Expression Of SLC7A11 Research Articles

Electroacupuncture improves cognitive function in high-fat diet/streptozocin-induced type 2 diabetic mice by inhibiting autophagy-related ferroptosis.

At present, there lacks a definitive pharmaceutical intervention or therapeutic approach for diabetes-associated cognitive impairment. Herein, we delved into the impact of electroacupuncture on cognitive function in high-fat diet/streptozocin (HFD/STZ)-induced T2DM mice and underlying mechanisms. Hippocampal insulin resistance was determined by western blot analysis. Cognitive function was evaluated by Morris water maze test. The morphology of the hippocampal neurons was observed through hematoxylin & eosin staining and Nissl staining. Synaptic plasticity was assessed by western blot analysis. Immunofluorescence, immunohistochemistry, western blot and real-time PCR were employed to detect the levels of ferroptosis markers, autophagy markers, and netrin-1. Electroacupuncture treatment exhibited ameliorative outcomes on spatial learning, memory function, hippocampal insulin resistance, neuronal damage, and synaptic plasticity in T2DM mice. Furthermore, it effectively suppressed neuronal ferroptosis within the hippocampus by upregulating GPX4 and SLC7A11 expression, and reducing 4-HNE expression. Meanwhile, electroacupuncture intervention increased the levels of Beclin1 and LC3II/LC3I, as well as decreased the levels of p62 and phosphorylated-mTOR in the hippocampus of T2DM mice, suggesting that electroacupuncture facilitated autophagy activation by inhibiting mTOR activity. 3-MA-mediated autophagy inhibition undermined the beneficial effects of electroacupuncture on neuronal ferroptosis and cognitive deficits in T2DM mice. Additionally, the beneficial effects of electroacupuncture on autophagy and ferroptosis was achieved by upregulation of netrin-1 in the hippocampus. Our study revealed that that electroacupuncture therapy inhibited neuronal ferroptosis via the activation of autophagy, thereby ameliorating cognitive deficits in T2DM mice.

To explore the protective mechanism of promethazine against hippocampal neuron injury based on network pharmacology and experimental verification.

This study aims to investigate the effect of promethazine (PMZ) on hippocampal neuronal injury through network pharmacology and in vivo experiments. Network pharmacology: The intersection genes of PMZ and Alzheimer Disease (AD) were obtained, and the core genes of PMZ in AD were screened. The intersection genes were enriched by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. In the in vitro experiment, mouse hippocampal neurons (HT22) were divided into control, glutamate (GLU) model, and GLU + PMZ treatment groups. The control group was given a complete culture medium, the model group was given GLU for 24 hours, the treatment group was given PMZ pretreatment for 3 hours, and then GLU was administered for 24 hours. Cell viability was determined, cell morphology was observed by microscopy, reactive oxygen species levels and glutathione content were detected, and protein expression of P53, PTGS2, SLC7A11, and GPX4 was detected by western blotting. Network pharmacology: A total of 317 PMZ targets, 1934 AD genes, 125 intersection genes, and 18 core genes, including P53 and PTGS2. Gene Ontology enrichment analysis showed that the effect of PMZ on AD was mainly related to cell proliferation, inflammation, hypoxia, synaptic structure, plasma membrane, and oxidoreductase activity. Kyoto Encyclopedia of Genes and Genomes results showed neuroactive ligand-receptor interaction, cell senescence, cancer pathway, PI3K-AKT signal pathway, neurodegeneration, and HIF-1 signal pathway. In vitro experiments: PMZ improved the GLU-induced decrease in cell viability and morphological changes in hippocampal neurons. PMZ inhibited reactive oxygen species levels and increased glutathione content in injured hippocampal neurons. Up-regulated of P53, SLC7A11 and GPX4 expression, and inhibited expression of PTGS2. PMZ regulates the SLC7A11-GPX4 antioxidant system to protect hippocampal neurons from oxidative stress injury.

