Expression Of Solute Carrier Family Research Articles

Mitochondria-mediated ferroptosis induced by CARD9 ablation prevents MDSCs-dependent antifungal immunity

BackgroundCaspase Recruitment Domain-containing protein 9 (CARD9) expressed in myeloid cells has been demonstrated to play an antifungal immunity role in protecting against disseminated candidiasis. Hereditary CARD9 ablation leads to fatal disseminated candidiasis. However, the myeloid cell types and molecular mechanisms implicated in CARD9 protecting against disseminated candidiasis remain wholly elusive.MethodsThe role of CARD9 ablation in exacerbating disseminated candidiasis was determined in vivo and in vitro. The molecular mechanism by which CARD9 ablation promotes acute kidney injury in disseminated candidiasis was identified by RNA-sequencing analysis. The expression of mitochondrial proteins and ferroptosis-associated proteins were measured by Quantitative real-time PCR and western blot.ResultsCARD9 ablation resulted in a reduced proportion of myeloid-derived suppressor cells (MDSCs) and a substantially lower expression of solute carrier family 7 member 11 (SLC7A11) in the kidneys, which increased susceptibility to acute kidney injury and renal ferroptosis during disseminated Candida tropicalis (C. tropicalis) infection. Moreover, CARD9-deficient MDSCs were susceptible to ferroptosis upon stimulation with C. tropicalis, which was attributed to augmented mitochondrial oxidative phosphorylation (OXPHOS) caused by reduced SLC7A11 expression. Mechanistically, C-type lectin receptors (CLRs)-mediated recognition of C. tropicalis promoted the expression of SLC7A11 which was transcriptionally manipulated by the Syk-PKCδ-CARD9-FosB signaling axis in MDSCs. FosB enhanced SLC7A11 transcription by binding to the promoter of SLC7A11 in MDSCs stimulated with C. tropicalis. Mitochondrial OXPHOS, which was negatively regulated by SLC7A11, was responsible for inducing ferroptosis of MDSCs upon C. tropicalis stimulation. Finally, pharmacological inhibition of mitochondrial OXPHOS or ferroptosis significantly increased the number of MDSCs in the kidneys to augment host antifungal immunity, thereby attenuating ferroptosis and acute kidney injury exacerbated by CARD9 ablation during disseminated candidiasis.ConclusionsCollectively, our findings show that CARD9 ablation enhances mitochondria-mediated ferroptosis in MDSCs, which negatively regulates antifungal immunity. We also identify mitochondria-mediated ferroptosis in MDSCs as a new molecular mechanism of CARD9 ablation-exacerbated acute kidney injury during disseminated candidiasis, thus targeting mitochondria-mediated ferroptosis is a novel therapeutic strategy for acute kidney injury in disseminated candidiasis.

Perfluorooctanoic acid inhibits cell proliferation through mitochondrial damage

Grown evidence has shown that the liver and reproductive organs were the main target organs of perfluorooctanoic acid (PFOA). Herein, we studied a toxic mechanism of PFOA using HeLa Chang liver epithelial cells. When incubated with PFOA for 24 h or 48 h, cell proliferation was inhibited in a concentration- and time-dependent fashion, but interestingly, the feature of dead cells was not notable. Mitochondrial volume was increased with concentration and time, whereas the mitochondrial membrane potential and produced ATP amounts were significantly reduced. Autophagosome-like vacuoles and contraction of the mitochondrial inner membrane were observed in PFOA-treated cells. The expression of acetyl CoA carboxylase (ACC) and p-ACC proteins rapidly decreased, and that of mitochondrial dynamics–related proteins increased. The expression of solute carrier family 7 genes, ChaC glutathione-specific gamma-glutamylcyclotransferase 1, and 5S ribosomal RNA gene was up-regulated the most in cells exposed to PFOA for 24 h, and the KEGG pathway analysis revealed that PFOA the most affected metabolic pathways and olfactory transduction. More importantly, PPAR alpha, fatty acid binding protein 1, and CYP450 family 1 subfamily A member 1 were identified as the target proteins for binding between PFOA and cells. Taken together, we suggest that disruption of mitochondrial integrity and function may contribute closely to PFOA-induced cell proliferation inhibition.

