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ObjectiveTo investigate the effect of Zuoguiwan on the ovarian function in the rat model of cyclophosphamide-induced premature ovarian failure （POF） based on the changes of ferroptosis pathway. MethodForty SD rats were randomized into blank， model， and low- and high-dose （2， 8 g·kg-1， respectively） Zuoguiwan groups， with 10 rats in each group. The rats in the other groups except the normal group were intraperitoneally injected with CTX at a dose of 50 mg·kg-1 on the first day and 8 mg·kg-1 from the second day to the fifteenth day for the modeling of POF. After modeling， the rats were administrated with corresponding drugs or normal saline by gavage for four weeks. Hematoxylin-eosin staining was performed to observe the pathological changes in the ovarian tissue. The mitochondria of the ovarian tissue was observed by electron microscopy. The serum levels of follicle-stimulating hormone （FSH）， estradiol （E2）， luteinizing hormone （LH）， anti-Mullerian hormone （AMH）， malondialdehyde （MDA）， catalase （CAT）， superoxide dismutase （SOD）， and iron ion were measured by biochemical methods and enzyme-linked immunosorbent assay. Western blot was employed to determine the protein levels of glutathione peroxidase 4 （GPX4）， solute carrier family 7 member 11 （SLC7A11）， ferritin heavy chain （FTH1）， and acyl-CoA synthetase long chain family member 4 （ACSL4）. ResultCompared with the blank group， the model group showcased significantly increased atretic follicles， atrophied， fragmented， and vacuolated mitochondria， and reduced， loose， and disordered cristae in mitochondria. Compared with the model group， high-dose Zuoguiwan increased mature follicles， the volume of mitochondria in the ovary， alleviated the vacuolation， and improved the number and arrangement of mitochondrial cristae. Compared with the blank group， the modeling elevated the levels of iron， MDA， FSH， and LH， up-regulated the expression of GPX4， SLC7A11， and FTH1 （P<0.05， P<0.01）， decreased the activities of SOD and CAT， lowered the levels of E2 and AMH， and down-regulated the expression of ACSL4 （P<0.05， P<0.01）. Compared with the model group， drug interventions lowered the levels of iron， MDA， FSH， and LH， down-regulated the expression of GPX4， SLC7A11， and FTH1 （P<0.05， P<0.01）， increased the activity of CAT， elevated the levels of E2 and AMH， and up-regulated the expression of ACSL4 （P<0.05， P<0.01）. ConclusionZuoguiwan may inhibit the occurrence of ferroptosis by regulating the SLC7A11/GPX4 axis， thereby improving the ovarian function of POF rats.
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Objective:To investigate the mechanism of interferon γ(IFN-γ)combined with ferroptosis inducer Erastin in the inhibi-tion of the growth of oral tongue squamous cell carcinoma(OTSCC).Methods:The expression of SLC7A11 in OTSCC was studied by bioinformatics analysis and immunohistochemical staining.SLC7A11 gene in OTSCC CAL-27 cells was knocked out by CRISPR-CAS9,and the survival rate of WT and SLC7A11 KO cells treated with Erastin was measured by MTT assay.Glutathione kit,lipid oxidation kit and flow cytometry were used to detect the changes of lipid peroxides in the cells treated with Erastin.After 24 h pretreatment with IFN-γ,MTT assay was used to detect the changes of cell sensitivity to Erastin,and the changes in lipid peroxides were detected by glu-tathione kits,lipid oxidation kits and flow cytometry.Results:Bioinformatics analysis and immunohistochemical staining showed that SLC7A11 was highly expressed in OTSCC.SLC7A11 KO CAL-27 cells were more sensitive to Erastin than WT cells.The GSH content of SLC7A11 KO cells was lower than that of WT cells,and the lipid peroxide content was higher than that of WT cells after treatment with Erastin.IFN-γ increased cell sensitivity to Erastin,decreased GSH content and increased lipid peroxides content in the cells.Conclusion:IFN-γ can reduce GSH and increase MDA and Lipid ROS levels by degrading SLC7A11,this increases the sensitivity of OTSCC to Erastin.
