Project description:Ferroptosis is an iron-dependent regulated cell death caused by the accumulation of lipid peroxidation for the uncontrolled metabolism. Serum, as the major medium for the cultured cells, resembles the contents of the extracellular fluid in vivo and provides biomolecules for cellular metabolism. The efficiency of ferroptosis induction is influenced by several factors including the extracellular environment. However, the effect of serum on ferroptosis remains largely unclear. We found that cells cultured in different serums have varying efficiencies in ferroptosis induction. By purifying and identifying active serum components, we discovered that serum protein apolipoprotein H (APOH) play essential role in inhibiting ferroptosis. Moreover, APOH activates the phosphoinositide 3-kinase (PI3K)/AKT-Sterol regulatory element-binding proteins (SREBPs) pathway. SREBPs upregulate the stearoyl-CoA desaturase (SCD) increasing cellular monounsaturated fatty acid-containing phospholipids (MUFA-PLs), leading to ferroptosis inhibition. Our findings indicate that APOH, as an extracellular protein, plays an important role in cellular lipid metabolism and inhibition of ferroptosis, thus may having therapeutic applications in cancer treatment and ferroptosis-related diseases.
Project description:Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate this form of cell death are needed. We applied two independent approaches, a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines to uncover acyl-CoA synthetase long-chain family member 4 (Acsl4) as an essential component for ferroptosis execution.
Project description:Ferroptosis is an iron-dependent form of cell death driven by biochemical and metabolic alterations resulting in oxidation within the lipid compartment. Calcium is a potent signaling molecule ascribed to diverse cellular processes including migration, neurotransmitter function, and cell death. Here we elucidate a crucial link between calcium homeostasis and ferroptotic cell death through the identification of the tetraspanin MS4A15. Ectopic MS4A15 expression specifically protects against ferroptosis by depleting endoplasmic reticulum stores. In an unexpected connection, prolonged calcium dysregulation stimulates fundamental remodeling to ferroptosis-resistant monounsaturated and plasmalogen lipid species. Application of this discovery revealed that augmenting luminal calcium sensitizes cancer cell lines previously refractory to ferroptosis. This finding provides a unique mechanistic basis for ferroptosis sensitivity and resolves a long-standing query into the role of calcium in oxidative cell death. Manipulating calcium homeostasis offers an unprecedented strategy for overcoming therapy resistance in cancer.
Project description:Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5, also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis.
Project description:Ferroptosis, a recently discovered form of regulated cell death, has been closely linked to tumor progression. However, the underlying mechanism of ferroptosis in non-small cell lung cancer (NSCLC) remains unclear. In this study, we conducted transcriptome sequencing on NSCLC samples. Overall, our study suggests that suppressing LCN2 can effectively inhibit the development of NSCLC by promoting ferroptosis
Project description:Aims: Oligoasthenozoospermia (OAS) causes male infertility. However, the etiology and pathogenesis of OAS are unclear, and specific therapy is lacking. Ferroptosis contributes to the progress of various diseases; however, its role in OAS is unknown. This study aimed to explore the mechanism of OAS and to find effective treatments. Results: Human OAS sperm exhibits biochemical and morphological hallmarks of ferroptosis. Ferroptosis represents a crucial role in OAS induced by cyclophosphamide (CP) of mice in vivo, and inhibiting ferroptosis can effectively improve OAS. Further search for safe, stable and clinically applicable of natural compounds found Salidroside (Sal)improved the sperm quality of OAS by attenuates ferroptosis-mediated lipid peroxidation in germ cells by increasing the expression of GPX4, and thus ameliorates OAS in vivo. To further investigate at which stage of spermatogenesis Sal acts, the result revealed that Sal increases the expression of GPX4 starting from primary spermatocytes gradually by immunohistochemistry. In vitro, we verified the above results in vivo using a mouse spermatocytes cell line, GC-2 cells. Mechanistically, integrated RNA-Seq and bioinformatic analysis showed that Sal likely promotes GPX4 expression by inhibiting NF-κB Pathway, thereby inhibiting ferroptosis. Innovation: Our findings support the view that ferroptosis plays an important role in patients with OAS, and provide convincing evidence that Sal ameliorates OAS by inhibiting ferroptosis-mediated lipid peroxidation via NF-κB pathway suppression. Conclusions: Thus, ferroptosis plays an important role in OAS, and Sal could ameliorate OAS by attenuating ferroptosis-mediated lipid peroxidation via NF-κB pathway inhibition.
Project description:Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive and lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting TNBC from internal and external pressure, including metabolic stress. We tested the hypothesis that the iron-dependent cell death pathway, ferroptosis, is a ADAR1-protected metabolic vulnerability in TNBC by showing that ADAR1 knockdown sensitizes TNBC cells to GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled to mass spectrometry (LC-MS) to measure intracellular lipid contents, we showed that ADAR1 loss increased the abundance of polyunsaturated fatty acid phospholipids (PUFA-PL), of which peroxidation is the primary driver of ferroptosis. Transcriptomic analyses led to the discovery of the proto-oncogene MDM2 contributing to the lipid remodeling in TNBC upon ADAR1 loss. A phenotypic drug screen using a ferroptosis-focused library was performed to identify FDA-approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss to suppress TNBC tumorigenesis. By demonstrating that ADAR1 regulates the metabolic fitness of TNBC through desensitizing ferroptosis, we aim to leverage this metabolic vulnerability to inform basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC.
Project description:Arachidonic and adrenic acids in the membrane play key roles in ferroptosis, but how these fatty acids are manipulated in cells is largely unknown. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen revealed that darapladib, an inhibitor of Lp-PLA2, synergistically induced ferroptosis in the presence of GPX4 inhibitors. Notably, darapladib was able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, Lp-PLA2 was located in the membrane and cytoplasm and suppressed ferroptosis, suggesting the critical role of intracellular Lp-PLA2. Lipidomic analysis showed that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriched phosphatidylethanolamine (PE) species and reduced lysophosphatidylethanolamine (lysoPE) species. Moreover, combination treatment with darapladib and PACMA31, a GPX4 inhibitor, efficiently inhibited tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.
Project description:Ferroptosis is a type of cell death caused by radical-driven lipid peroxidation, leading to membrane damage and rupture. Here we show that enzymatically produced sulfane sulfur (S0) species, specifically hydropersulfides, scavenge endogenously generated free radicals and, thereby, suppress lipid peroxidation and ferroptosis. By providing sulfur for S0 biosynthesis, cysteine can support ferroptosis resistance independently of the canonical GPX4 pathway. Our results further suggest that hydropersulfides terminate radical chain reactions through the formation and self-recombination of perthiyl radicals. The autocatalytic regeneration of hydropersulfides may explain why low micromolar concentrations of persulfides suffice to produce potent cytoprotective effects on a background of millimolar concentrations of glutathione. We propose that increased S0 biosynthesis is an adaptive cellular response to radical-driven lipid peroxidation, potentially representing a primordial radical protection system.