Icariin, astragaloside a and puerarin mixture attenuates cognitive impairment in APP/PS1 mice via inhibition of ferroptosis-lipid peroxidation

Alzheimer's disease (AD) is a neurodegenerative disease that seriously threatens the quality of life of the elderly. Its pathogenesis has not yet been fully elucidated. Ferroptosis, a cell death caused by excessive accumulation of iron-dependent lipid peroxides, has been implicated in the pathogenesis of AD. Uncontrolled lipid peroxidation is the core process of ferroptosis, and inhibiting lipid peroxidation of ferroptosis may be an important therapeutic target for AD. Based on previous studies, we mixed standards of icariin, astragaloside IV, and puerarin, named the standard mixture YHG, and investigated the effect of YHG on ferroptosis -lipid peroxidation in APP/PS1 mice. DFX, a ferroptosis inhibitor, was used as a control drug. In this study, APP/PS1 mice were used as an AD animal model, and behavioral experiments, iron level detection, Transmission electron microscopy (TEM) observation, lipid peroxidation level detection, antioxidant capacity detection, immunofluorescence, Western blot and real-time qPCR were performed. It was found that YHG could reduce body weight, significantly improve abnormal behaviors and the ultrastructure of hippocampal neurons in APP/PS1 mice. The results of biochemical tests showed that YHG reduced the contents of iron, malondialdehyde (MDA) and lipid peroxide (LPO) in brain tissue and serum, and increased the levels of superoxide dismutase (SOD) and reduced glutathione (GSH). Immunofluorescence, WesternBlot and real-time qPCR results showed that YHG could promote the expression of solute carrier family 7 member 11 (SLC7A11), solute carrier family 3 member 2 (SLC3A2) and glutathione peroxidase 4(GPX4). Inhibited the expression of long-chain acyllipid coenzyme a synthetase 4(ACSL4) and lysophosphatidyltransferase 3 (LPCAT3). This study suggests that the mechanism by which YHG improves cognitive dysfunction in APP/PS1 mice may be related to the inhibition of ferroptosis-lipid peroxidation.

HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis

Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance.Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

Increased SLC7A3 Expression inhibits Tumor Cell Proliferation and Predicts a Favorable Prognosis in Breast Cancer.

Arginine plays significant and contrasting roles in breast cancer growth and survival. However, the factors governing arginine balance remain poorly characterized. We aimed to identify the molecule that governs arginine metabolism in breast cancer and to elucidate its significance. We analyzed the correlation between the expression of solute carrier family 7 member 3 (SLC7A3), the major arginine transporter, and breast cancer survival in various databases, including GEPIA, UALCAN, Metascape, String, Oncomine, KM-plotter, CBioPortal and Prognosis. Additionally, we validated our findings through bioinformatic analyses and experimental investigations, including colony formation, wound healing, transwell, and mammosphere formation assays. Our analysis revealed a significant reduction in SLC7A3 expression in all breast cancer subtypes compared to adjacent breast tissues. Kaplan-Meier survival analyses demonstrated that high SLC7A3 expression was positively associated with decreased nodal metastasis (HR=0.70, 95% CI [0.55, 0.89]), ER positivity (HR=0.79, 95% CI [0.65, 0.95]), and HER2 negativity (HR=0.69, 95% CI [0.58, 0.82]), and increased recurrence-free survival. Moreover, low SLC7A3 expression predicted poor prognosis in breast cancer patients for overall survival. Additionally, the knockdown of SLC7A3 in MCF-7 and MDA-MB-231 cells resulted in increased cell proliferation and invasion in vitro. Our findings indicate a downregulation of SLC7A3 expression in breast cancer tissues compared to adjacent breast tissues. High SLC7A3 expression could serve as a prognostic indicator for favorable outcomes in breast cancer patients due to its inhibitory effects on breast cancer cell proliferation and invasion.

Ferroptosis plays a crucial role in lung cell damage caused by ventilation stretch