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BACKGROUND:Disturbances in bone metabolism have a significant association with ferroptosis in steroid-induced osteonecrosis of the femoral head(SONFH).Furthermore,the pathologic process of SONFH is characterized by the presence of cartilage damage and degeneration.However,the specific regulatory targets and the relationship between ferroptosis and cartilage concerning SONFH remain unclear. OBJECTIVE:To employ bioinformatics and machine learning techniques to identify specific genes associated with ferroptosis that target cartilage and to investigate the correlation between ferroptosis and cartilage,thereby providing novel ideas and methodologies for the study and treatment of SONFH. METHODS:Disease datasets pertinent to the study and ferroptosis-related genes were retrieved from the GEO and FerrDb databases.Subsequently,the disease datasets were normalized and differential analysis using the R language to identify ferroptosis-related differential genes(Fe-DEGs).We conducted Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analysis of Fe-DEGs.Furthermore,ferroptosis-related signature genes were filtered based on the protein-protein interaction network of Fe-DEGs and machine learning methods.Finally,the rabbits were divided into normal and model groups.The normal group was given the same dose of saline to simulate the modeling drug,and the animal model of SONFH in rabbits was constructed by injection of modified horse serum combined with methylprednisolone.After successful modeling,the expression of signature gene was verified between different groups,and the phenotype of ferroptosis in cartilage was analyzed. RESULTS AND CONCLUSION:Through the normalization and differential analysis of the dataset,a total of 1 315 differentially expressed genes were identified.Additionally,379 ferroptosis-related genes were obtained from the FerrDb database.After intersecting both gene sets,19 Fe-DEGs were obtained.The GO analysis revealed that Fe-DEGs were mainly involved in biological processes such as cell migration and cellular response to oxidative stress,cellular components such as kinase complexes,amino acid complexes,and cytoplasmic membranes,as well as molecular functions such as kinase activity,receptor activity,and protein binding.The KEGG analysis revealed that Fe-DEGs were mainly enriched in the FoxO signaling pathway,vascular endothelial growth factor signaling pathway,and FcγR-mediated phagocytosis.Constructing a protein-protein interaction network and using machine learning,we identified the ferroptosis-related signature gene,CA9.The gene set enrichment analysis of the signature gene CA9 revealed an upregulated expression in biological processes such as fatty acid metabolism and O-GlcNAc glycosylation modification,while being inhibited in terms of neural activity and ligand-receptor interactions.RT-PCR and western blot results showed that compared with the normal group,the expressions of ACSL4 and CA9 at mRNA and protein levels were significantly higher in the model group(P<0.05),while the expressions of SLC7A11 and GPX4 at mRNA and protein levels were significantly lower in the model group(P<0.05),coinciding with the expression levels of the signature genes in the dataset.These findings indicate that the cartilage of SONFH is closely related to ferroptosis,and targeting the signature gene may provide certain ideas and directions for the study and treatment of SONFH.
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AIM:To investigate the mechanism through which esculetin induces ferroptosis of mouse breast cancer 4T1 cells.METHODS:Molecular docking of esculetin with p53,solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4)proteins was performed,and Kaplan-Meier curves and time-dependent receiver oper-ating characteristic curves were drawn.The 4T1 cells were divided into 6 groups,namely the control(CON),1/2 IC50,IC50,2 IC50,erastin,and capecitabine groups.The appropriate drug concentration for treating 4T1 cells was screened by CCK-8 assay.The invasion and migration abilities of 4T1 cells following esculetin treatment at the selected drug concentra-tion were analyzed by scratch test and Transwell assay.Mitochondrial morphological change were examined by electron mi-croscopy.The levels of ferroptotic cell death were then quantified by Fe2+,reactive oxygen species(ROS),malondialde-hyde(MDA),glutathione(GSH),and GPX4 assays.Western blot was performed to evaluate the protein levels of p53,SLC7A11,GPX4 and acyl-CoA synthetase long-chain family member 4(ACSL4).RESULTS:Compared with CON group,the esculetin 1/2 IC50,IC50 and 2 IC50 groups showed smaller size,increased membrane density,and decreased ridge of mitochodria,as well as decreased levels of GSH and GPX4,reduced cell invasion and migration abilities,and de-creased levels of SLC7A11 and GPX4 proteins(P＜0.05).Furthermore,these groups exhibited increased levels of Fe2+,ROS,and MDA,as well as elevated p53 and ACSL4 protein abundance(P＜0.05).CONCLUSION:Esculetin pro-motes ferroptosis of 4T1 cells through a mechanism involving the p53/SLC7A11/GPX4 regulatory axis.
