this anabolic process, SLC7A11 is upregulated to provide sufficient cystine, which helps alleviate inflammation‐related ROS production. In the MyoGlu study (myokine‐glucose metabolism) [17], SLC7A11 mRNA expression was positively correlated with insulin sensitivity in muscle but negatively correlated with insulin sensitivity in adipose tissue. This suggests that elevated cystine/glutamate transport is associated with lower insulin resistance in muscle and higher insulin resistance in adipose tissue.

Although research on disulfidptosis has primarily emerged from the field of oncology—particularly in tumor cells with high SLC7A11 expression—it remains to be determined whether this mechanism is applicable to T2DM. In cancer cells [63], SLC7A11 is significantly upregulated in gastric cancer tissues, and its knockdown suppresses cell proliferation and migration while enhancing sensitivity to ferroptosis by modulating the PI3K/AKT signaling pathway. It primarily promotes tumor survival and progression through the inhibition of ferroptosis. In a mouse study on glucose metabolism [54], insulin secretion and glucose clearance capacity were enhanced at a young age but became impaired with aging and a high‐fat diet. These findings suggest a dual role for SLC7A11 in maintaining β‐cell function and glucose homeostasis. Future studies should focus on evaluating SLC7A11 expression in human diabetic tissues or animal models to elucidate its role in β‐cell dysfunction in diabetes.

4. Discussion

In studies on the six fundamental mechanisms of cellular disulfide death, diabetes has been found to be related to some of these basic mechanisms. The research on cellular disulfide death utilized UMRC6, H460, and A549 cells with high expression of SLC7A11, as well as 786‐O cells with overexpression of SLC7A11.

Disulfidptosis is a novel form of cell death induced jointly by glucose starvation and high expression of SLC7A11, triggered by abnormal accumulation of disulfide bonds. Its death mechanism potentially links to the pathology of diabetes. The xCT system‐regulated cystine uptake and GSH synthesis affect pancreatic β‐cell function. Glucose starvation induces an increase in disulfide bonds within actin cytoskeletal proteins, which serve as sensors and mediators of oxidative stress signaling, impairing insulin secretion and promoting the development of type 2 diabetes. Under glucose deprivation, high SLC7A11 expression causes NADPH depletion, leading to the formation of abnormal disulfide bonds in actin cytoskeletal proteins such as β‐actin. This process, mediated via the Rac‐WRC pathway, results in F‐actin contraction, cytoskeletal rearrangement, and plasma membrane detachment. The depolymerized state of the cytoskeleton influences the regulation of pancreatic cells. Such cytoskeletal disorganization not only mediates disulfidptosis but is also associated with diabetes‐related muscle dysfunction and β‐cell injury. Inhibition of SLC7A11 or GLUT can induce disulfidptosis in cancer cells, promote diabetic wound healing, and inhibit angiogenesis, suggesting their potential as novel therapeutic targets for diabetes and its complications, including β‐cell protection and the development of glucose‐responsive drugs.

NADPH is a key cofactor in cellular redox reactions and plays a regulatory role in insulin signaling by modulating insulin secretion and metabolic homeostasis through enhanced NADPH production. The antidiabetic drug metformin can induce ferroptosis to suppress cancer by downregulating SLC7A11 protein levels. Type 2 diabetes is associated with islet amyloid formation, a process that involves the upregulation of Slc7a11 to supply sufficient cysteine for inflammatory responses and to mitigate the associated increase in ROS production. In MyoGlu, SLC7A11 expression is linked to higher insulin sensitivity in muscle and lower sensitivity in adipose tissue. Diabetes activates the NADPH oxidase system, particularly the NOX‐4 enzyme, leading to increased ROS generation and oxidative stress, ultimately resulting in damage to multiple organs, such as the liver and kidneys. The NADPH/NOX‐4 axis serves as a critical link between diabetes and its complications.

SLC7A11, as the core component of the cystine‐glutamate antiporter system (xCT), maintains GSH synthesis and redox homeostasis by mediating cystine uptake. Under glucose starvation conditions, its high expression induces abnormal disulfide cross‐linking of intracellular actin cytoskeletal proteins, leading to cytoskeletal rearrangement, impaired cell migration, and F‐actin contraction, ultimately triggering disulfidptosis. Knockout or inhibition of SLC7A11 can block this process. In the pathology of diabetes, dysfunction of SLC7A11 exacerbates oxidative stress, disrupts disulfide bond pairing in proinsulin within pancreatic β‐cells, causing impaired insulin secretion and promoting disease progression. Meanwhile, inhibition of SLC7A11 improves wound healing in diabetic patients, highlighting its bidirectional potential as a therapeutic target for diabetes.

In studies of the mechanisms underlying disulfidptosis, linkage with other literature has revealed that SLC7A11 expression correlates with insulin sensitivity in muscle and adipose, alterations in the pattern of insulinogenic disulfide bonding in β‐cells affect insulin production and secretion, changes in the polymerization state of the actin cytoskeleton can affect insulin secretion, diabetes mellitus has an essential effect on F‐actin. The role of the WRC in regulating actin polymerization and plate pseudopod formation is required to promote disulfidptosis, and GLUT inhibitors correlate with glucose regulation levels. NADPH regulates insulin, and diabetic nephropathy has four essential genes that correlate with disulfidptosis.

5. Prospection

In the investigation of the fundamental mechanisms underlying disulfidptosis, literature review allows for the identification of connections between this cell death pathway and diabetes as well as its complications. Future studies may apply these findings to pancreatic β‐cells, providing new avenues and strategies for diabetes treatment. However, research on disulfidptosis remains incomplete. Although this review explores the potential links between diabetes and disulfidptosis, further related studies are needed to advance the field.

Funding

The authors have nothing to report.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.