system Xc- belongs to the heterodimeric amino acid transporter (HAT) family, comprising the light chain subunit SLC7A11 and the heavy chain subunit SLC3A2 (4F2hc) (20). These two subunits are connected via extracellular covalent disulfide bonds and fulfill distinct roles (21). SLC7A11 is a multi-pass transmembrane protein that facilitates the activity of system Xc- (22), while SLC3A2 is a single-pass transmembrane protein, acting as a stabilizing agent for the stability and proper membrane localization of SLC7A11 (23). system Xc- is situated on the cell membrane and functions as a sodium-independent reverse transporter, expelling internal glutamate and absorbing extracellular cystine at a 1:1 ratio (24, 25). Cysteine is an amino acid involved in protein synthesis, post-translational modifications, and maintaining redox balance (26, 27). It serves as a precursor for antioxidants and biological macromolecules with antioxidant qualities such as GSH (composed of cysteine, glutamate, and glycine), taurine, and hydrogen sulfide (26, 27). The cellular cysteine acquisition pathway involves the synthesis of homocysteine with serine. This process occurs in tissues, including the liver, kidney, pancreas, and specific cell lines in the transsulfuration metabolic pathway (28). However, most cysteine is absorbed from the extracellular environment via the system Xc- ( Figure 1 ). Unstable extracellular cysteine rapidly oxidizes to cystine, which the system Xc- transports into the cell. The high reductive environment inside the cell quickly converts cystine back to cysteine.

Cysteine and glutamate combine enzymatically to form γ-glutamylcysteine by glutamate-cysteine ligase. Glutathione synthase adds glycine to γ-glutamylcysteine to form reduced glutathione. This synthesized reduced glutathione acts as a cofactor for ROS detoxification enzymes such as glutathione peroxidase (GPX) and participates in the breakdown of peroxides such as hydrogen peroxide. This process depletes GSH and helps to protect cells from oxidative damage incurred by ROS. Reduced GSH is oxygenated to glutathione disulfide in the presence of GPX. Subsequently, glutathione reductase utilizes NADPH to regenerate reduced GSH from glutathione disulfide (20). As a primary antioxidant in cells, the continuous synthesis and regeneration of reduced GSH are indispensable for maintaining cellular redox homeostasis and mitigating oxidative stress-induced damage (29). This ongoing supply of GSH is particularly crucial in conditions characterized by elevated oxidative stress, such as chronic inflammation or metabolic disorders like diabetes (30). Furthermore, the transport of extracellular cystine into the cell via the system Xc- is critical for sustaining intracellular levels of cysteine and GSH (24).

In the subsequent discussion, we shall now address the extended functions of system Xc-, including roles in oxidative stress, ferroptosis, and immune-inflammatory responses. Given that SLC3A2 also acts as a chaperone for multiple other amino acid transporter proteins and has multifunctional capabilities beyond its role in system Xc- (23). We will concentrate on investigating the impact of SLC7A11 on diabetic wound healing, specifically its regulatory roles in various physiological and pathological mechanisms.

Multiple mechanisms precisely control SLC7A11’s expression and activity to maintain its appropriate function in organisms ( Figure 1 ). These include transcriptional regulation by transcription factors, epigenetic regulators, and post-transcriptional regulatory mechanisms such as tuning its mRNA levels, subcellular localization, protein stability, and transporter protein activity (20). In this section, we will explore how various mechanisms regulate SLC7A11 and the downstream biological effects it mediates.

Several recent studies have revealed the crucial role of oxidative stress in diabetic wound healing. ROS are a class of molecules formed from oxygen, including free radicals and non-radical species such as singlet oxygen, superoxide anions, hydrogen peroxide, and hydroxyl radicals. Even low levels of ROS are beneficial against external damage (84). However, excess reactive nitrogen species and ROS in tissues can lead to oxidative stress. Oxidative stress and decreased antioxidant capacity cause redox imbalance and further damage cells and tissues, a significant reason for the non-healing of diabetic wounds (85). Redox imbalance is usually associated with an excessive accumulation of oxidative products and decreased activity of antioxidant enzymes. Clinical research has indicated that the high oxidative stress state in delayed healing diabetic wounds is related to hyperglycemia and tissue hypoxia. Antioxidant enzyme activities are also significantly reduced in patients with long-standing type 2 diabetes mellitus (T2DM) (86). Oxidative stress affects the normal wound-healing process and is closely related to neurovascular complications and ischemic hypoxic injury, which together account for the delayed healing of diabetic wounds.

