Disulfidptosis: a new target for central nervous system disease therapy.

Cell death maintains balance in morphogenesis by clearing damaged or obsolete cells during a state of physical health or illness ( Newton et al., 2024 ). Programmed cell death occurs during the development of normal neurons to establish a spatial and temporal framework. Additionally, various types of cell death, such as pyroptosis, apoptosis, ferroptosis, and necrosis, which involve abnormal signaling cascades and interrelationships, are involved in the pathological mechanism of neurological disorders ( Moujalled et al., 2021 ). Recently, a novel form of programmed death called disulfidptosis was proposed, the mechanism of which is the focus of cancer research. Disulfidptosis cell death genes are potentially linked to various cancer types and may function as candidate genes for cancer diagnosis, prognosis, and therapeutic biomarkers ( Liu and Tang, 2023 ). Copper death genes may be associated with various cancer types and could function as potential biomarkers for cancer diagnosis, prognosis, and treatment ( Liu and Tang, 2022 ). Boyi Gan and colleagues defined disulfidptosis in 2023 as high SLC7A11 expression and NADPH depletion, resulting in the suppression of cystine/cysteine conversion under conditions of glucose starvation, which leads to disulfide bond accumulation, disulfide stress, and collapse of the cytoskeleton. Pyroptosis is an immunogenic programmed cell death that effectively activates tumor immunogenicity and reprograms the immunosuppressive microenvironment to improve cancer immunotherapy. However, an overexpression of SLC7A11 promotes the biosynthesis of glutathione to maintain redox balance and combat pyroptosis ( Zhu et al., 2024b ). Apoptosis occurs in development, tissue homeostasis, and immune function. Unlike disulfidptosis, apoptosis does not typically involve protein aggregation induced by oxidative stress or is centered around dysfunction of the actin network ( Xiao et al., 2024 ). Ferroptosis is a novel form of programmed cell death characterized by iron-dependent oxidative damage, lipid peroxidation, and the accumulation of reactive oxygen species ( Zuo et al., 2022 ). Disulfidptosis is a form of cell death caused by oxidative reductive imbalance resulting from amino acid metabolism and glucose metabolism disorders ( Wang et al., 2024 ). In the physiological system, the thiol disulfide redox involves the reduction of disulfide to thiol and the oxidation of thiol to disulfide ( Ghosh et al., 2023 ). Disulfidptosis is caused by the imbalance between thiols and disulfides, resulting in disulfide stress. In contrast, ferroptosis is caused by lipid peroxidation and excessive oxidative stress due to iron ion deposition. Some researchers speculate that disulfidptosis is a specific form of oxidative stress-induced cell death that corresponds to diseases of various systems in the humaccn body, such as the respiratory, digestive, urinary, and reproductive systems ( Chen et al., 2024 ). The prevalence of central nervous system diseases (CNSD), such as brain tumors, neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, etc.), and ischemic stroke has increased significantly, severely affecting general health conditions and imposing significant financial and societal strain on individuals affected by these conditions ( Zhang X. et al., 2021 ). The accumulation of high levels of reactive oxygen species, neurotoxic substances, and inflammatory cytokines forms the pathological mechanism underlying CNSD, which results in dysfunction of the nervous system and the development of therapeutic targets for neurological diseases ( Patel, 2016 ). A study revealed that deleting ETHE1, a mitochondrial sulfur dioxygenase involved in sulfide catabolism in encephalopathy, leads to fatal sulfide toxicity; these findings suggest that most mammalian brains have a very limited ability to break down sulfide and that sulfide accumulation can cause brain damage ( Tiranti et al., 2009 ). Previously, the processes and causes of the diverse pathological mechanisms underlying CNS disorders were elusive; Central nervous system (CNS)-related diseases exhibit a high mortality rate and pose significant risks to both physical and mental health, making them a critical focus of research ( He et al., 2024 ). Therefore, by conducting a literature review, we propose that thiometabolism is closely related to specific cellular redox reactions that depend on the thiol/disulfide ratio. A detailed mapping of disulfidptosis in nervous system disease may reveal the network regulating the crucial targets of the pathological process and provide new insights into potential clinical treatment directions for neurological disorders.