High glucose Induces Podocyte Ferroptosis through BAP1/SLC7A11 Pathway

BackgroundFerroptosis plays an important role in the development of diabetic nephropathy (DN). However, its specific regulatory mechanisms remain unclear. MethodsMPC5 cells were cultured in high glucose (HG) medium to stimulate the HG environment in vitro. Ferroptosis and oxidative stress were assessed by measuring malondialdehyde (MDA) levels, cystine uptake capacity, and reactive oxygen species (ROS). C91A and wild type (WT) MPC5 cells were constructed to further explore the specific regulatory mechanism of BAP1 on SLC7A11. ResultsErastin-induced ferroptosis was sensitized by HG, leading to a significant reduction in glutathione (GSH) levels, increased oxidative stress, and inhibited cystine uptake in podocytes. HG suppressed the expression of SLC7A11. Overexpression of SLC7A11 improved cystine uptake and reduced oxidative stress. Furthermore, HG increased BAP1 levels. Silencing BAP1 up-regulated SLC7A11 and mitigated ferroptosis. Cell proliferation was reduced after SLC7A11 knockdown.In BAP1 WT cells, but not in its C91A mutant cells, the transcription of SLC7A11 was downregulated and the level of ferroptosis was increased. ConclusionHG inhibits cystine uptake in podocytes by promoting the expression of BAP1 and inhibiting H2Aub deubiquitination on SLC7A11, leading to lipid peroxide accumulation and ferroptosis in podocytes.

LRP1B Suppresses Immunotherapy Efficacy in Lung Adenocarcinoma by Preventing Ferroptosis.

Immune biomarkers for non-small-cell lung cancer (NSCLC) are programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB). However, they cannot accurately predict the effectiveness of immunotherapy. Identifying appropriate biomarkers that can differentiate between beneficiary groups is imperative. We identified lipoprotein receptor-related protein 1B (LRP1B) mutation as a potential biomarker for immunotherapy by analyzing clinical data, combined with bioinformatics analysis. The effects of LRP1B on ferroptosis were assessed using qRT-PCR, Western blotting, CCK-8 assay, and flow cytometry. The potential mechanism underlying the regulation of ferroptosis by LRP1B was elucidated using qRT-PCR, Western blotting, ChIP, and dual-luciferase reporter gene assays. Through the collection and analysis of clinical data, we had established that LRP1B mutations are closely associated with immunotherapy. Bioinformatics analysis revealed significant differences in the expression levels of PD-L1 and TMB between patients with LRP1B mutation and wild-type patients in lung adenocarcinoma (LUAD). Furthermore, we observed that patients with LRP1B mutation in LUAD had significantly higher levels of tumor-infiltrating lymphocytes (TILs) than wild-type patients. In addition, we found that patients with LRP1B mutation in LUAD had significantly prolonged progression-free survival (PFS) compared to wild-type patients. However, the differences of PD-L1 expression, TILs, and PFS were not observed in patients with LRP1B mutation in lung squamous cell carcinoma (LUSC). These findings provided strong evidence that LRP1B mutation was a potential biomarker for immunotherapy in LUAD. Moreover, our invivo experiments indicated that knockdown of LRP1B enhanced the efficacy of mPD-1, and mechanistic studies revealed that LRP1B regulated the sensitivity of cells to ferroptosis by modulating the expression of SLC7A11 through altering the phosphorylation level of STAT3. Further analysis revealed that LRP1B knockdown promoted immunotherapy invivo. Our results confirmed that LRP1B affected the efficacy of immunotherapy by modulating the sensitivity of NSCLC cells to ferroptosis. LRP1B mutations represent a highly promising immunotherapeutic biomarker for NSCLC.

Integrated analysis of disulfidptosis-related genes SLC7A11, SLC3A2, RPN1 and NCKAP1 across cancers

Disulfidptosis, a newly identified form of regulated cell death associated with disruption of disulfide bond formation in the endoplasmic reticulum, involves the dysregulation of disulfidptosis-related genes (DRGs) that may contribute to cancer development and progression. However, the molecular mechanisms and clinical implications of DRGs in different cancer types remain poorly characterized. Therefore, in this comprehensive study, we investigated the expression, prognostic value, and functional roles of four recently identified DRGs (SLC7A11, SLC3A2, RPN1, and NCKAP1) across various cancers. Especially, in clinical samples of glioblastoma, we found that RPN1 was significantly correlated with patient survival. Through mutation landscape analysis, we identified diverse missense mutations in these DRGs, with NCKAP1 exhibiting the highest mutation frequency (5.9% in skin cutaneous melanoma). Additionally, we observed positive correlations between these DRGs and tumor stemness (DNAss DNA stemness score and RNAss RNA stemness score) as well as RNA modifications, particularly m6A modification, in several cancer types. Furthermore, high expression of SLC7A11, RPN1, and NCKAP1 was positively associated with infiltration of T-helper type 2 (Th2) cells in various cancers, while high expression of SLC7A11, SLC3A2, and RPN1 correlated with tumor mutational burden (TMB) in 10, 4, and 8 tumor types, respectively. Utilizing a protein–protein interaction network, we identified the RHO GTPases Activate WASPs and WAVEs pathway as significantly enriched, suggesting the involvement of these DRGs in cancer-related signaling pathways. Collectively, our findings provide novel insights into the molecular mechanisms and clinical implications of DRGs in pan-cancer, highlighting their potential as biomarkers and therapeutic targets for cancer treatment.

