MAPK14 drives Ferroptosis and immune dysfunction in pediatric Sepsis-induced acute lung injury

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology Pub Date : 2025-04-04 DOI:10.1016/j.cellimm.2025.104948

Ning Zhang , Yuanyuan Fan , Juan Chen , Juan Gu , Xiangming Yan

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Abstract

Objective

Sepsis-induced acute lung injury (ALI) is driven by inflammation, oxidative stress, and immune suppression. MAPK14 (p38α) plays a role in ferroptosis and immune regulation, but its specific function in pediatric sepsis remains unclear. Therefore, our study aimed to explore the role and underlying mechanism of MAPK14 in pediatric sepsis.

Methods

Bioinformatics analysis of GSE26440 and FerrDb identified ferroptosis-related genes in pediatric sepsis. STRING database was used to predict the proteins associated with MAPK14. MAPK14 expression in whole blood samples, LPS-treated MLE-12 cells, and a CLP mouse model was detected by qRT-PCR and western blot. Ferroptosis was assessed by measuring MDA, GSH, and Fe²⁺ levels, while ROS accumulation was analyzed using DCFH-DA staining and DHE staining. A cycloheximide (CHX) assay was performed to assess TTP53 protein stability. MPO immunohistochemistry and PD-L1 immunofluorescence assessed neutrophil infiltration, and flow cytometry evaluated neutrophil apoptosis.

Results

Bioinformatics analysis of GSE26440 and FerrDb identified MAPK14 as a ferroptosis-related gene in pediatric sepsis. MAPK14 expression was upregulated in sepsis patient samples, LPS-treated MLE-12 cells and CLP mouse lung tissues. Overexpression of MAPK14 led to increased MDA and Fe²⁺ levels, reduced GSH, and elevated ROS fluorescence intensity, confirming its role in promoting ferroptosis. Mechanistically, MAPK14 upregulated TTP53, which in turn suppressed SLC7A11 and GPX4, further driving ferroptosis. MAPK14 overexpression stabilized TTP53 and enhanced its activity. Additionally, MAPK14 enhanced MPO and PD-L1 expression to promote neutrophil infiltration and immune suppression. Additionally, MAPK14 overexpression inhibited neutrophil apoptosis, promoted neutrophil infiltration and enhanced immune suppression.

Conclusion

MAPK14 drives ferroptosis via the TTP53/SLC7A11/GPX4 pathway and exacerbates immune suppression by promoting neutrophil infiltration.

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来源期刊

Cellular immunology 生物-免疫学

CiteScore

8.20

自引率

2.30%

发文量

102

审稿时长

30 days

期刊介绍： Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.