In this review, we emphasized that NADPH metabolism, high SLC7A11 expression, and the cystine/cysteine balance are important metabolic features of disulfidptosis. By describing the endogenous and exogenous elements involved in novel cell death disulfidptosis and identifying associations between disulfidptosis and CNS disorders, such as neurodegenerative diseases, gliomas, and ischemic stroke, this review summarizes disulfidptosis-related genes involved in neurodegenerative diseases, gliomas, and ischemic strokes and discusses how disulfide stress and redox imbalance contribute to the onset and progression of CNSD. The Trx and Grx systems, which play antioxidant defense roles during disulfide stress, are involved in neurological diseases. In the future, we can use bioinformatics analysis and in vitro and in vivo experiments to detect target genes and protein proteins associated with disulfidptosis in neurological diseases to search for clinical biomarkers for treatment. We suggest that disulfidptosis might be a crucial novel pathological mechanism underlying CNS diseases. Moreover, some similarities between disulfidptosis and ferroptosis/cuproptosis may reveal new insights into the pathogenesis of CNS diseases and help develop more comprehensive therapeutic strategies. Therefore, it is necessary to conduct a thorough analysis of other pathways involved in mediating disulfidptosis. However, the potential mechanism of disulfidptosis still needs further exploration, and this innovative approach will provide a basis to overcome future challenges. Will disulfidptosis only occur in the actin cytoskeleton, and are other proteins sensitive to disulfide stress? What are the differences between disulfide bonds and other protein post-translational modifications, especially with regard to glutathionylation? In future basic and clinical research, can we select appropriate therapeutic drugs for patients with central nervous system diseases based on their susceptibility to disulfidptosis? Exploring the mechanism underlying disulfidptosis and its contribution to various central nervous system diseases has crucial theoretical and practical value for identifying effective treatment strategies.

Alzheimer’s disease (AD) is a prevalent condition characterized by progressive degeneration of the brain, which may involve an increase in oxidative stress, a decrease in antioxidant enzymes, and consequent disruption of the redox dynamic balance ( Yu et al., 2024 ). Eight disulfidptosis-related genes (DRGs) significantly affect the beginning and progression of AD. Specifically, the activity of the SLC7A11, SLC3A2, and GYS1 genes increases, whereas the activity of the OXSM, NUBPL, NDUFA11, NCKAP1, and LRPPRC genes decreases ( Zhu et al., 2023 ) ( Table 1 ). Additionally, a differential analysis of the gene expression matrix of AD revealed seven characteristic genes associated with the breakage of disulfide bonds, including MYH9, IQGAP1, ACTN4, DSTN, ACTB, MYL6, and GYS1, which accurately assess subtypes of AD and diagnose AD ( Ma et al., 2023 ). Some studies have suggested that dynamic disruption of the actin cytoskeleton occurs during the progression of AD. A detailed understanding of the mechanisms of the actin cytoskeleton can pave the way for developing innovative synapse-targeted therapeutic interventions and identifying new biomarkers to monitor synaptic loss in Alzheimer’s disease ( Pelucchi et al., 2020 ). Thioredoxin-1 (Trx-1) is a multifunctional molecule that has anti-inflammatory properties in human tissues and plays significant neuroprotective roles in AD ( Jia et al., 2024 ). In addition, the dysregulation of the thioredoxin system increases susceptibility to cell death, and changes in Trx and TrxR levels are significantly associated with the progression of AD ( Qaiser et al., 2024 ). Disulfidptosis-related genes in the CNS. Research on neurodegenerative, neuroinflammatory, and neuro-oxidative stress in related brain diseases revealed that genetic and environmental factors affect Trx function and that the Trx system may be an important target for disease intervention and treatment ( Bjørklund et al., 2022 ). Glutaredoxin (Grx) 1 regulates redox signal transduction and protein redox homeostasis by catalyzing reversible s-glutathione modification, thereby exerting neuronal effects ( Gorelenkova and Mieyal, 2019 ). Therefore, controlling oxidative stress responses and maintaining redox balance through the Trx and Grx systems are highly important for the prevention and treatment of Alzheimer’s disease, which prompted us to further explore the correlation between disulfide cell death and these processes. Parkinson’s disease is also a prevalent neurodegenerative disease characterized by a progressive decrease in neurological function ( Bloem et al., 2021 ). A previous study revealed that significant alterations in the distribution of antioxidant enzymes and high levels of free radicals play important roles in the development of Parkinson’s disease ( Li et al., 2022 ). The accumulation of ROS leads to nigrostriatal neuronal death in PD ( Trist et al., 2019 ). Additionally, dynamic