Mechanical ventilation is an essential respiratory support in acute respiratory distress syndrome and intensive care cases. However, it is possible to cause ventilator-induced lung damage (VILI). In this work, we used a microfluidic device to provide a mechanical ventilation with cyclic stretch (30% total area change rate and 15 cycles per min) and oxygen (air) flux applied by a controlled pressured airflow. Compared to static control, the ventilation stretch resulted in significant death of A549 cells accompanied by increased lipid peroxidation, mitochondrial reactive oxygen species (ROS) production, and ferrous ion accumulation, while by decreased protein expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) proteins, as well as ratio of reduced-to-oxidized glutathione. The resulted A549 cell death could be alleviated by two ferroptosis inhibitors, deferoxamine and ferrostatin-1. These similar phenomena also occurred in other three types of human lung cells, such as primary alveolar type II epithelial cells, primary alveolar microvascular endothelial cells, and bronchial epithelial cell line. From the A549 RNA sequence analysis, the gene ontology (GO) based on 85 ferroptosis-related genes (FRGs) indicated that several iron homeostasis-related biological processes and molecular functions were involved in the ventilation-stretch-induced cell death, while the gene set enrichment analysis (GSEA) based on 2901 differentially expressed genes (DEGs) showed that glutathione metabolism was significantly suppressed. Finally, solute carrier family 39 member 14 (SLC39A14), a transporter of uptake extracellular divalent metal ion, was selected to be knocked down to verify its role in the ventilation-stretch-induced death of A549. Our results suggest that ferroptosis may be an alternative pathway for VILI, but it needs to be confirmed by further animal experiments and clinical data.

METTL3 and METTL14 regulate IL-6 expression via RNA m6A modification of zinc transporter SLC39A9 and DNA methylation of IL-6 in periodontal ligament cells

The inflammatory response is a key process in periodontitis. The N6-methyladenosine (m6A) modification has been proven to be involved in various physiological and pathological processes. This study aims to investigate the role and downstream mechanism of N6-adenosine-enzyme subunits methyltransferase (METTL) 3 and 14 in the inflammatory response of periodontal ligament cells (PDLCs). The total m6A content and the expression of METTL3 and METTL14 were upregulated in lipopolysaccharide (LPS)-stimulated PDLCs. Knockdown of METTL3 or METTL14 suppressed the LPS-induced interleukin (IL)-6 expression, as shown by quantitative polymerase chain reaction (qPCR) and enzyme linked immunosorbent assay (ELISA). Mechanistically, conjoint analysis of m6A sequencing of METTL3-knockdown and METTL14-knockdown PDLCs revealed that the expression of solute carrier family 39 member 9 (SLC39A9) was mediated in a m6A-dependent manner. The suppression of LPS-induced IL-6 by METTL3 or METTL14 knockdown was partially counteracted by SLC39A9 knockdown, which induced downregulation of intracellular zinc via immunofluorescence staining. Amplicon bisulfite sequencing (AmpBS) demonstrated that METTL3/14 knockdown increased the methylation at one position of the IL-6 promoter, while SLC39A9 knockdown decreased it, which was basically consistent with the intracellular zinc concentration and negatively associated with IL-6 expression. Moreover, METTL3 or METTL14 knockdown attenuated the LPS-induced phosphorylation of p38 and JNK mitogen-activated protein kinase (MAPK), which was partially counteracted by SLC39A9 knockdown. These results revealed the “LPS-METTL3/14-SLC39A9-zinc-IL-6” axis and involvement of p38 and JNK MAPK signaling pathway in the inflammatory responses of PDLCs.

SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

In what area of biology has a "new" type of cell death been discovered?

Cell death is a fundamental physiological process that occurs in all organisms and is crucial to each organism's evolution, ability to maintain a stable internal environment, and the development of multiple organ systems. Disulfidptosis is a new mode of cell death that is triggered when cells with high expression of solute carrier family 7 member 11 (SLC7A11) are exposed to glucose starvation to initiate the process of cell death. The disulfidptosis mechanism is a programmed cell death mode that triggers cell death through reduction-oxidation (REDOX) reactions and disulfur bond formation. In disulfidptosis, disulfur bonds play a crucial role and cause the protein in the cell to undergo conformational changes, eventually leading to cell death. This mode of cell death has unique characteristics and regulatory mechanisms in comparison with other modes of cell death. In recent years, an increasing number of studies have shown that the disulfidptosis mechanism plays a key role in the occurrence and development of a variety of diseases. For example, cancer, cardiovascular diseases, neurodegenerative diseases, and liver diseases are all closely related to cell disulfidptosis mechanisms. Therefore, it is of paramount clinical significance to conduct in-depth research regarding this mechanism. This review summarizes the research progress on the disulfidptosis mechanism, including its discovery history, regulatory mechanism, related proteins, and signaling pathways. Potential applications of the disulfidptosis mechanism in disease therapy and future research directions are also discussed. This mechanism represents another subversive discovery after ferroptosis, and provides both a fresh perspective and an innovative strategy for the treatment of cancer, as well as inspiration for the treatment of other diseases.