Edaravone mitigates calcium oxalate-induced renal tubular epithelial cell injury by inhibiting autophagy-mediated ferroptosis.

Edaravone (EDA) has been found to exert protective effects on kidney injury. Nevertheless, the functions of EDA in kidney stones as well as the potential mechanism are vague. Calcium oxalate (CaOx) was used to induce kidney stones cell model with human renal tubular epithelial cell line HK-2. CCK-8 assay was employed to detect cell viability injury. Oxidative stress was measured by DCFH-DA staining and detection of MDA, SOD, and GSH. Staining of FerroOrange and western blot were applied for ferroptosis. In addition, autophagy was elucidated by western blot and immunofluorescence staining. The data showed that CaOx treatment aggravated HK-2 cell viability injury, increased the levels of ROS, MDA, and Fe2+ in HK-2 cells, and reduced the contents of SOD and GSH. Additionally, CaOx enhanced the expression of KIM1, TFR1, LC3II/LC31, and BECLIN1 in HK-2 cells, while resulting in a decrease in the expression of GPX4, SLC7A11, and P62. Pretreatment of EDA mitigated CaOx-induced oxidative stress and ferroptosis, as well as autophagy in renal tubular epithelial cells. However, autophagy inducer rapamycin (Rap) reversed the protective role of EDA on renal tubular epithelial cell injury, oxidative stress, and ferroptosis. In conclusion, EDA contributes to suppressing oxidative stress and ferroptosis in CaOx-induced HT22 cells by restraining autophagy, which may be a potential candidate for the treatment of kidney stones caused by renal tubular epithelial cell damage.

Citrus rhoifolin alleviated DSS-induced acute colitis by activating CEMIP/SLC7A11-mediated cystine uptake and inhibiting epithelial ferroptosis.

Pharmacological inhibition of ferroptosis, a specific form of regulated cell death, has emerged as a promising therapeutic strategy for alleviating symptoms and enhancing endoscopic outcomes in patients suffering from ulcerative colitis. Rhoifolin, a prominent bioactive constituent abundant in the widely consumed fruit Citrus grandis (grapefruit), has garnered attention for its ability to diminish the levels of reactive oxygen species (ROS), which are key inducers of ferroptosis across diverse cellular contexts. In this study, we aimed to investigate whether rhoifolin exerts its beneficial effects on colitis by modulating the process of epithelial ferroptosis. Colitis model was successfully established in C57BL/6 mice through the administration of 2.5% dextran sulfate sodium (DSS) solution for a duration of 9days, which was freely accessible for drinking. RNA sequencing was conducted to delve into the mechanisms underlying the rhoifolin-mediated effects on colitis. To evaluate the impact of rhoifolin on ferroptosis in epithelial cells, several key indicators were measured, including mitochondrial morphology, colonic glutathione (GSH) levels, lipid peroxidation product contents, and ROS levels. The results indicated that rhoifolin exhibited profound anti-colitis properties and effectively curbs ferroptosis in epithelial cells of mice subjected to DSS treatment. The RNA sequencing analysis further revealed that rhoifolin stimulated a remarkable upregulation of colonic cell migration-inducing protein (CEMIP) expression by approximately 2.4-fold in colitis-affected mice. Notably, depletion of CEMIP significantly blocked the rhoifolin-induced increase in the cystine transporter solute carrier family 7 member 11 (SLC7A11, from 1.9-fold to approximately 1.1-fold), as well as the elevation of cystine uptake (from 1.72-fold to 1.2-fold) and glutathione (GSH) biosynthesis (from 2.1-fold to 1.2-fold), and the suppression of epithelial ferroptosis (from 0.51-fold to 0.94-fold) in mice with colitis. Molecular docking investigations have pinpointed crucial amino acid residues within CEMIP, specifically His267, His289, and Phe265, as the primary interaction sites (docking score: -7.8kcal/mol), facilitating the engagement of rhoifolin via hydrogen bonding interactions. Rhoifolin significantly mitigated DSS-induced colitis primarily through inhibiting epithelial ferroptosis. The activation of CEMIP by citrus-derived rhoifolin led to a notable upregulation of SLC7A11 expression, thereby enhanced cystine uptake and facilitated GSH biosynthesis, ultimately suppressed the occurrence of ferroptosis in epithelial cells.