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Polysaccharide of Balanophora involucrata Hook. f. (BPS), the major component of Balanophora involucrata Hook. f., was confirmed the protective effect on liver injury in our previous study. This research aimed to investigate the protective mechanism of BPS on experimental liver injury by attenuating cell ferroptosis through modulating solute carrier family 7 member 11/glutathione peroxidase 4 (SLC7A11/GPX4) pathway. The animal experiment was approved by the Experimental Animal Ethical Committee of Hubei Minzu University and all rats had received human care in compliance with the institutional animal care guidelines. Rats were given intraperitoneal injection of (D-galactosamine, D-GalN) solution (800 mg·kg-1) one time to establish the acute liver injury model. The results showed aspartate amino transferase (AST), alanine aminotransferase (ALT) and 4-hydroxynonenal (4-HNE) levels in serum were decreased, and the contents of reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA) and lipid peroxide (LPO) in liver tissues also decreased and glutathione (GSH) level increased after BPS administration with 200 mg·kg-1. Besides, BPS reduced iron deposition and increased the expression of SLC7A11 and GPX4 proteins in liver tissue. In conclusion, BPS ameliorated experimental liver injury by alleviating cell ferroptosis through SLC7A11/GPX4 pathway. The present study pointed to the possibility of utilizing BPS for protection against liver injury in clinic.
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Drug resistance of cancer cells is the main causes of chemotherapy failure, and gene mutation or function loss is key factor to induce drug resistance. Previous studies have shown that hairy and enhancer of split 1 (HES1) is up-regulated in herceptin-resistant gastric cancer cells, and inhibition of its activity can reverse its resistance while the potential mechanism has not yet been elucidated. In this study, we employed CRISPR/Cas9 to establish HES1 knock-out cell line (△HES1/NCI N87R) to investigate the functions of HES1 in herceptin resistance of NCI N87R cells and its potential mechanisms. We investigated proteomics profiling of △HES1/NCI N87R cells based on quantitative proteomics. Gene ontology analysis was conducted by GeneSet Enrichment Analysis (GSEA) and Metascape database, and pathway enrichment analysis was done using GeneAnalytics database. The selected molecules were quantified by Western blot and some pathways were verified by using inhibitors. The results showed that the resistance to herceptin of △HES1/NCI N87R cells decreased compared to NCI N87R cells. Proteomic data demonstrated that the expression of 1 263 genes changed significantly in △HES1/NCI N87R cells, among which 761 genes were up-regulated while 502 ones down-regulated comparing with NCI N87R cells. Pathway analysis showed that ferroptosis, fatty acid β-oxidation, autophagy and glutathione metabolism, etc. exhibited notable changes in △HES1/NCI N87R cells. The functional studies showed that the levels of iron ion and malondialdehyde increased, and glutathione decreased in △HES1/NCI N87R cells. It was further found that Fer-1, a ferroptosis inhibitor, could reverse the expression of pTP53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in △HES1/NCI N87R cell, and reduce the sensitivity of △HES1/NCI N87R cells to herceptin. It is suggested that HES1 regulated the resistance of NCI N87R cells to herceptin through TP53/SLC7A11/GPX4 signaling pathway, and targeting TP53/SLC7A11/GPX4 signal axis mediated by HES1 is a potential strategy to reverse herceptin resistance in gastric cancer.