Long noncoding RNA CASC11 suppresses sorafenib-triggered ferroptosis via stabilizing SLC7A11 mRNA in hepatocellular carcinoma cells

As a frontline treatment for patients with advanced hepatocellular carcinoma (HCC), sorafenib is an effective drug approved by the Food and Drug Administration (FDA). Ferroptosis, a newly defined programmed cell death process with the hallmark of the accumulation of iron-dependent lipid peroxides, can be induced by sorafenib treatment. Our previous study identified oncogenic roles of long noncoding RNA (lncRNA) Cancer susceptibility candidate 11 (CASC11) in HCC progression. However, the relationship between CASC11 and sorafenib-induced ferroptosis in HCC remains unclear. In the present study, we aim to investigate the role of CASC11 in sorafenib-induced ferroptosis in HCC cell lines and determine the involved molecular mechanisms. Here, we demonstrated that sorafenib decreased CASCL11 expression. Knockdown of CASC11 enhanced sorafenib-induced ferroptosis, while overexpression of CASC11 exerted the opposite effect in HCC cells. Moreover, CASC11 led to the accumulation of intracellular malondialdehyde (MDA), lipid reactive oxygen species (ROS) and Fe2+ while depleting glutathione (GSH), thereby suppressing sorafenib-induced ferroptosis and cell death. Ferrostatin-1 (Ferr-1), a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by the silence of CASC11 in HCC cells. Mechanistically, CASC11 upregulated the expression of solute carrier family 7 member 11 (SLC7A11) which is critical for ferroptosis inhibition. CASC11 associated with and stabilized SLC7A11 mRNA. In summary, our data revealed, for the first time, that CASC11 inhibits the sorafenib-induced ferroptosis in HCC cells via regulating SLC7A11, providing a new basis for clinical therapeutic strategies for patients with HCC.

High SLC20A1 Expression Indicates Poor Prognosis in Prostate Cancer.

High expression of solute carrier family 20 member 1 (SLC20A1) indicates poor clinical outcomes for patients with breast cancer subtypes treated with endocrine therapy and radiotherapy. However, the association between SLC20A1 expression and clinical outcomes in prostate cancer remains to be determined. Open-source datasets (The Cancer Genome Atlas prostate, Stand Up to Cancer-Prostate Cancer Foundation Dream Team, and The Cancer Genome Atlas PanCancer Atlas) were downloaded and analyzed. SLC20A1 expression was analyzed in prostate cancer and normal prostate tissue. Survival analysis using Kaplan-Meier curves and Cox regression analysis were performed to examine patient prognosis, as well as the effects of endocrine therapy and radiotherapy on high SLC20A1 expression in patients with prostate cancer. SLC20A1 was higher in prostate cancer than in normal prostate tissues. High SLC20A1 expression predicted poor disease-free and progression-free survival. Following endocrine therapy, no significant difference in prognosis was observed between patients with high SLC20A1 and those with low SLC20A1 expression. However, following radiotherapy, high SLC20A1 expression tended to be associated with a poor clinical outcome. SLC20A1 may serve as a prognostic biomarker for prostate cancer, and the recommended treatment for patients with high SLC20A1 expression is endocrine therapy.

Dietary isoleucine supplementation enhances growth performance, modulates the expression of genes related to amino acid transporters and protein metabolism, and gut microbiota in yellow-feathered chickens