Transcriptome combined with Mendelian randomization to screen key genes associated with mitochondrial and programmed cell death causally associated with diabetic retinopathy.

Mitochondrial dysfunction in the retina can induce apoptosis of retinal capillary cells, leading to diabetic retinopathy (DR). This study aimed to explore key genes related to programmed cell death (PCD) and mitochondria in DR via bioinformatic analysis. A differential analysis was performed to identify differentially expressed genes (DEGs) between DR and control samples using the GSE94019 dataset from the Gene Expression Omnibus (GEO) database. Pearson correlation analysis was then utilized to select genes linked to mitochondrial function and PCD (M-PCD). Candidate genes were identified by overlapping DR-DEGs and M-PCD genes, followed by functional annotation. Mendelian randomization (MR) analysis was employed to identify genes with causal relationships to DR. Key genes were identified through protein-protein interaction (PPI) analysis using six algorithms (DEgree, DMNC, EPC, MCC, Genes are BottleNeck, and MNC) within Cytoscape software. The expression patterns of these genes were validated using GSE94019 and GSE60436 datasets, as well as RT-qPCR. Enrichment analysis provided insights into the function and pathways of these key genes in DR. Differential immune cell profiles were determined via immune infiltration analysis, followed by exploring the relationships between immune cells, cytokines, and the identified genes. Correlations between key genes and apoptosis genes were also examined. In vivo experiments using RT-PCR, immunohistochemistry (IHC), and western blot analysis confirmed that MYC and SLC7A11 expression was significantly elevated in DR rat retinal tissues. From 658 candidate genes, 12 showed significant causal associations with DR. MYC and SLC7A11 were particularly notable, showing upregulated expression in DR samples and involvement in apoptosis and diabetes-related pathways. These genes were significantly associated with apoptotic genes and correlated positively with altered immune cell types and cytokines, suggesting a link between immune response and DR pathogenesis. In vivo findings confirmed that MYC and SLC7A11 expression was elevated in DR rat retinal tissues. Key genes (MYC and SLC7A11) associated with mitochondrial function and PCD in DR were identified, offering insights into DR's pathological mechanisms and potential targets for diagnostic and therapeutic strategies.

Etomoxir Sodium Salt Promotes Imidazole Ketone Erastin-Induced Myeloid-Derived Suppressor Cell Ferroptosis and Enhances Cancer Therapy.

Although ferroptosis inducers trigger ferroptotic tumor cells and immune cells in the tumor microenvironment (TME), imidazole ketone erastin (IKE)'s induction of ferroptosis shows no effect on tumor growth in immunocompetent tumor-bearing mice due to the presence of myeloid-derived suppressor cells (MDSCs). Treatment of the carnitine palmitoyltransferase 1a (CPT1A)-specific inhibitor decreases the immunosuppressive function of MDSCs and enhances ferroptotic inducer-initiated tumor cell ferroptosis. However, whether blocking CPT1A could enhance IKE-induced MDSC ferroptosis and thereby inhibit tumor growth is still unclear. Here, we report that a CPT1A-specific inhibitor, etomoxir sodium salt (Eto), and IKE combined treatment increased MDSC ferroptosis. Interestingly, the combination treatment of Eto and IKE blocked MDSCs' immunosuppressive function and accumulation by downregulating the expression of SLC7A11, GPX4, and ARG1 while promoting T-cell proliferation and infiltration into tumor tissues to enhance cancer therapy. These data provide a rationale for the combination therapy of a specific CPT1A inhibitor, Eto, with IKE in clinical settings.

Angiotensin II Induces Vascular Endothelial Dysfunction by Promoting Lipid Peroxidation-Mediated Ferroptosis via CD36.