thiol-disulfide homeostasis is disrupted in patients with Parkinson’s disease ( Vural et al., 2017 ). The expression of the Parkinson’s disease-related gene Parkin contributes to the network of sulfhydryl groups available in the cell, including glutathionylation, which involves reversible post-translational modifications of selected cysteine residues ( El et al., 2023 ). Moreover, a cluster analysis of S-glutathionylated targets, which are known to play a role in apoptosis and inflammation according to the Gene Ontology (GO) collection or Kyoto Encyclopedia of Genes and Genomes (KEGG), revealed a putative overlapping association between Grx1 and neurodegenerative diseases ( Gorelenkova and Mieyal, 2019 ). Higher amounts of TRX and GRX were found to protect cells from the reactive dopamine metabolite 6-OHDA-benzenediol, which is critical for neuronal survival in dopamine-induced cell death ( Arodin et al., 2014 ). Bioinformatics analysis and in vitro and in vivo experiments have shown that the abnormal balance of thiol/disulfide bonds leading to oxidative stress is the pathological mechanism underlying neuronal damage in neurodegenerative diseases. Therefore, further investigation of its association with disulfidptosis is highly important. Neurogliomas are the predominant malignant tumors that originate in the CNS ( Ostrom et al., 2023 ). Recently, the disulfidptosis related genes (DRGs) SLC3A2, NDUFA11, OXSM, NUBPL, LRPPRC, RPN1, and GYS1 were found to be significantly associated with glioma cells. The upregulation of the disulfidptosis-related gene SLC3A2 influences immune cell infiltration in gliomas, notably macrophage infiltration, and impacts tumor migration and invasion, consequently affecting the tumor microenvironment ( Xu Y. et al., 2024 ). Additionally, a study revealed that high expression of LRPPRC was positively correlated with a favorable prognosis for gliomas, but increased expression of RPN1 and GYS1 was associated with an unfavorable prognosis ( Guo et al., 2023 ). Additionally, thioredoxin NADPH reductase (TrxR) plays a crucial role in the progression of malignancies ( Branco et al., 2020 ). The redox function of thioredoxin is largely dependent on TrxR, with NADPH serving as an electron donor ( Saccoccia et al., 2014 ). SLC7A11 was identified as the gene that is most significantly associated with disulfidptosis in tumors ( Huang et al., 2023 ; Xu B. et al., 2024 ). SLC7A11 expression in gliomas plays a significant role in tumorigenesis, tumor progression, and resistance to conventional chemotherapy. Several studies have shown that glioma cells upregulate the expression of SLC7A11, which regulates glutathione production and glioma growth ( Polewski et al., 2016 ). Nrf2 is a transcription factor that is sensitive to redox changes and capable of regulating the expression of the intracellular redox balance proteins GPX4 and SLC7A11 in glioma cells ( Gao et al., 2020 ). Chrysomycin A (Chr-A) further altered the levels of nicotinamide adenine dinucleotide phosphate (NADPH), leading to oxidative stress and downregulation of Nrf-2 to inhibit glioblastoma ( Liu D. N. et al., 2024 ). The upregulation of disulfidptosis related genes SLC3A2 and SLC7A11 promotes the occurrence and progression of glioma tumors, therefore, a signal target of disulfidptosis may be used in the therapeutic schedule for neurogliomas. Stroke includes both ischemic and hemorrhagic stroke; both lead to abnormal cerebral blood flow and disrupt the delivery of oxygen and glucose, resulting in cellular dysfunction, such as mitochondrial oxidative phosphorylation and bioenergetic stress ( An et al., 2021 ; Zheng J. et al., 2018 ). In ischemic stroke, blood vessel blockage results in glucose and oxygen deficiency, which triggers several biological response pathways and ultimately leads to irreversible brain damage ( Sharma et al., 2022 ). Trx/TrxR is an NADPH-dependent cellular thiol reduction-antioxidant system, and the PPP and glucose oxidative decomposition are the main sources of NADPH ( Wang et al., 2022 ). Reduced coenzyme II (NADPH) is the reduced form of NADP+ and is derived mainly from the pentose phosphate pathway (PPP) of glucose oxidative degradation, and NADPH depletion is also associated with ischemic stroke ( Zhang and Peng, 2014 ). Clinical studies have proposed that changes in TyG-BMI, calculated via the formula [triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] BMI (kg/m2), are associated with the prognosis of stroke ( Huo et al., 2023 ; Yang et al., 2023 ). Thus, glucose starvation, which is an initial factor necessary for disulfidptosis, occurs in cerebral ischemia. Recently, differential gene expression analysis revealed that four DRGs (SLC2A3, SLC2A14, SLC7A11, and NCKAP1) are associated with stroke ( Liu S. P. et al., 2024 ). Single cell analysis shows that the seven types of DRGs (ACTB, IQGAP1, FLNA, PDLIM1, MYH10, INF2 and SLC7A11) are mainly distributed in the immune cell types of ischemic stroke ( Qin et al., 2023 ). Recent studies have found that SLC7A11 expression inhibits M1 polarization in microglia while promoting M2 polarization in OGD