This study investigated the effects of dietary isoleucine (Ile) on growth performance, intestinal expression of amino acid transporters, protein metabolism-related genes and intestinal microbiota in starter phase Chinese yellow-feathered chickens. Female Xinguang yellow-feathered chickens (n=1,080, aged 1 d) were randomly distributed to 6 treatments, each with 6 replicates of 30 birds. Chickens were fed diets with 6 levels of total Ile (6.8, 7.6, 8.4, 9.2, 10.0, and 10.8 g/kg) for 30 d. The average daily gain and feed conversion ratio were improved with dietary Ile levels (P < 0.05). Plasma uric acid content and glutamic-oxalacetic transaminase activity were linearly and quadratically decreased with increasing dietary Ile inclusion (P < 0.05). Dietary Ile level had a linear (P < 0.05) or quadratic (P < 0.05) effect on the jejunal expression of ribosomal protein S6 kinase B1 and eukaryotic translation initiation factor 4E binding protein 1. The relative expression of jejunal 20S proteasome subunit C2 and ileal muscle ring finger-containing protein 1 decreased linearly (P < 0.05) and quadratically (P < 0.05) with increasing dietary Ile levels. Dietary Ile level had a linear (P=0.069) or quadratic (P < 0.05) effect on the gene expression of solute carrier family 15 member 1 in jejunum and solute carrier family 7 member 1 in ileum. In addition, bacterial 16S rDNA full-length sequencing showed that dietary Ile increased the cecal abundances of the Firmicutes phylum, and Blautia, Lactobacillus, and unclassified_Lachnospiraceae genera, while decreased that of Proteobacteria, Alistipes, and Shigella. Dietary Ile levels affected growth performance and modulated gut microbiota in yellow-feathered chickens. The appropriate level of dietary Ile can upregulate the expression of intestinal protein synthesis-related protein kinase genes and concomitantly inhibit the expression of proteolysis-related cathepsin genes.

Single-cell transcriptomes reveal heterogeneity of chlorine-induced mice acute lung injury and the inhibitory effect of pentoxifylline on ferroptosis

To investigate the effect of pentoxifylline (PTX) on Chlorine (Cl2)-induced acute lung injury (ALI) by single-cell RNA sequencing (scRNA-seq). Female BALB/c mice were exposed to Cl2 at 400 ppm for 15 min. H&E staining was used to observe the degree of lung injury. scRNA-seq was conducted to analysis of normal and Cl2-exposed mice lung tissues. Immunofluorescence was used to observe genes of interest. Thirty-two mice were randomly divided into four groups: Control, Cl2, Cl2+Fer-1, Cl2+PTX. TEM, WB and ELISA were used to detect ferroptosis-related indicators. The 5, 8, 10, 12, 16, 20 clusters were epithelial cells and 4, 15, 18, 19, 21 clusters were endothelial cells. Pseudo-time analysis revealed the differentiation trajectory of epithelial cells and key regulatory genes (Gclc, Bpifa1, Dnah5 and Dnah9) during the process of injury. Cell–cell communication analysis identified several important receptor–ligand complexes (Nrp1-Vegfa, Nrp2-Vegfa, Flt1-Vegfa and Flt4-Vegfa). Ferroptosis were found up-regulated in epithelial and endothelial cells by GSVA analysis. Highly expressed genes to which closely related ferroptosis were found by SCENIC analysis. PTX could significantly decrease the levels of MDA and abnormal high expression of solute carrier family 7 member 11 (SLC7A11, the key transporter of cystine) as well as increase the expression of GSH/GSSG and glutathione peroxidase 4 (GPX4) (p < 0.05). This study revealed novel molecular features of Cl2-induced ALI. PTX may be a potential specific drug by inhibiting the process of ferroptosis in epithelial and endothelial cells.

Butyrate dictates ferroptosis sensitivity through FFAR2-mTOR signaling

Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. In particular, butyrate is known to induce apoptosis and autophagy. However, it remains largely unclear whether butyrate can regulate cell ferroptosis, and the mechanism by which has not been studied. In this study, we found that RAS-selective lethal compound 3 (RSL3)- and erastin-induced cell ferroptosis were enhanced by sodium butyrate (NaB). With regard to the underlying mechanism, our results showed that NaB promoted ferroptosis by inducing lipid ROS production via downregulating the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Moreover, the FFAR2-AKT-NRF2 axis and FFAR2-mTORC1 axis accounts for the NaB-mediated downregulation of SLC7A11 and GPX4, respectively, in a cAMP-PKA-dependent manner. Functionally, we found that NaB can inhibit tumor growth and the inhibitory effect could be eliminated by administrating MHY1485 (mTORC1 activator) and Ferr-1 (ferroptosis inhibitor). Altogether, in vivo results suggest that NaB treatment is correlated to the mTOR-dependent ferroptosis and consequent tumor growth through xenografts and colitis-associated colorectal tumorigenesis, implicating the potential clinical applications of NaB for future colorectal cancer treatments. Based on all these findings, we have proposed a regulatory mechanism via which butyrate inhibits the mTOR pathway to control ferroptosis and consequent tumorigenesis.

