Unveiling Therapeutic Targets for Liver Damage after Liver Transplantation: Gp78-ACSL4 Axis in Focus

Ischemia-reperfusion injury (IRI) is a major complication following liver transplantation, significantly impacting patient outcomes. This study sheds light on potential therapeutic targets by investigating the role of Gp78, an endoplasmic reticulum protein, in IRI-induced liver damage. Researchers employed a multi-omics approach, combining RNA sequencing, proteomics, and metabolomics, to gain a comprehensive understanding of the underlying mechanisms. The findings suggest that Gp78 deficiency protects against IRI by regulating lipid metabolism and ferroptosis. Notably, the Gp78-ACSL4 axis emerges as a promising target for developing novel therapeutic strategies to prevent IRI and improve liver transplant outcomes.

gp78-ACSL4 axis : a feasible target for the treatment of IRI-associated liver damage.

We're excited to present groundbreaking research on hepatic ischemia-reperfusion injury (IRI) recently published in Cell Death and Disease. The study, 'Gp78 Deficiency in Hepatocytes Alleviates Hepatic Ischemia-Reperfusion Injury via Suppressing ACSL4-Mediated Ferroptosis (DOI:10.1038/s41419-023-06294-x)', leveraged MetwareBio's RNA-Seq, proteomics, and metabolomics capabilities to delve into the role of Gp78, an E3 ligase, in liver IRI and ferroptosis. By generating hepatocyte-specific gp78 knockout (HKO) or overexpressed (OE) mice and employing a multiomics approach, the research aimed to uncover potential therapeutic avenues for IRI-associated liver damage.

Gp78 Expression Correlates with IRI Severity

In the study, the hepatic I/R model was successfully established in mice, and I/R triggered a significant decrease of gp78 in the liver of mice. Further investigation into whether Gp78 is dysregulated in major liver cells revealed that Gp78 is mainly expressed in liver cells, 2-3 times higher than in Kupffer cells, endothelial cells, and fibroblasts. Next, the article evaluated the correlation between pre transplant Gp78 levels and post transplant liver injury. The pre transplant Gp78 protein expression was positively correlated with post transplant serum ALT levels. In summary, gp78 may play a role in the hepatic I/R injury.

Multi-Omics Reveal Gp78's Role in Lipid Metabolism and Ferroptosis

To explore the potential mechanism by which gp78 aggravated liver IRI, this reasrch performed a multi-omics approach (transcriptomics, proteomics, and metabolomics) to study the characteristics of the liver during IRI. The GO enrichment of transcriptomic and proteomic analysis showed that DEGs were enriched in the pathways associated with ferroptosis. Besides, the KEGG enrichment of transcriptomic and proteomic analysis showed that lipid metabolic pathways involved in regulation including arachidonic acid (AA) metabolism, linoleic acid (LA) metabolism and glycerophospholipid metabolism. Furthermore, differences in fatty acid metabolism and iron toxicity pathways have been confirmed at the metabolomics level. Overall, these results indicated that gp78 promoted liver IRI partly by regulating ferroptosis.

Gp78 promotes ferroptosis partly by ACSL4

The article studied the expression of key genes in the change pathway, and the results showed that the expression levels of ACC1, ACSL4, LPCAT3 and other genes related to the fatty acid metabolism and ferroptosis were upregulated in gp78 OE mice compared with WT mice.  ACSL4 has been reported to promote the synthesis of PUFA-containing PEs and induce ferroptosis, with an increase in gp78 OE mice liver and a decrease in in gp78 HKO mice liver. After treatment with ACSL4 inhibitor Rosiglitazone in gp78 OE mice, serum ALT and AST levels decreased,  pathological liver damage was alleviated, andhepatocyte death was reduced. In addition, rosiglitazone also reduced the levels of pro-inflammatory cytokines and ferroptosis in gp78 OE mice. In summary, the gp78/ACSL4 axis plays a crucial role in ferroptosis and liver IRI.

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