ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury

Area of Science:

• Cell Biology
• Nephrology
• Biochemistry

Background:

• Ferroptosis, a regulated form of cell death, is implicated in acute kidney injury (AKI) pathogenesis.
• The precise molecular mechanisms linking ferroptosis to AKI remain incompletely understood.

Purpose of the Study:

• To elucidate the role of ferroptosis pathways in AKI.
• To identify key molecular targets for therapeutic intervention in AKI.

Main Methods:

• RNA-sequencing analysis of AKI mouse kidneys to identify differentially expressed genes.
• Validation of gene expression using RT-PCR, Western blot, and immunohistochemistry.
• Generation of ACSL4 knockout mice in kidney tubules (Cdh16Cre-ACSL4^F/F) to assess functional and pathological outcomes.
• In vitro studies to investigate HIF-1α regulation of ACSL4.
• Assessment of inflammation, macrophage infiltration, and neutrophil recruitment in response to ferroptosis.

Main Results:

• Acyl-CoA synthetase long-chain family member 4 (ACSL4) was identified as a significantly upregulated gene and a promoter of ferroptosis in AKI.
• ACSL4 knockout mice exhibited reduced ferroptosis, attenuated kidney injury, and decreased inflammation and macrophage infiltration.
• Hypoxia-inducible factor 1-alpha (HIF-1α) was found to negatively regulate ACSL4.
• Neutrophil recruitment was mediated by ferroptosis-induced macrophages, not directly by ferroptotic cells.
• The ACSL4 inhibitor rosiglitazone demonstrated significant protective effects against AKI.

Conclusions:

• ACSL4 plays a critical role in promoting ferroptosis and driving kidney injury and inflammation in AKI.
• Targeting ACSL4 represents a promising therapeutic strategy for managing AKI.
• Understanding ferroptotic immunogenicity provides new insights into AKI pathogenesis.