Neutrophil membrane-coated taurine nanoparticles protect against hepatic ischemia-reperfusion injury

Hepatic ischemia-reperfusion (I/R) injury is a multifactorial process caused by transient tissue hypoxia and the following reoxygenation, commonly occurring in liver transplantation and hepatectomy. Hepatic I/R can induce a systemic inflammatory response, liver dysfunction, or even multiple organ failure. Although we have previously reported that taurine could attenuate acute liver injury after hepatic I/R, only a tiny proportion of the systemically injected taurine could reach the targeted organ and tissues. In this present study, we prepared taurine nanoparticles (Nano-taurine) by coating taurine with neutrophil membranes and investigated the protective effects of Nano-taurine against I/R-induced injury and the underlying mechanisms. Our results showed that Nano-taurine restored liver function by declining AST and ALT levels and reducing histology damage. Nano-taurine decreased inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, NLR pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing CARD (ASC) and oxidants including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and reactive oxygen species (ROS), exhibiting anti-inflammatory and antioxidant properties. The expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was increased, while prostaglandin-endoperoxide synthase 2 (Ptgs2) was decreased upon administration of Nano-taurine, suggesting that inhibiting ferroptosis may be involved in the mechanism during hepatic I/R injury. These results suggest that Nano-taurine have a targeted therapeutic effect on hepatic I/R injury by inhibiting inflammation, oxidative stress, and ferroptosis.

Klotho protects against aged myocardial cells by attenuating ferroptosis

Klotho (KL) is a renal protein with aging-suppression properties that mediates its regulatory effect during cardiac fibroblast aging. However, to determine whether KL can protect aged myocardial cells by attenuating ferroptosis, this study aimed to investigate the protective effect of KL on aged cells and to explore its potential mechanism. Cell injury of H9C2 cells was induced with D-galactose (D-gal) and treated with KL in vitro. This study demonstrated that D-gal induces aging in H9C2 cells. D-gal treatment increased β-GAL(β-galactosidase) activity, decreased cell viability, enhanced oxidative stress, reduced mitochondrial cristae, and decreased the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase-4 (GPx4), and P53, which are primary regulators of ferroptosis. The results showed that KL can eliminate D-gal-induced aging in H9C2 cells, likely due to its ability to increase the expression of the ferroptosis-associated proteins SLC7A11 and GPx4. Moreover, pifithrin-α, a P53-specific inhibitor, enhanced the expression of SLC7A11 and GPx4. These results suggest that KL may be involved in D-gal-induced H9C2 cellular aging during ferroptosis, mainly through the P53/SLC7A11/GPx4 signaling pathway.

Hsa_circ_0070440 promotes lung adenocarcinoma progression by SLC7A11-mediated-ferroptosis.

Circular RNA (circRNA) has recently emerged as having a key role in cancer initiation and progression. A prior study exhibited that hsa_circ_0070440 (circ_0070440) was significantly up-regulated in lung cancer cells, but the role and molecular mechanism of circ_0070440 during lung adenocarcinoma (LUAD) development remain unclear. Quantitative real-time polymerase chain reaction (qRT-PCR), Reverse transcription-PCR (RT-PCR), RNase R digestion, and Nuclear/cytoplasmic fractionation assay were employed to validate circ_0070440. Proliferation, apoptosis, viability, and ferrous iron level were measured by colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), Annexin V-FITC/PI double staining, Cell Counting Kit-8 (CCK-8), and iron assay in LUAD cells. A xenograft mouse model was used for tumor growth in vivo. Western blot (WB) and immunohistochemistry (IHC) assays were utilized to determine the expression of solute carrier family 7 member 11 (SLC7A11), c-myc, and bcl-xL. The interactions between the circ_0070440/SLC7A11 axis and miR-485-5p were verified by RNA pull-down assay and dual-luciferase reporter assay. Circ_0070440 was significantly up-regulated in LUAD cells. Knockdown of circ_0070440 inhibited growth and promoted both apoptosis and ferroptosis of LUAD cells. Moreover, our results showed that circ_0070440 contributed to malignant progression and suppressed ferroptosis of LUAD by sponging miR-485-5p and upregulating SLC7A11 expression. Furthermore, circ_0070440 and SLC7A11 levels were up-regulated, and the miR-485-5p level was more down-regulated in the tumor tissues than in normal tissues of LUAD patients. Circ_0070440 modulated LUAD malignant progression and ferroptosis via targeting SLC7A11, implying a significant role of the circ_0070440/miR-485-5p/SLC7A11 axis in the diagnosis and treatment of LUAD.