models ( Zhao et al., 2024 ). A study revealed that increased SLC7A11 expression helps enhance GSH synthesis, which increases resistance to oxidative damage and prevents neuronal ferroptosis during cerebral ischemia ( Li et al., 2023 ; Yuan et al., 2021 ). Therefore, SLC7A11, a subunit of the Xc system that imports cystine through the export of glutamate at a 1:1 ratio, may be involved in the crosstalk between ferroptosis and disulfidptosis in ischemic stroke. Studies have shown the protective effects of Peroxiredoxin 1 (PRDX1) on stroke through disulfidptosis and the ischemic postconditioning’s (IPostC) mechanism. This marks an important step forward in stroke research and potential treatment development ( Liu S. et al., 2024 ). A precursor of cysteine, known as L-2-oxothiazolidine-4-carboxylic acid (OTC), decreases neurobehavioral performance in stroke models ( Liu Y. et al., 2020 ). Empirical clinical data have demonstrated that individuals exhibit considerably increased serum concentrations of homocysteine and cysteine in the acute phase of atherothrombotic stroke ( Salemi et al., 2009 ) . A study reported that cysteine levels can increase 10–13-fold over 8 h in the ischemic hippocampus and striatum, which are derived largely from GSH ( Slivka and Cohen, 1993 ). The accumulation of cysteine, which originates from GSH, substantially increased excitotoxic damage and disrupted the balance of GSH/GSSG tissue damage caused by stroke in a rat model ( Qu et al., 2006 ). Disulfidptosis is a method of cell death that involves a reduction–oxidation (redox) reaction and the production of disulfide bonds ( Wang et al., 2023 ). Moreover, preliminary research has indicated that alterations in thiol levels during oxidative stress may be associated with the size of the infarct resulting from ischemic stroke. Additionally, reversing thiol deficiency and restoring the thiol-disulfide balance that reduce disulfide accumulation and inhibit oxidative damage, which can impede the damage caused by ischemic stroke ( Bektas et al., 2016 ). Trx/TrxR is an NADPH-dependent cellular thiol reduction antioxidant system associated with disulfide stress. NADPH originates from the PPP, in which the oxidative decomposition of glucose is affected by hypoxia ( Wang et al., 2022 ). The Trx system is crucial for regulating apoptosis, redox status, and antioxidant defenses ( Matsuzawa, 2017 ). Therefore, Trx may have a neuroprotective function in individuals suffering from acute ischemic stroke, and serum Trx levels are novel diagnostic and prognostic indicators that are also closely related to the severity of intracranial hemorrhage and long-term mortality. Additionally, the overexpression of Grx1 decreases the level of S-glutathionylation, reduces the depletion of GSH and the formation of disulfide bonds, and suppresses neuron damage during focal ischemia ( Takagi et al., 1999 ). Nuclear factor E2-associated factor 2 (Nrf2) is a transcription factor that binds to Kelch-like ECH-associated protein 1 (KEAP1) ( Suzuki et al., 2023 ). In the nucleus, they function along with other coactivators to initiate the transcription of target genes under certain stimuli, such as oxidative stress, disrupting binding ( Baird and Yamamoto, 2020 ). The Keap1-Nrf2 system is a sulfhydryl-based sensor-effect device that maintains redox homeostasis and is vital to cellular defense against exogenous and endogenous oxidative and electrophilic stress ( Yamamoto et al., 2018 ). Endogenous Nrf2 is activated after ischemic stroke, resulting in an initial increase in the expression of overall Nrf2 protein and a subsequent decrease in the ischemic zone ( Tian et al., 2020 ; Yang et al., 2009 ). Oxygen–glucose deprivation/reperfusion (OGD/R)-induced ferroptosis can be reversed by accelerating the transcription of GPX4 via the Nrf2-SLC7A11 signaling pathway ( Liu et al., 2023b ), which may be associated with disulfidptosis. After transient middle cerebral artery occlusion in Nrf2 gene knockout mice, the induction and activation of antioxidant enzymes are inhibited, resulting in a larger stroke area ( Zhang et al., 2017 ). A study revealed that Nrf2 siRNA injection decreases the protein and mRNA expression of Trx1 in middle cerebral artery occlusion (MCAO) model rats; therefore, Trx1 is regulated by Nrf2, which has a neuroprotective function ( Li et al., 2015 ). Under ischemic conditions, Nrf2 can regulate the disulfidptosis-related proteins SLC7A11 and the Trx system. Therefore, whether Nrf2 is a regulatory target of disulfidptosis after cerebral ischemia deserves further investigation. Further investigations are needed to determine which of these factors are important target signals of disulfidptosis and whether a temporal sequential relationship exists between the occurrence of disulfidptosis and ferroptosis in stroke. These studies suggest that an imbalance in thiol/disulfide redox reactions during disulfidptosis might constitute a novel pathogenic pathway of stroke or other disorders of the CNS; deeper insights into the mechanism underlying disulfidptosis may provide new targets and new treatments for CNS diseases.

