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Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [scRNA-seq]

ABSTRACT: Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE231934 | GEO | 2025/04/28

REPOSITORIES: GEO

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Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis

Project description:Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. However, the lack of effective and safe clinical precautionary measure is still the main problem in preventing hepatic ferroptosis. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis. Therefore, we provide mechanistic evidence for the IFN-stimulated DHX58 in promoting the translation of m6A-modified Gpx4 mRNA, and suggest the promising clinical potential of IFN-α pre-treatment in the prevention of hepatic ferroptosis.

2024-05-24 | PXD042083 | Pride

Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [DHX58 RIP-Seq]

Project description:Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis.

2025-04-28 | GSE231843 | GEO

Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [m6A RIP]

Project description:Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis.

2025-04-28 | GSE231842 | GEO

Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [DHX58 RIP-Seq]

Project description:Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [DHX58 RIP-Seq]

| PRJNA968014 | ENA

Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [m6A RIP]

Project description:Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [m6A RIP]

| PRJNA968015 | ENA

Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis

Project description:Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis

| PRJNA968011 | ENA

Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [scRNA-seq]

Project description:Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis [scRNA-seq]

| PRJNA970262 | ENA

Targeting GPX4-mediated ferroptosis alleviates liver injury in a rat model of intestinal failure-associated liver disease

Project description:Background: Intestinal failure-associated liver disease (IFALD) is a common complication of long-term parenteral nutrition (PN) that is associated with significant morbidity and mortality. Ferroptosis, as an iron-dependent regulated cell death, has been shown to play an important role in the development of several liver diseases. This study focuses on investigating whether the ferroptosis phenomenon is present in TPN-induced IFALD and further exploring the potential regulatory mechanisms. Methods: Ferroptosis hallmarkers were measured in children with short bowel syndrome (SBS) who had long-term PN use and caused IFALD. Sprague-Dawley (SD) rats were used to establish a rat model of IFALD with a concomitant ferroptosis inhibition intervention using liproxstain-1. The mir-431 lineage was identified as a potential upstream regulatory mir-RNA by mir-RNA sequencing. HepG2 and 293T cell line was used to demonstrate that mir-431 regulates ferroptosis through the GPX4 pathway at the cellular level in vitro. Results: Ferroptosis is upregulated in liver of children with IFALD. Liproxstain-1 downregulates ferroptosis in a rat model of IFALD and attenuates hepatic steatosis through the lipid metabolism pathway. In vitro HepG2 and 293T cell experiments reveal that mir-431 affects ferroptosis by regulating GPX4 protein. Conclusions: Ferroptosis plays an important role in the development of IFALD. Liproxstain-1 inhibits ferroptosis and attenuates hepatic steatosis in a rat model of IFALD through the lipid metabolism pathway. Mir-431 negatively regulates GPX4 protein-induced ferroptosis.

2024-01-01 | GSE223895 | GEO

Exploring the phenomenon of ferroptosis in liver disease associated with intestinal failure in children with SBS

2024-01-01 | GSE222802 | GEO

Autophagy of OTUD5 Destabilizes GPX4 to Confer Ferroptosis-Dependent Kidney Injury

Project description:Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We show that OTU deubiquitinase 5 (OTUD5) is a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. In this work, our study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

2023-11-29 | GSE244330 | GEO

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