Angiotensin II (Ang II) is an effective vasoconstriction peptide, a major effector molecule of the renin-angiotensin-aldosterone system (RAAS) and one of the important causes of endothelial dysfunction. Ferroptosis is considered to be involved in the occurrence and development of cardiovascular diseases. This study is dedicated to exploring the role and mechanism of Ang II-induced ferroptosis in HUVECs and to finding molecular targets for vascular endothelial injury and dysfunction during the progression of hypertension. In this study, we found that with the increase in exposure concentration, the intracellular ROS content and apoptosis rate increased significantly, the NO release decreased significantly in the medium- and high-concentration groups and the ET-1 content in the high-concentration group increased significantly. The expression of ZO-1 protein was significantly decreased in the high-concentration group. The expression of p-eNOS, VE-cadherin and Occludin protein showed a dose-dependent downward trend, while the ICAM-1 protein showed an upward trend. Ang II caused lipid metabolism disorders in HUVECs, and the PL-PUFAs associated with ferroptosis were significantly increased. In addition, Ang II promoted a significant increase in intracellular free Fe2+ content and MDA and a significant decrease in GSH content. Furthermore, the expression of GPX4, SLC7A11 and SLC3A2 was down-regulated, the expression of ACSL4, LPCAT3 and ALOX15 was up-regulated, and the ratio of p-cPLA2/cPLA2 was increased. After the intervention of ferroptosis inhibitor Fer-1, the injury and dysfunction of HUVECs induced by Ang II were significantly rescued. Immunofluorescence results showed that the expression of CD36 showed a significant increasing trend and was localized in the cytoplasm. Over-expression of CD36 promoted Ang II-induced ferroptosis and endothelial dysfunction. In conclusion, Ang II induces the injury of HUVECs, decreases vascular diastole and endothelial barrier-related molecules, and increases vascular constriction and adhesion-related molecules, which may be related to CD36 and its mediated lipid peroxidation and ferroptosis signals.

The LINC01094/miR-545-3p/SLC7A11 Signaling Axis Promotes the Development of Gastric Cancer by Regulating Cell Growth and Ferroptosis.

This study aimed to investigate the role and mechanism of action of LINC01094 in the development of gastric cancer (GC). The expression levels of LINC01094 in GC patients and healthy individuals were analyzed online using the Cancer Genome Atlas database. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses were performed to determine the expression of LINC01094/miR-545-3p/SLC7A11 in GC tissues and cells. Functional experiments (MTT assay, colony formation assay, and flow cytometry) were conducted to assess the effect of LINC01094 and miR-545-3p on cell proliferation, viability, apoptosis, cell cycle, and reactive oxygen species. Correlations between LINC01094 and miR-545-3p, as well as SLC7A11, were analyzed and validated using the dual-luciferase reporter assay and RNA immunoprecipitation. The levels of Fe2+, malondialdehyde, and glutathione in the cells were measured biochemically, and the protein expression levels of Bcl-2, cleaved caspase3, Cyclin D1, and p21 were detected by Western blotting. LINC01094 was significantly upregulated in the GC tissues and cells with a targeting relationship with miR-545-3p; the expression levels of LINC01094 and miR-545-3p were negatively correlated. Knockdown of LINC01094 notably inhibited the proliferation and viability of GC cells and promoted cell ferroptosis, which, however, was abrogated by the silencing of miR-545-3p. These findings indicate that miR-545-3p could target and positively correlate with SLC7A11 expression. Additionally, LINC01094 could promote GC cell progression and affect cellular ferroptosis by regulating the miR-545-3p/SLC7A11 signaling axis.

FXR deficiency induced ferroptosis via modulation of the CBP-dependent p53 acetylation to suppress breast cancer growth and metastasis

Farnesoid X receptor (NR1H4/FXR) functions as a scavenger of lipid peroxide products and drives the proliferation and metastasis of various cancers. However, the underlying molecular mechanisms remain poorly understood. In our study, we found that the expression levels of FXR, vimentin and SLC7A11 were significantly higher in breast cancer tissues, particularly in metastatic cancer tissues compared to non-metastatic ones. Furthermore, the increased FXR expression was positively correlated with vimentin and SLC7A11 in clinical tumor specimens. In addition, a high level of FXR correlated with poor prognosis in patients with breast cancer. Both Z-Guggulsterone (Z-GS), as a pharmacological inhibitor of FXR, and silencing FXR curbed proliferation and migration of breast cancer cells by promoting ferroptosis. Notably, our results showed that FXR competitively bound to CREB-binding protein (CBP) to suppress the interaction between p53 and CBP in the nucleus, and thus prevented p53 acetylation at lys382, which was essential for upregulating the expression of SLC7A11. Conversely, FXR knockdown increased the interaction between p53 and CBP and promoted p53 acetylation, which ultimately led to facilitating ferroptosis in breast cancer cells. More importantly, we also found that Z-GS inhibited TGF-β1-induced tumor growth and metastasis of breast cancer primarily through ferroptosis via regulating CBP-dependent p53 acetylation in nude mice. In conclusion, the FXR was first reported as a tumor promoter that enhanced the proliferation and metastasis of breast cancer cells through regulating CBP-dependent p53 K382 acetylation. It proposes that FXR may serve as a potential therapeutic target for the treatment of breast cancer.