Research on the pathogenesis and treatment of disulfidptosis is still in the early stage and has focused mainly on various types of cancer. A review of the literature on drug intervention for disulfidptosis target genes and signaling pathways may provide new directions for research on CNS therapy. N-acetylcysteine (NAC) have antioxidant, anti-inflammatory, and neuroprotective processes in the CNS ( Santos et al., 2017 ). One study suggested that NAC acts as an antioxidant to increase the intracellular concentration of GSH, which is the critical biological thiol responsible for maintaining the cellular redox balance ( Tenório et al., 2021 ). NAC promotes the regeneration of free thiols through disulfide exchange, preventing the accumulation of cystine or other disulfides under glucose starvation (e.g., Cys-Cys + NAC → Cys + NAC-Cys) ( Sarıtaş et al., 2024 ). In recent clinical trials on acute ischemic stroke, it has been found that intravenous injection of N-acetylcysteine can enhance the safety and efficacy of recombinant tissue plasminogen activator (rtPA or alteplase) adjuvant therapy ( Zhao et al., 2017 ). In summary, in the carrier experiment, NAC can increase GSH and reduce the accumulation of cystine and disulfide. We believe that NAC may have a therapeutic effect on inhibiting neuronal disulfidptosis after CNSD. Lipoic acid (α-LA), also known as thioctic acid, includes a reduced (dihydro-lipoic acid, DHLA) form, which exerts its neuroprotective effect on neurodegenerative disorders by inhibiting the formation of oxidizing material and promoting neurotransmitters ( Santos et al., 2017 ). Liraglutide (LIRA), a glucagon-like peptide-1 (GLP-1) analog widely used in clinical applications, enhances the expression of Trx, Nrf2, and p-Erk1/2 to establish a protective effect against neurodegenerative diseases ( Liu J. et al., 2020 ). Salidroside (Sald), a traditional Chinese medicine, may suppress oxidative stress by inducing Trx and peroxiredoxin-I (PrxI) in neuroblastoma ( Zhang et al., 2010 ). Ebselen, a synthetic organoselenium compound, protects neurons from damage caused by free radicals by interacting with thiols, peroxynitrites, and hydroperoxides ( Wang J. et al., 2020 ). The antioxidant Dl-3-n-butylphthalide can hinder the NLRP3 inflammasome and decrease the severity of AD-like symptoms by affecting the Nrf2-TXNIP-TrX pathway ( Wang et al., 2019 ). Disulfidptosis may be an important pathological mechanism in neurodegenerative diseases. In response to the imbalance of intracellular sulfur metabolism, thiol and disulfide balance, as well as the systemic regulation of Trx and Grx and the cross-talk between cell death after the occurrence of the disease, effective interventions and treatment drugs have been explored to identify pathways and multiple approaches for treating neurodegenerative diseases. Disulfidptosis is a novel mode of programmed cell death, and the investigation and intervention of pathological mechanisms may reveal various effective targets. This information can be used to treat associated CNS diseases effectively ( Table 2 ). Disulfidptosis-related therapeutic drugs.