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Objective To explore the role and mechanism of puerarin in ameliorating acetaminophen(APAP)-induced acute liver injury in mice based on ferroptosis signaling pathway.Methods Twenty-four C57BL/6J mice were randomly divided into normal group,model group,and puerarin low-and high-dose groups(50 and 200 mg·kg-1),6 mice in each group;all the administration groups were given continuous gavage(10 mL·kg-1)once a day pre-dosed for 3 days.One hour after the last dose,APAP(300 mg·kg-1)was intraperitoneally injected into the mice of the model group and the puerarin low-and high-dose groups to replicate the drug-induced liver injury(DILI)mouse model.After 24 hours,the serum levels of alanine transaminase(ALT),aspartate aminotransferase(AST),and lactate dehydrogenase(LDH)were measured by the microplate assay;HE staining was used to observe the histopathological changes in liver tissue;the apoptosis of hepatocytes was observed by the TUNEL staining assay;the levels of malondialdehyde(MDA)were measured by the TBA assay;the mRNA expression levels of reactive oxygen species(ROS),4-hydroxynonenal(4-HNE),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11)were detected by immunofluorescence;qRT-PCR was performed to measure the mRNA levels of ferroptosis-related genes GPX4,transferrin receptor(TFRC),and solute carrier family 11 member 2(SLC11A2)in liver tissue.Results Compared with the normal group,the serum ALT,AST,and LDH levels of mice in the model group were significantly elevated(P＜0.01);the liver lobules showed obvious damage,with swelling and rupture of hepatocytes,cytoplasmic vacuolisation,fragmentation of nuclei,congestion of the hepatic blood sinusoids and infiltration of inflammatory cells,and an increase in apoptotic cells;the level of MDA in the hepatic tissues was significantly elevated(P＜0.05);the red fluorescence(positive expression)of ROS and 4-HNE was significantly enhanced(P＜0.05,P＜0.01),and the red fluorescence(positive expression)of GPX4 and SLC7A11 was significantly weakened in liver tissue(P＜0.01);the mRNA expressions of GPX4 and SLC11A2 in liver tissue were significantly down-regulated(P＜0.05),and there was a tendency for the down-regulation of TFRC expression but the difference was not statistically significant(P＞0.05).Compared with the model group,the serum AST and LDH levels of mice in the low-and high-dose groups of puerarin were significantly reduced(P＜0.05,P＜0.01),and there was a decrease in serum ALT,but the difference was not statistically significant(P＞0.05);the structure of the liver lobules was clearer,with radial arrangement of hepatic cords,and the area of necrotic liver tissue and apoptotic cells were significantly reduced;the level of MDA in the liver tissue was significantly reduced(P＜0.05);the red fluorescence(positive expression)of ROS and 4-HNE in liver tissue were significantly attenuated(P＜0.05,P＜0.01).The red fluorescence(positive expression)of GPX4 and SLC7A11 in liver tissue of the mice in the puerarin low-dose group were significantly enhanced(P＜0.05,P＜0.01),and there was a tendency to enhance the red fluorescence(positive expression)of GPX4 and SLC7A11 in the liver tissue of the mice in the puerarin high-dose group,but the difference was not statistically significant(P＞0.05).The mRNA expressions of GPX4 and TFRC in liver tissue of mice in low-dose puerarin group was significantly up-regulated(P＜0.05),while the mRNA expressions of GPX4 and SLC11A2 in high-dose puerarin group were significantly up-regulated(P＜0.05).Conclusion Puerarin had a significant protective effect on APAP-DILI,which may be related to its inhibition of cellular ferroptosis through the SLC7A11/GPX4 pathway.
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Objective:To investigate the effect and mechanism of ionizing radiation on ferroptosis in mouse hepatocytes.Methods:Twenty-four C57BL/6J mice were divided into two groups by random number table method: healthy control group (control group, n=6) and irradiation group (whole liver was irradiated with a single dose of 30 Gy X-ray, n=18). Mice were sacrificed at 6, 24 and 72 h (6 mice per time point) after irradiation to obtain liver tissue and plasma samples. The contents of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma were measured by automatic biochemical analyzer. The prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured by automatic biochemical analyzer. Pathological changes of liver tissues were observed by hematoxylin-eosin (HE) staining. The iron deposition in liver tissues was detected by Prussian blue staining. The expression levels of 4-Hydroxynonenal (4HNE) and hepcidin in the liver were determined by immunohistochemical staining, and quantitative analysis was performed. Plasma malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, total antioxidant capacity (T-AOC) and glutathione (GSH) content were determined by microplate reader analysis according to the kit instructions. The expression levels of transferrin receptor 1 (TfR1), p53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the liver were measured by Western blot. Results:Compared with the control group, the plasma contents of ALT ( t=5.15, 5.47, both P<0.001) , AST at 6 and 24 h after irradiation were increased ( t=8.42, 2.50, both P<0.001), the plasma PT was prolonged ( t=3.12, P=0.011) and the APTT was shortened ( t=3.26, P=0.009) at 72 h after radiation in the irradiation group. Histopathological results showed that evident liver edema was observed at 6, 24 and 72 h after irradiation ( t=9.58, 10.09, 18.70, all P<0.001). Different degrees of iron deposition were observed ( t=8.57, 15.31, 32.11, all P<0.001). The infiltration of hepcidin positive cells was significantly increased after irradiation ( t=5.36, 13.17, 17.11, all P<0.001). The number of 4HNE positive cells was significantly increased ( t=18.86, 22.67, 9.12, all P<0.001). At the same time, ionizing radiation induced a significant increase in plasma MDA content ( t=4.36, 7.47, 8.22, all P<0.001), and a decrease in SOD ( t=4.52, 5.80, 7.60, all P<0.001), T-AOC ( t=13.24, 20.49, 24.96, all P<0.001) and GSH ( t=2.78, 6.07, 11.25, P=0.020, <0.001, <0.001), respectively. The expression level of TfR1 protein was significantly up-regulated ( t=3.46, 5.40, P=0.026, 0.006), whereas that of GPX4 protein was significantly down-regulated ( t=11.88, 30.63, both P<0.001) at 24 and 72 h after irradiation. At 6, 24 and 72 h after irradiation, the expression level of p53 protein was significantly up-regulated and maintained at a high level ( t=7.84, 4.25, 8.22, P=0.001, 0.013, 0.001), while that of SLC7A11 protein was significantly down-regulated ( t=9.29, 19.96, 9.09, all P<0.001). Conclusion:Ionizing radiation induces the ferroptosis in hepatocytes, and its mechanism may be related to the activation of p53-SLC7A11-GPX4 pathway.