TRIM46 accelerates H1N1 influenza virus-induced ferroptosis and inflammatory response by regulating SLC7A11 ubiquitination.

Influenza A (H1N1) virus is an acute respiratory infection responsible for enormous morbidity and mortality worldwide. The tripartite motif-containing protein 46 (TRIM46) has an antiviral function that inhibits various viral infections. This study is designed to explore the role and mechanism of TRIM46 in the progress of H1N1 infection. Herein, we infected A549 or 16HBE cells with the H1N1 virus at different times to assess TRIM46 and solute carrier family 7 member 11 (SLC7A11) expression. TRIM46 and Influenza A nucleoprotein mRNA levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). TRIM46, solute carrier family 7 member 11 (SLC7A11), and Nucleoprotein protein levels were detected using protein level were detected by western blot assay. Cell virulence was determined using Virulence assay (TCID50) assay. Cell viability was determined using Cell Counting Kit-8 (CCK-8) assay. Reactive oxygen species (ROS), intracellular iron content, Malondialdehyde (MDA), and Glutathione (GSH) levels were determined using special assay kits. The stability of SLC7A11 was assessed by Cycloheximide (CHX) assay. Interaction between TRIM46 and SLC7A11 was verified using Co-immunoprecipitation (CoIP) assay. The biological role of TRIM46 was assessed in H1N1 virus-challenged lung injury mice in vivo. TRIM46 level was significantly increased during H1N1 virus infection, and SLC7A11 expression was decreased. TRIM46 downregulation could suppress H1N1 virus replication and relieve H1N1 infection-induced ferroptosis and inflammation in A549 or 16HBE cells. Mechanistically, TRIM46 could promote SLC7A11 ubiquitination and decrease its stability. TRIM46 knockdown repressed H1N1 virus-induced lung injury in vivo. TRIM46 could contribute to influenza A H1N1 virus infection by promoting SLC7A11 ubiquitination in A549 cells, which indicates that targeting TRIM46 may improve the prognosis of patients.

Targeting Disulfidptosis with Potentially Bioactive Natural Products in Metabolic Cancer Therapy.

Metabolic cancers are defined by metabolic reprogramming. Although this reprograming drives rapid tumour growth and invasion, it also reveals specific metabolic vulnerabilities that can be therapeutically exploited in cancer therapy. A novel form of programmed cell death, known as disulfidptosis, was identified last year; tumour cells with high SLC7A11 expression undergo disulfidptosis when deprived of glucose. Natural products have attracted increasing attention and have shown potential to treat metabolic cancers through diverse mechanisms. We systematically searched electronic databases involving PubMed, Web of Science, Gooale Scholar. To ensue comprehensive exploration, keywords including metabolic reprogramming, metabolic cancer, disulfidptosis, natural products and some other words were employed. In this review, we focus on the shared characteristics and metabolic vulnerabilities of metabolic cancers. Additionally, we discuss the molecular mechanisms underlying disulfidptosis and highlight key regulatory genes. Furthermore, we predict bioactive natural products that target disulfidptosis-related genes, offering new perspectives for anticancer strategies through the modulation of disulfidptosis. By summarizing current research progress, this review mainly analyzed the potential mechanisms of natural products in the treatment of metabolic cancer.

