Serum Apolipoprotein H Alters Cellular Lipid Composition to Inhibit Ferroptosis
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ABSTRACT:
PROVIDER: PRJNA994124 | ENA |
REPOSITORIES: ENA
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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.
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Project description:Nobiletin targets USP5 to inhibit ferroptosis and alleviate doxorubicin-induced cardiotoxicity
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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.
2017-06-01 | GSE86384 | GEO
Project description:This study aimed to investigate the regulatory mechanism of M2 microglial exosomes (M2-exosomes) on neuronal ferroptosis during the progression of neuropathic pain (NP). IL-4 was used to induce M2 polarization of resting BV2 microglia. Subsequently, M2-exosomes were extracted from M2-polarized microglia and then sequenced. We further performed high-throughput sequencing for BV2 microglia and N2a neuronal cells that were cocultured with M2-exosomes. The effects of M2-exosomes on microglia and neuronal cells were detected by qRT-PCR, western blot, immunofluorescence, and flow cytometry in vitro. For the in vivo experiments, NP model mice were constructed using the chronic constriction sciatic nerve injury (CCI) method and injected intrathecally with M2-exosomes. Pain behavior and neuronal ferroptosis in the NP model mice were then assessed. The in vitro experiments indicated that M2-exosomes inhibited BV2 microglial inflammation response. The sequencing results for N2a neuronal cells treated with M2-exosomes showed that ferroptosis and the MAPK signaling pathway were significantly enriched. We further demonstrated that M2-exosomes reversed erastin-induced neuronal ferroptosis and inhibited activation of the p38 MAPK pathway in neuronal cells. Specifically, M2-exosomes increased expression of the ferroptosis antagonist factor GPX4 and decreased lipid peroxidation and mitochondrial ferrous levels in neuronal cells. The in vivo experiments using the CCI model showed that M2-exosomes increased GPX4 expression in spinal cord neuronal cells, inhibited the increase in ferrous content, and alleviated hyperalgesia. Our findings suggest that M2-exosomes activate the GPX4 antioxidant factor and inhibit p38 MAPK signaling pathways in neuronal ferroptosis, thereby improving pain hypersensitivity in NP.
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Project description:Idiopathic pulmonary fibrosis (IPF), a chronic interstitial fibrosing pneumonia of unknown cause, is characterized by an irreversible decrease in alveolar cells and an increase in fibroblasts. In our research, the numbers of AT2 cells and fibroblasts are abnormally regulated, but AT1 cells are significantly reduced in lung tissue sections from patients with IPF and mice. By analyzing the single-cell sequence from GEO database and experimental validation both in vivo and in vitro, it is found that the abnormally regulated AT2 cells secreting a large amount of MDK to activate the CTHRC1+ fibroblasts LRP1 receptor and inhibit the ferroptosis of fibroblasts. Further, by activating the LRP1 receptor in CTHRC1+ fibroblasts, the RNA-seq results reveal that the expression level of OTUB1 increased significantly. The ubiquitination experiment results showed that OTUB1, as a deubiquitinated molecule, can directly bind to the ferroptosis inhibitory protein SLC7A11, removing the ubiquitination modification of SLC7A11 and stabilizing its expression level to inhibit ferroptosis in fibroblasts. Meanwhile, this molecular pathway was verified in mice by dropping adenovirus through the airway, and the same experimental results as in vitro were verified. In conclusion, our study verified that IPF leads to abnormal regulation of AT2 secreting MDK, which activates LRP1 receptor and increases OTUB1 in fibroblasts. Deubiquitylation modification of OTUB1 stabilizes the expression level of SLC7A11, which results in a decrease in fibroblast ferroptosis, leading to an abnormal regulation of its programmed death, ultimately the deterioration of IPF.