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Objective To investigate whether Andrographolide(AG)can alleviate intestinal injury in sepsis by ac-tivating the SLC7A11/GPX4 axis in ferroptosis.Methods Forty rats were randomly divided into sham group(sham group),sepsis group(CLP group),AG low,medium and high dose groups(5,10 and 20 mg/kg).HE staining was used to observe the pathological changes of Intestinal tract.ELISA method was used to determine Inter-leukin 6(IL-6),tumour necrosis factor α(TNF-α),intestinal fatty acid binding protein(I-FABP),D-lactate content.The mechanism of ferroptosis was explored with AG high dose group(AG20 group),forty rats were ran-domly divided into sham group,CLP group,ferroptosis inhibitor(Fer-1)group,AG20+Fer-1 group.HE staining and transmission electron microscopy were used to observe the pathological changes of Intestinal tract.The kits were used to determine oxidative stress MDA,GSH levels and Fe3+content.Western blot was used to detect the protein levels of solute carrier family 7 member 11(SLC7A11),glutathione peroxidase 4(GPX4),and ferritin heavy poly-peptide 1(FTH-1).Results Compared with the sham group,the CLP group showed severe morphological damage to the small intestine,with significantly higher levels of inflammation,I-FABP and D-lactate(all P＜0.05),the AG group reversed these changes in a concentration-dependent manner(all P＜0.05).Compared with the CLP group,the AG20 and Fer-1 groups showed improved pathological damage to the small intestine,with lower levels of MDA and Fe3+and higher levels of GSH,SLC7A11,GPX4 and FTH-1 protein expression increased(all P＜0.05),and pathological injury and oxidative stress were reduced in the AG20+Fer-1 group,and SLC7A11,GPX4 and FTH-1 protein expression increased more significantly(all P＜0.05).Conclusion The mechanism by which AG attenuates intestinal injury in sepsis may be related to SLC7A11/GPX4 axis activation in ferroptosis.
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Objective:To observe the effects of electroacupuncture on the expression of cortical solute carrier family 7 member 11(SLC7A11),glutathione(GSH)and glutathione peroxidase 4(GPX4)in rats with post stroke spasticity(PSS),and to explore the mechanism of electroacupuncture in the treatment ferrozosis in PSS.Methods:Thirty SD male rats were randomly divided into sham group,model group and electroacupuncture group.A modified Zea-Longa wire bolus+internal capsule injection NMDA method was used to produce a rat model of PSS.In the electroacupunc-ture group,the affected side of Yanglingquan and Quchi were needled once/day for 30 min/time for 7 d.In the sham group and the model group,only fixation without intervention was performed during the same period.Zea-Longa Neuro-logical Function Score was used to detect the neurological function of rats,electrophysiological tracing method was used to detect the muscle tone of rat quadriceps,Western Blot was used to detect the protein expression of rat cortical SLC7A11 and GPX4,Enzyme-linked immunosorbent assay(ELISA)was used to detect the GSH content of rat cortex,and real time RT-PCR was used to detect the mRNA of rat cortical SLC7A11 and GPX4 mRNA expression.Results:Neurological function scores were elevated;quadriceps muscle tone was increased;GSH content was decreased;the protein expression of SLC7A11 and GPX4 was significantly decreased;the expression of SLC7A11 mRNA and GPX4 mRNA was significantly decreased.Electroacupuncture treatment resulted in lower neurological function scores,lower quadriceps muscle tone,increased GSH content in rat cortex,significantly up-regulated protein expression of SLC7A11 and GPX4,and significantly increased expression of SLC7A11 and GPX4 mRNA.Conclusion:Electroacupuncture on"Yanglingquan"and"Quchi"could improve limb spasticity and promote the recovery of neurological function in PSS rats,and its mechanism of action may be related to the inhibition of ferroptosis of cortical cells by electroacupuncture regulating the SLC7A11 and GPX4 expression.