Lycium barbarum polysaccharide alleviates ferroptosis in Sertoli cells through NRF2/SLC7A11/GPX4 pathway and ameliorates DEHP-induced male reproductive damage in mice

Di-(2-ethylhexyl)phthalate (DEHP) is a common plasticizer that has been shown to significantly negatively affect male reproductive health. On the other hand, Lycium barbarum polysaccharide (LBP) has been shown to improve reproductive function. Therefore, we hypothesized that LBP may ameliorate DEHP-induced male reproductive damage. Herein, we found that LBP could alleviate DEHP-induced testicular damage and sperm abnormalities. Furthermore, histomorphological analysis of mice testis revealed that LBP primarily ameliorated the DEHP-induced male reproductive damage by targeting Sertoli cells. Moreover, the detection of the function-related genes of Sertoli cells confirmed this finding. The serum of mice in the Control, DEHP, and DEHP+LBP groups was analyzed using non-targeted metabolomics to further elucidate the mechanism of action of LBP in improving DEHP-induced male reproductive damage. According to the results, the differential metabolites were mainly enriched in the glutamate metabolism pathway, implying that LBP may alleviate the ferroptosis-related DEHP-induced testicular injury. Related ferroptosis markers were also found in mice testis. These findings collectively suggest that LBP may ameliorate DEHP-induced testicular injury via alleviating ferroptosis in Sertoli cells. To clarify the specific mechanism, we constructed a cell model in vitro by treating TM4 cells (the Sertoli cell line) with LBP and MEHP (the in vivo DEHP metabolite). Our findings revealed that LBP can improve the function of DEHP-affected Sertoli cells. Furthermore, the analysis of lipid peroxidation, Fe2+ content, and ferroptosis-related protein expressions demonstrated that LBP could ameliorate MEHP-induced ferroptosis in TM4 cells. To clarify the specific mechanism, glutamate metabolism-related proteins involved in the ferroptosis pathway were detected. According to the results, there were significant changes in the expression of NRF2, SLC7A11 and GPX4 proteins, which are involved in the ferroptosis glutamate metabolism pathway. Furthermore, supplementation of NRF2, SLC7A11, and GPX4 inhibitors (ML385, Erastin, and RSL3, respectively) blocked the therapeutic effect of LBP in alleviating MEHP-induced ferroptosis in TM4 cells, implying that LBP could also ameliorate MEHP-induced ferroptosis via the NRF2/SLC7A11/GPX4 pathway. In summary, these findings show that LBP can alleviate DEHP/MEHP-induced ferroptosis through the NRF2/SLC7A11/GPX4 pathway, ameliorating Sertoli cell dysfunction and improving the DEHP-induced male reproductive damage. Therefore, the clinical administration of LBP could be an effective strategy for preventing DEHP-induced male reproductive injury.

Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRASG12C inhibitor resistant tumors

The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.

OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis

Lupus nephritis (LN) is a prevalent and severe manifestation of systemic lupus erythematosus (SLE), leading to significant morbidity and mortality. OTUB1, a deubiquitinating enzyme, has emerged as a potential therapeutic target due to its role in cellular protection and regulation of ferroptosis, a form of cell death linked to LN. Our study revealed significantly reduced OTUB1 expression in the glomeruli of LN patients and podocytes, correlated with disease severity. CRISPR/Cas9-mediated OTUB1 knockout in podocytes resulted in pronounced injury, indicated by decreased levels of nephrin and podocin. Ferrostatin-1 treatment effectively mitigated this injury, restoring SLC7A11 expression and significantly reducing MDA levels, Fe2+ levels, BODIPY C11 expression, and normalized cysteine and glutathione expression. In the MRL/lpr mouse model, Ferrostatin-1 significantly improved renal function decreased proteinuria, and ameliorated renal histopathological changes, including reduced glomerular endothelial swelling, mesangial cell proliferation, and leukocyte infiltration. These results underscore the protective role of Ferrostatin-1 in modulating the pathogenesis of LN. OTUB1 plays a crucial protective role against podocyte injury in LN by regulating ferroptosis. Ferrostatin-1 effectively mitigates podocyte damage induced by OTUB1 deficiency, suggesting that targeting ferroptosis could be a promising therapeutic strategy for LN.

Enhancer of Zeste Homolog 2 Protects Mucosal Melanoma from Ferroptosis via the KLF14-SLC7A11 Signaling Pathway.