There are currently many types of cell death, such as pyroptosis, apoptosis, and autophagy, but only ferroptosis and cuproptosis are related to disulfidptosis. The cell death in three types of cell death, namely disulfidptosis ferroptosis, and cuproptosis, is related to redox homeostasis. One or more key factors may act as switches for cells to oscillate between the three modes of cell death. It is speculated that this common switch is cystine to cysteine ( Wang et al., 2024 ). Recent research has found that a new type of carrier free nanoparticle has been developed to effectively treat cancer through the combined effect of ferroptosis and cuproptosis ( Zhu et al., 2024a ). The DIXON group first postulated that ferroptosis, a type of programmed cell death initiated by lipid peroxidation, depends on iron ( Seibt et al., 2019 ). Some proteins implicated in disulfidptosis are also associated with the initiation and progression of ferroptosis. First, System Xc (cystine/glutamate antiporter) is constructed from the heavy chain SLC3A2 and light chain SLC7A11 (xCT) ( Tu et al., 2021 ). SLC7A11, following its overexpression, imports cystine to suppress ferroptosis through GSH biosynthesis and antioxidant defense ( Koppula et al., 2021 ). Moreover, the upregulation of SLC7A11 contributes to the emergence of disulfidptosis by increasing the input of cystine and causing an imbalance in the cystine/cysteine ratio, which in turn promotes disulfidptosis ( Liu X. et al., 2024 ). Second, NADPH is required for inhibiting lipid oxidation and serves as an indicator of ferroptosis in various types of tumor cells ( Wang et al., 2023 ). NADPH depletion also induces a high cystine/cysteine ratio, leading to disulfide stress, which facilitates disulfidptosis ( Dixon et al., 2012 ). Another relevant mechanism includes the disulfide-glutathione redox couple (GSH/GSSG) ( Ursini and Maiorino, 2020 ). GSH inhibits cellular ferroptosis by stimulating the production of glutathione peroxidase (GPX4) to reduce lipid peroxidation products ( Dixon et al., 2012 ). Additionally, GSH and GSSG act as crucial constituents of the thiol/disulfide redox system ( Circu and Aw, 2011 ), which may be closely related to disulfide stress. During ferroptosis, NADPH is a key regulator that acts as a cofactor and functions along with GRX to reverse the conversion of GSSG to GSH, sustain the balance between GSH and GSSG, and inhibit lipid peroxidation damage ( Seibt et al., 2019 ; Lu, 2013 ). During signal cascades, enzymes in the Trx family (Trxs and Grxs) also play a significant role in maintaining the balance of oxidation–reduction reactions, such as the ratio of GSH/GSSG, by regulating thiol/disulfide conversion ( Aoyama, 2021 ; Musaogullari and Chai, 2020 ). Consequently, the regulation of the expression of the membrane transporter SLC7A11, NADPH depletion because of glucose starvation, and subsequent disruption of the balance of thiol/disulfide bonds may serve as a common link between disulfidptosis and ferroptosis ( Figure 2 ), potentially involving intersecting molecular pathways. Cuproptosis is a newly recognized type of cell death, and the process involves reliance on copper, accumulation of proteins modified with fatty acids, and reduction of Fe-S cluster proteins ( Chen et al., 2022 ). During cuproptosis, copper accumulation may be regulated by ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS) ( Tsvetkov et al., 2022 ). FDX1 interferes with redox homeostasis to induce cuproptosis in endometriosis, which is mediated by glucose-6-phosphate (G6PD); these changes suppress the proliferation and metastasis of endometrial cells ( Lu et al., 2023 ). Moreover, a previous study revealed that G6PD significantly affects REDOX homeostasis by regulating glycolytic flux through the pentose phosphate pathway (PPP) ( Garcia et al., 2021 ). It also produces NADPH, which is an essential cofactor for glutathione (GSH/GSSG) conversion ( Luzzatto et al., 2020 ). Some related studies have reported that p53 regulates the metabolism of glycolysis and oxidative phosphorylation by acting as the rate-limiting enzyme of the PPP by binding to glucose-6-phosphate dehydrogenase (G6PD) ( Vousden and Ryan, 2009 ). Furthermore, p53 suppresses NADPH production by inhibiting malic enzyme or G6PD ( Jiang et al., 2011 ). Consequently, ferroptosis, cuproptosis, and disulfidptosis may involve interrelated crosstalk mechanisms involving glycolysis and oxidative phosphorylation in the context of circulatory disturbance.