Effects of Zearalenone on Apoptosis and Copper Accumulation of Goat Granulosa Cells In Vitro.

Zearalenone (ZEA), also known as F-2 toxin, is a mycotoxin. Despite numerous reports of ZEA impairing livestock production performance and fertility, little information is available, including information about the mechanism underlying damage to cell metal ion transport. Copper, which is essential for cell survival as a metal ion, can consist of a variety of enzymes that facilitate abundant metabolic processes. However, the accumulation of copper in cells can have toxic effects. Here, we intended to determine whether ZEA could impair goat granulosa cells (GCs) and alter the cellular copper concentration. GCs were divided into a negative control (NC) group (cells cultured with 0.1% dimethyl sulfoxide (DMSO) for 8 h) and a ZEA group (cells cultured with 200 μmol/L ZEA diluted in DMSO for 8 h). The results showed that ZEA could inhibit GC proliferation and impair cell viability. GCs showed significant increases in the apoptosis rate and oxidative stress levels, while their ability to synthesize estrogen decreased. In addition, RNA-seq results showed dramatic changes in the expression of copper transport-related genes. The expression levels of ATPase copper transporting alpha (ATP7A) and ATPase copper transporting beta (ATP7B) were significantly downregulated (p &lt; 0.01), while the expression of solute carrier family 31 member 1 (SLC31A1) was not modified in the ZEA group compared with the NC group. In accordance with these trends, the copper concentration increased significantly in the ZEA group (p &lt; 0.01). In summary, our results show that ZEA can negatively affect GCs and cause copper accumulation. This finding may provide a prospective line of research on the relationship between ZEA and the transport of copper ions in GCs.

Aberrant Expression of Solute Carrier Family 35 Member A2 Correlates With Tumor Progression in Breast Cancer.

A recent study suggested that solute carrier family 35 member A2 (SLC35A2) is related to poor prognosis in patients with breast cancer. SLC35A2 transports uridine diphosphate-galactose from the cytosol to the lumen of the endoplasmic reticulum and Golgi. Immunohistochemical expression of SLC35A2 was evaluated using tissue microarrays. Cell growth, migration, and invasion of breast cancer cells were examined following loss- and gain-of-expression of SLC35A2. Normal breast tissue exhibited SLC35A2 immunoreactivity in the nucleus. A progressive increase in cytoplasmic expression from in situ carcinoma to invasive carcinoma was observed. There was a correlation between cytoplasmic SLC35A2 expression and breast cancer stage (p<0.001). MDA-MB-468 and MCF-7 cells transfected with SLC35A2 shRNA had unchanged cell viability but significantly reduced cell migration and invasion. In contrast, MDA-MB-231 and HCC1806 cells transfected with the SLC35A2 expression vector showed increased migration. Breast cancer progression is accompanied by differential expression patterns of SLC35A2. The migratory or invasive capacity of breast cancer cells is associated with SLC35A2 expression.

Licochalcone A Induces Ferroptosis in Hepatocellular Carcinoma via Reactive Oxygen Species Activated by the SLC7A11/GPX4 Pathway.

Liver cancer is a common malignant tumor, and its incidence is increasing yearly. Millions of people suffer from liver cancer annually, which has a serious impact on global public health security. Licochalcone A (Lico A), an important component of the traditional Chinese herb licorice, is a natural small molecule drug with multiple pharmacological activities. In this study, we evaluated the inhibitory effects of Lico A on hepatocellular carcinoma cell lines (HepG2 and Huh-7), and explored the inhibitory mechanism of Lico A on hepatocellular carcinoma. First, we evaluated the inhibitory effects of Lico A on hepatocellular carcinoma, and showed that Lico A significantly inhibited and killed HepG2 and Huh-7 cells in vivo and in vitro. Transcriptomic analysis showed that Lico A inhibited the expression of solute carrier family 7 member 11 (SLC7A11), which induced ferroptosis. We confirmed through in vivo and in vitro experiments that Lico A promoted ferroptosis in hepatocellular carcinoma cells by downregulating SLC7A11 expression, thereby inhibiting the glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway and inducing activation of reactive oxygen species (ROS). In this study, we suggest that Lico A is a potential SLC7A11 inhibitor that induces ferroptotic death in hepatocellular carcinoma cells, thereby providing a theoretical basis for the development of natural small molecule drugs against hepatocellular carcinoma.