Mucosal melanoma (MM) is epidemiologically, biologically, and molecularly distinct from cutaneous melanoma. Current treatment strategies have failed to significantly improve the prognosis for MM patients. This study aims to identify therapeutic targets and develop combination strategies by investigating the mechanisms underlying the tumorigenesis and progression of MM. We analyzed the copy number amplification of enhancer of zeste homolog 2 (EZH2) in 547 melanoma patients and investigated its correlation with clinical prognosis. Utilizing cell lines, organoids, and patient-derived xenograft models, we assessed the impact of EZH2 on cell proliferation and sensitivity to ferroptosis. Further, we explored the mechanisms of ferroptosis resistance associated with EZH2 by conducting RNA sequencing and chromatin immunoprecipitation sequencing. EZH2 copy number amplification was closely associated with malignant phenotype and poor prognosis in MM patients. EZH2 was essential for MM cell proliferation in vitro and in vivo. Moreover, genetic perturbation of EZH2 rendered MM cells sensitized to ferroptosis. Combination treatment of EZH2 inhibitor with ferroptosis inducer significantly inhibited the growth of MM. Mechanistically, EZH2 inhibited the expression of Krüpple-Like factor 14 (KLF14), which binds to the promoter of solute carrier family 7 member 11 (SLC7A11) to repress its transcription. Loss of EZH2 therefore reduced the expression of SLC7A11, leading to reduced intracellular SLC7A11-dependent glutathione synthesis to promote ferroptosis. Our findings not only establish EZH2 as a biomarker for MM prognosis but also highlight the EZH2-KLF14-SLC7A11 axis as a potential target for MM treatment.

Puerarin Ameliorates Ferroptosis in Neuronal Injury Through the PI3K/AKT Signaling Pathway

Ferroptosis plays an important role in the pathogenesis of neuronal damage, generally mediated by iron and lipid peroxidation. In the present study, we measured the protective effects of puerarin against corticosterone-induced neuronal injury via PI3K/AKT-mediated activation of nuclear factor erythroid 2-related factor 2 (Nrf2). After exposing corticosterone-treated PC12 cells to indicated compounds, we measured the key regulators of ferroptosis (ferritin, SLC7A11, and Ptgs2), ferroptosis events (levels of iron, ROS, MDA, and GSH), and the PI3K/AKT/Nrf2 axis. Corticosterone induced ferroptosis in PC12 cells, evidenced by reduced levels of ferritin, SLC7A11, and GSH and increased levels of iron, ROS, and MDA. These effects were reversed by inhibiting ferroptosis with ferrostatin-1. Puerarin-mediated activation of Nrf2 repressed ferroptosis in corticosterone-treated PC12 cells by upregulating ferritin and SLC7A11 expression. Moreover, the protective effects of puerarin on ferroptosis in corticosterone-treated cells relied on the activation of the PI3K/AKT pathway though the upregulation of nuclear Nrf2. These findings indicate that ferroptosis plays an essential role in corticosterone-induced neuronal damage, and puerarin protects against ferroptosis in corticosterone-treated cells via PI3K/AKT-mediated activation of Nrf2.

Unraveling the Ferroptosis-inducing Potential of Methanol Leaves Extract of Prosopis Juliflora Via Downregulation of SLC7A11 and GPX4 mRNA Expression in A549 Lung Cancer Cells.

Prosopis juliflora has been employed in many traditional treatments. As evidenced by our earlier research, Prosopis juliflora leaf methanol extract (PJME) has a promising future in the fight against lung cancer. It may also be used in conjunction with other treatments to effectively manage lung cancer. The main objective of this study was to explore the potential of PJME to inhibit lung cancer in A549 cells, along with its underlying mechanisms of action. The antiproliferative effects were determined using MTT and LDH tests. Apoptosis- inducing capacity was evaluated using the DAPI staining, caspase-3 test, cytochrome C assay, PARP cleavage, and qRT-PCR. To investigate the mechanism of action of PJME in lung cancer, the levels of ROS, MMP, GSH, MDA, and specific ferroptosis indicators were measured. The experimental data of the current study indicated that exposure of A549 cells to PJME reduced cell viability and increased cellular cytotoxicity. The apoptosis-inducing ability of PJME in A549 cells was validated by enhanced nuclear condensation, level of the caspase- 3, cytochrome C, and PARP release. In addition, qRT-PCR investigations verified that the administration of PJME led to a decrease in the expression of anti-apoptotic gene Bcl2 while enhancing the mRNA level of pro-apoptotic genes, such as Bax and caspase-3, in A549 cells. The study also found that PJME has the ability to activate ferroptosis pathways, as evidenced by elevated reactive oxygen species (ROS) generation, changes in the levels of antioxidant markers (MDA and GSH), and decreased expression of SLC7A11 and GPX4. The results of the present study clearly showed that PJME inhibited the proliferation of A549 cells and induced ferroptosis by reducing the expression of the important targets SLC7A11 and GPX4. Further research is necessary to fully understand the clinical efficacy of PJME before it can be investigated as supplemental or adjuvant therapy for lung cancer.