Screening of ferroptosis-related genes in sepsis-induced liver failure and analysis of immune correlation

Abstract

Purpose Sepsis-induced liver failure is a kind of liver injury with a high mortality, and ferroptosis plays a key role in this disease. Our research aims to screen ferroptosis-related genes in sepsis-induced liver failure as targeted therapy for patients with liver failure. Methods Using the limma software, we analyzed the differentially expressed genes (DEGs) in the GSE60088 dataset downloaded from the Gene Expression Omnibus (GEO) database. Clusterprofiler was applied for enrichment analysis of DEGs enrichment function. Then, the ferroptosis-related genes of the mice in the FerrDb database were crossed with DEGs. Sepsis mice model were prepared by cecal ligation and perforation (CLP). ALT and AST in the serum of mice were measured using detection kit. The pathological changes of the liver tissues in mice were observed by hematoxylin-eosin (H & E) staining. We detected the apoptosis of mice liver tissues using TUNEL. The expression of Hmox1, Epas1, Sirt1, Slc3a2, Jun, Plin2 and Zfp36 were detected by qRT-PCR. Results DEGs analysis showed 136 up-regulated and 45 down-regulated DEGs. Meanwhile, we found that the up-regulated DEGs were enriched in pathways including the cytokine biosynthesis process while the down-regulated DEGs were enriched in pathways such as organic hydroxy compound metabolic process. In this study, seven genes (Hmox1, Epas1, Sirt1, Slc3a2, Jun, Plin2 and Zfp36) were obtained through the intersection of FerrDb database and DEGs. However, immune infiltration analysis revealed that ferroptosis-related genes may promote the development of liver failure through B cells and natural killer (NK) cells. Finally, it was confirmed by the construction of septic liver failure mice model that ferroptosis-related genes of Hmox1, Slc3a2, Jun and Zfp36 were significantly correlated with liver failure and were highly expressed. Conclusion The identification of ferroptosis-related genes Hmox1, Slc3a2, Jun and Zfp36 in the present study contribute to our understanding of the molecular mechanism of sepsis-induced liver failure, and provide candidate targets for the diagnosis and treatment of the disease.

Med1 inhibits ferroptosis and alleviates liver injury in acute liver failure via Nrf2 activation

“…In the liver of mice with ALF induced by acetaminophen or LPS/D-GalN, the expression of classical markers associated with ferroptosis, such as PTGS2, SLC7A11 genes, and lipid peroxidation products (4-HNE and MDA) increase [ 4 , 30 ]. Furthermore, in sepsis-induced liver failure, ferroptosis-associated genes are upregulated [ 31 ], suggesting an important role of ferroptosis in the development of liver failure due to diverse etiologies.…”

Ferroptosis in hepatocellular carcinoma, from mechanism to effect

“…The liver contains large numbers of hyporeactive NK cells, which are an important source of hepatic tolerance that can expose the body to enteric exogenous antigens on a daily basis without causing inflammation. We do not know whether NK cells themselves are subject to ferroptosis, but in a study of sepsis, researchers reported that many ferroptosis-related genes were dysregulated in models of liver failure and promoted liver failure by interacting with NK cells ( 86 ).…”

A critical appraisal of ferroptosis in Alzheimer’s and Parkinson’s disease: new insights into emerging mechanisms and therapeutic targets

“…It has been demonstrated that HMOX-1 forms complexes with CYP1A2, CYP1A1, and CYP2D6, but not all P450 enzymes ( Connick et al, 2021 ). Both HMOX-1 ( Chen Q. et al, 2022 ; Luo et al, 2023 ) and POR ( Zou et al, 2020 ) come out as ferroptosis hub-genes in multiple bioinformatics reports and are bonafide Nrf2/Bach1 target genes ( Table. 1 ).…”