In diabetic wounds, continuous cell death triggers inflammatory responses, disrupting the tissue repair process (78, 82, 124). During this process, phagocytic cells such as macrophages clear the dead cells from the wound through a process known as efferocytosis to mitigate these negative effects. Among these, DCs are a heterogeneous group of professional phagocytes capable of recognizing and engulfing apoptotic cells. DCs are essential in maintaining tissue homeostasis by regulating innate and adaptive immune responses. Co-stimulatory molecules such as CD80, CD86, and MHC-II are essential for DCs maturation and subsequent activation of native CD4 T cells. Their deficiency may lead to T cell immunosuppression or tolerance, whereas effective efferocytosis by DCs suppresses the immune responses to self-antigens. Meanwhile, abundant evidence highlights the favorable aspects of efferocytosis by DCs in diabetic wound healing. After phagocytosing infected apoptotic cells, DCs release large amounts of cyclooxygenase-2, PGE2, IL-10, and TGF-β, which contribute to balancing inflammatory responses and promoting tissue repair (125–127). Recent research has revealed that SLC7A11 primarily regulates efferocytosis in dendritic cells within diabetic mouse skin wounds, acting as a critical regulatory factor in diabetic wound healing. DCs treated with erastin or SLC7A11-KO show increased aerobic glycolysis, which fulfills the bioenergetic demands of efferocytosis. Pharmacologically inhibiting the function of SLC7A11 significantly enhances wound healing in diabetic mice (5). Experiments indicate that in db/db mice, which are prone to diabetes, reduced efferocytosis and lower levels of GDF15 are associated with high expression of SLC7A11 (5). Therefore, inhibiting SLC7A11 in wounds can promote diabetic wound healing through at least two mechanisms: improving cellular efferocytosis and enhancing the release of factors such as GDF15 by efferocytic cells ( Figure 3A ).

Among the multiple pathological mechanisms leading to abnormalities in diabetic wound healing, there is gradually a widespread concern about the impairment of wound healing by hyperglycemia-induced ROS accumulation and oxidative stress. Ferroptosis, an iron-dependent form of non-apoptotic cell death typically characterized by the accumulation of lipid ROS (14), has been proven to be closely associated with the pathological process of diabetic wound healing (17). Ferroptosis damages wound healing in diabetic patients by affecting the pathology of ROS and lipid peroxidation products (15). In a high-glucose environment, the increased ROS, lipid peroxidation, and ferroptosis-related proteins in fibroblasts and endothelial cells lead to reduced viability and migration rates, whereas the ferroptosis inhibitor Fer-1 can significantly alleviate these adverse effects (13). An animal study showed that pharmacological inhibition of ferroptosis reduces the expression of inflammatory and oxidative stress markers in diabetic rat wounds and promotes wound healing by activating the PI3K/AKT pathway (13). Thus, effective inhibition of ferroptosis may positively affect diabetic wound healing. Notably, SLC7A11 plays a vital role in the ferroptosis mechanism through its unique function in mediating cystine/glutamate exchange ( Figure 3B ). SLC7A11 promotes cellular cystine uptake, providing the necessary precursors for synthesizing GSH, which is crucial for detoxifying cytotoxic lipid peroxides by glutathione peroxidase 4 (GPX4). By utilizing GSH, GPX4 reduces lipid peroxides to lipid alcohols, thereby inhibiting the occurrence of ferroptosis (128). In diabetic conditions, sustained high glucose-induced oxidative stress results in the downregulation of SLC7A11 expression, which decreases intracellular cystine levels. This reduction leads to depleted GSH biosynthesis and inhibits GPX4 activity, ultimately triggering ferroptosis (129). Therefore, activating SLC7A11 to import cystine and promote glutathione synthesis can effectively prevent the accumulation of lipid peroxides and the occurrence of ferroptosis, protecting diabetic wound healing (20).