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Glioma is the most common primary brain tumor in adults and is essentially a polygenic abnormal disease. Solute carrier family 7 member 11 (SLC7A11) is a core component of the cystine/glutamate transporter and its expression is regulated at the transcriptional and translational levels. SLC7A11 mediates glioma cells proliferation, invasion and chemoradiotherapy resistance through regulation of oxidative stress and ferroptosis. Deep study of SLC7A11 will provide new theoretical basis and therapeutic targets for the treatment of gliomas.
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Circular RNAs (circRNAs),a kind of novel non-coding RNAs, have been shown to play animportant role in cellular redox reactions. In the previous study, we found that hsa_circ_0087354 wasclosely related to the cellular redox state by real-time PCR. After overexpression of hsa_circ_0087354, the relative expression of ROS1 were decreased significantly (P < 0. 01), while the levels of SOD1 wereincreased significantly (P < 0. 05) . The activities of SOD and Gpx as well as GSH concentration weresignificantly increased (P < 0. 01), and cell proliferation was promoted in cells (P < 0. 05) . Bioinformatics analysis predicted that there were binding sites between hsa-miR-199-3p and hsa_circ_0087354 as well as solute carrier family 7 member 11 (SLC7A11), which might have a targetedregulatory relationship. Dual luciferase reporter assay confirmed the targeted regulatory relationshipbetween hsa-miR-199-3p with hsa_circ_0087354, and SLC7A11. Overexpressed hsa_circ_0087354 plasmid and ctrl plasmid were constructed, hsa-miR-199a-3p, hsa-miR-199b-3p and hsa-miR-NC mimicswere synthesized. Real-time PCR analysis showed that the relative expression of hsa-miR-199-3p was observably decreased (P < 0.01), while the relative expression of SLC7A11 in cells was dramaticallyincreased after transfection of has_circ_0087354 plasmid (P < 0.05) . After transfection with hsa-miR-199-3p, the relative expressions of SLC7A11 were markedly decreased (P < 0.001) . The activities ofSOD and Gpx, GSH concentration (P<0.01), and cell proliferation rate (P < 0.05) were significantlyreduced. In conclusion, hsa_circ_0087354 could enhance the expression of SLC7A11, promote theproliferation of cells and reduce the oxidative stress by adsorption of hsa-miR-199-3p.
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The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11
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Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.
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Humans , Ferroptosis/immunology , Immunotherapy , Neoplasms/therapy , RadiotherapyABSTRACT
AIM: To evaluate the effect of SLC7A11 in dexmedetomidine pretreatment induced reduction of ferroptosis caused by intestinal ischemia-reperfusion (II/R) injury in mice. METHODS: Twenty-four healthy meal SPF C57BL/6J mice, aged 8 weeks, weighing 22-25 g, were randomly divided into Sham operation group (S group), intestinal I/R group (II/R group), dexmedetomidine group (DEX group) and dexmedetomidine plus SLC7A11 inhibitior group (DIKE group), with 6 mice in each group. Intestinal ischemia was induced by occluding the superior mesenteric artery for 45 min followed by 30 min of reperfusion to establish the model of II/R injury. In DEX and DIKE groups, Dexmedetomidine 25 μg/kg was intraperitoneally injected at 30 min before clamping the superior mesenteric artery. The same amount of normal saline was injected in the S group and the II/R group. In DIKE group, SLC7A11 inhibitior Imidazole ketone erastin 50 mg/kg was intraperitoneally injected at 90 min before ischemia. Mice were sacrificed 30 min after reperfusion, and small intestinal tissues in length 5 cm away from the ileocecal valvum were obtained for microscopic examination of pathological changes of intestinal mucosa and for determination of contents of Fe