2026-05-01 | GSE262882 | GEO
Project description:This study aimed to investigate the regulatory mechanism of M2 microglial exosomes (M2-exosomes) on neuronal ferroptosis during the progression of neuropathic pain (NP). IL-4 was used to induce M2 polarization of resting BV2 microglia. Subsequently, M2-exosomes were extracted from M2-polarized microglia and then sequenced. We further performed high-throughput sequencing for BV2 microglia and N2a neuronal cells that were cocultured with M2-exosomes. The effects of M2-exosomes on microglia and neuronal cells were detected by qRT-PCR, western blot, immunofluorescence, and flow cytometry in vitro. For the in vivo experiments, NP model mice were constructed using the chronic constriction sciatic nerve injury (CCI) method and injected intrathecally with M2-exosomes. Pain behavior and neuronal ferroptosis in the NP model mice were then assessed. The in vitro experiments indicated that M2-exosomes inhibited BV2 microglial inflammation response. The sequencing results for N2a neuronal cells treated with M2-exosomes showed that ferroptosis and the MAPK signaling pathway were significantly enriched. We further demonstrated that M2-exosomes reversed erastin-induced neuronal ferroptosis and inhibited activation of the p38 MAPK pathway in neuronal cells. Specifically, M2-exosomes increased expression of the ferroptosis antagonist factor GPX4 and decreased lipid peroxidation and mitochondrial ferrous levels in neuronal cells. The in vivo experiments using the CCI model showed that M2-exosomes increased GPX4 expression in spinal cord neuronal cells, inhibited the increase in ferrous content, and alleviated hyperalgesia. Our findings suggest that M2-exosomes activate the GPX4 antioxidant factor and inhibit p38 MAPK signaling pathways in neuronal ferroptosis, thereby improving pain hypersensitivity in NP.
2026-08-21 | GSE306183 | GEO
Project description:This study aimed to investigate the regulatory mechanism of M2 microglial exosomes (M2-exosomes) on neuronal ferroptosis during the progression of neuropathic pain (NP). IL-4 was used to induce M2 polarization of resting BV2 microglia. Subsequently, M2-exosomes were extracted from M2-polarized microglia and then sequenced. We further performed high-throughput sequencing for BV2 microglia and N2a neuronal cells that were cocultured with M2-exosomes. The effects of M2-exosomes on microglia and neuronal cells were detected by qRT-PCR, western blot, immunofluorescence, and flow cytometry in vitro. For the in vivo experiments, NP model mice were constructed using the chronic constriction sciatic nerve injury (CCI) method and injected intrathecally with M2-exosomes. Pain behavior and neuronal ferroptosis in the NP model mice were then assessed. The in vitro experiments indicated that M2-exosomes inhibited BV2 microglial inflammation response. The sequencing results for N2a neuronal cells treated with M2-exosomes showed that ferroptosis and the MAPK signaling pathway were significantly enriched. We further demonstrated that M2-exosomes reversed erastin-induced neuronal ferroptosis and inhibited activation of the p38 MAPK pathway in neuronal cells. Specifically, M2-exosomes increased expression of the ferroptosis antagonist factor GPX4 and decreased lipid peroxidation and mitochondrial ferrous levels in neuronal cells. The in vivo experiments using the CCI model showed that M2-exosomes increased GPX4 expression in spinal cord neuronal cells, inhibited the increase in ferrous content, and alleviated hyperalgesia. Our findings suggest that M2-exosomes activate the GPX4 antioxidant factor and inhibit p38 MAPK signaling pathways in neuronal ferroptosis, thereby improving pain hypersensitivity in NP.
2026-08-21 | GSE306181 | GEO
Project description:Early-onset pre-eclampsia (ePE) is a severe pregnancy complication affecting millions of pregnancies worldwide, resulting in significant maternal and fetal morbidity. The etiology of ePE is associated with defective trophoblast functions, leading to abnormal placental development. Regulatory factors released by endometrial glands are crucial for proper placental development. While circumstantial evidence indicates that defective endometrial gland development or function may lead to defective placental development and ePE in humans, direct evidence has been lacking. This study explored the role of endometrial gland-derived factors both in vitro and in vivo and correlated the findings with the clinical phenotypes of ePE. Our findings revealed that the secretome of organoids derived from the endometrial tissues of ePE patients impeded spiral artery remodeling and thus disrupted proper placental perfusion. Transcriptomic and proteomic analyses identified an increased apolipoprotein D (APOD) production in ePE organoids and decidual tissues compared to their normotensive (NT) counterparts. Overexpression of endometrial APOD impaired the vascular remodeling functions of extravillous trophoblasts (EVT) and endothelial cells in vitro. These findings were corroborated using an endometrial-specific APOD knock-in mouse model. APOD-induced ferroptosis through the PI3K/Akt pathway in both human ePE placentas and the mouse model. Moreover, elevated APOD levels were detected in the first-trimester serum of pregnant women who subsequently developed ePE. These results provide the first direct evidence that dysregulated endometrial gland secretome is a maternal cause of defective placental development and ePE. Clinically, APOD could serve as a biomarker for early detection of ePE, enabling early intervention with the potential to improve outcomes for both mothers and their babies.
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