In T2DM, disruption of the insulin signaling pathway is a known pathological factor leading to impaired wound healing (130). Reduction in the number of cell surface insulin receptors, the impediments of PI3K activation, and subsequent signal transmission within the insulin signaling pathway contribute to ineffective insulin work, thereby developing insulin resistance (131). In addition, insulin regulates the differentiation of skin keratin-forming cells and glucose transport through IR-related signals (132). Expression of insulin receptor, insulin receptor substrate 1 (IRS-1), insulin receptor substrate 2 (IRS-2), Src Homology 2 Domain Containing, Extracellular Signal-Regulated Kinase (ERK) and AKT are increased in healing wound tissues compared to intact skin. In contrast, these pathways are weakened in the injured skin of diabetic rats. Topical application of insulin normalizes wound healing time in diabetic animals, subsequently reversing defective insulin signal transduction (133). In pancreatic β-cells, insulin secretion is tightly associated with the glucose metabolism process and its various by-products, ranging from ATP and glutamate (19) to ROS (134). This relatively unrestricted glucose metabolic pathway renders β-cells particularly sensitive to oxidative stress induced by hyperglycemia (135, 136). The Slc7a11 gene is upregulated to provide sufficient cysteine to cope with the inflammatory response and alleviate the increase in ROS production, mitigating cellular damage (137). Studies indicate that constitutive deficiency of system Xc- results in approximately a threefold decrease in GSH levels in the islets, characteristic upregulation of Chac1 due to cysteine deficiency, and reduced β-cell-specific gene expression and increased markers of endoplasmic reticulum stress, thus diminishing insulin secretion both in vitro and in vivo (137). Furthermore, ferroptosis induced by the inhibition of system Xc- with erastin has been shown to impair islet viability (138). Even though intracellular glutamate enhances insulin secretion, extracellular glutamate might activate ionic receptors, thereby slowing insulin exocytosis ( Figure 4 ). This process is regulated by system Xc- (19), presenting a double-edged sword for pancreatic β-cells.

The mTOR pathways play a core role in maintaining cellular and physiological homeostasis, closely associated with various growth disorders such as obesity and T2DM, and regulate insulin sensitivity and glucose homeostasis (139). PI3K also activates another serine/threonine kinase, AKT, a key signaling hub for multiple cellular functions. Activation of AKT affects a series of downstream pathways, including cell survival, proliferation, aging, apoptosis, and angiogenesis (140, 141). Studies show that reduced activity of the PI3K/AKT signaling pathway weakens cellular responses such as insulin uptake, thus promoting the development of DM (140). In DM, multiple signaling pathways, including epidermal growth factor receptor (EGFR)/PI3K/AKT and extracellular signal regulated kinases (ERKs), are affected and activate their downstream Bcl2-associated death signaling, increasing apoptosis and decreasing proliferation, then impeding wound healing (142). Further research highlights the prominent role of SLC7A11 in regulating these changes. It was shown that SLC7A11-mediated uptake of cystine and PI3K/AKT signaling activates mTORC1, at least partly through the Rag-mTORC1-4EBP signaling axis to promote GPX4 protein synthesis (18). This activation enhances MUFA synthesis and inhibits autophagy by upregulating the SCD1-SREBP1 axis, thus preventing lipid peroxidation and ferroptosis (143). This mechanism differs from the conventional model in which SLC7A11 regulates GPX4 and inhibits ferroptosis via cysteine-mediated GSH synthesis, forming the SLC7A11-GSH-GPX4 axis. Additionally, the interaction between mTOR signaling targets and GPX4 regulates autophagy-dependent ferroptosis in human pancreatic cancer cells (144). Notably, SLC7A11 can modulate selenium uptake and directly enhance selenium-dependent GPX4 protein levels (145, 146). However, this mechanism seems to promote GPX4 synthesis by a cellular sensing mechanism independent of mTORC1 mediation (147).

Diabetic wounds are primarily characterized by persistent stagnation in a non-productive inflammatory stage, leading to compromised formation and consolidation of mature granulation tissue (148, 149). This prolonged inflammatory phase, unrelated to the successful control of local infections, suggests that the susceptibility of diabetic wounds to infections (150–152) might stem from a primary defect in innate immune response mechanisms (153, 154). During the healing process, the plasticity of macrophages allows them to transition from an initial pro-inflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), facilitating tissue repair (155, 156). However, in non-healing diabetic wounds, macrophage dysfunction leads to a pronounced pro-inflammatory state (157). The reduced capability of macrophages in diabetic patients to perform efferocytosis may also contribute to the decreased prevalence of the M2 phenotype, partially promoting an increase in M1 macrophages (158). Meanwhile, hyperglycemia serves as a primary trigger for excessive inflammatory responses. Research indicates that hyperglycemia and its related factors, such as AGEs, TNF-α, and other pro-inflammatory signaling proteins, exhibit significant cytotoxicity detrimental to the recovery of wound tissues (58, 159). AGEs promote macrophage polarization to the M1 phenotype through autophagy activation (160). Due to their heightened response to inflammatory stimuli, macrophages release more inflammatory factors and exhibit reduced phagocytosis of pathogens and apoptotic cells, thus impairing pathogen clearance (161). The PI3K-AKT-mTOR signaling pathway mediates the perception of environmental and metabolic cues, influencing macrophage polarization in a complicated and not yet fully defined manner (162). Amino acids and other potential metabolic inputs into the Akt-mTORC1 axis align M2 activation with metabolic status (163). For example, glutamine metabolism promotes the production of UDP-GlcNAC, a crucial modifier of various M2 markers (164). Oxidative metabolism has also been shown to correlate with M2 activation, even though specific mechanisms remain unclear. These factors collectively contribute to the pro-inflammatory, pro-oxidative, and pro-degradative environment within diabetic wounds (165). Therefore, targeting SLC7A11 to modulate the immune and inflammatory responses in diabetic wounds presents a promising therapeutic strategy. Ginsenoside Rg5, a rare ginsenoside, exerts hypoglycemic effects by improving insulin resistance and mitochondrial biogenesis in diabetic mice (166). Recent studies indicate that ginsenoside Rg5 can inhibit the expression and activity of SLC7A11 through physical binding, essentially counteracting SLC7A11’s negative regulation of glycolysis, which facilitates the efferocytosis by DCs ( Table 1 ) (167).

SLC7A11 promotes cystine uptake and glutathione biosynthesis, thus preventing oxidative stress and ferroptosis (20), constituting one of the primary antioxidative mechanisms in diabetic wounds. Consequently, pharmacological modulation of SLC7A11 to enhance antioxidation represents a promising therapeutic strategy, as illustrated in Table 1 . Xanthohumol, a prenylated dietary flavonoid derived from hops, has been shown to mitigate oxidative damage and accelerate diabetic wound healing through NRF2 activation, positioning it as a potential nutritional supplement and candidate drug for treating diabetic skin ulcers (168). Similarly, bee venom significantly enhances wound closure in diabetic mice by increasing the expression of collagen and β-defensin 2 and restoring the levels of Angiopoietin-1 and NRF2 (the agonist ligands of Tie-2), thereby enhancing downstream signaling of Tie-2 (169). Traditional antidiabetic drugs target SLC7A11 to inhibit ferroptosis and exert antioxidative effects. Canagliflozin, an antidiabetic drug, benefits cardiovascular health in a diabetic cardiomyopathy model by regulating cardiac iron balance and the system Xc-/GSH/GPX4 axis to inhibit ferroptosis (170). Liraglutide, used for treating obesity and diabetes, inhibits ferroptosis in db/db mice by enhancing the expression of the SLC7A11 and NRF2/HO-1/GPX4 signaling pathways, reducing ferritin deposition and lowering intracellular lipid ROS (171).

Extensive research indicates that bioactive compounds extracted from animals and plants effectively regulate the expression and activity of SLC7A11. Quercetin, a natural dietary flavonoid, improves the levels of the antioxidative protein GPX4 and SLC7A11 in the lung tissues of patients with neutrophilic airway inflammation, reversing lung ferroptosis (172). Components extracted from the medicinal plant Stemona, such as Tuberostemonine, alleviate pulmonary fibrosis by regulating SLC7A11, GPX4, and GSH, reducing iron and ROS accumulation (173). The well-known diabetes-ameliorating effects of Glabridin (Glab) from licorice have been demonstrated. A recent studies show that Glab protects diabetic rat kidneys by enhancing SOD and GSH activities, increasing the expression of SLC7A11, GPX4, and SLC3A2, and lowering malondialdehyde and iron concentrations as well as transferrin receptor 1 expression, thereby inhibiting ferroptosis (174). Astaxanthin, a natural ketocarotenoid pigment, mitigates IL-1β-induced chondrocyte ferroptosis by regulating intracellular ROS, iron, and mitochondrial iron levels and by inhibiting the expression of SLC7A11, GPX4, and ferritin, providing relief for osteoarthritis (175). Cryptochlorogenic acid from mulberry leaves activates the system Xc-/GPX4/NRF2 pathway. It inhibits nuclear receptor coactivator 4, improving blood glucose levels, iron content, lipid peroxidation, and pancreatic damage in a diabetes model (176). Additionally, some drugs regulate SLC7A11 in a p53-dependent manner, such as zeaxanthin, which regulates GPX4, SLC7A11, and other targets by downregulating p53 expression, reducing cellular lipid peroxidation and intervening in the development of non-alcoholic fatty liver disease (177). The medications mentioned have been demonstrated to mitigate oxidative stress and ferroptosis in disease by modulating the expression and activity of SLC7A11 and its downstream molecules, thereby alleviating the progression of the disease. This molecular mechanism of action, achieved based on targeting SLC7A11, provides a potential therapeutic strategy for treating diabetic wounds.