ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury

The term ferroptosis coined in 2012 causes acute kidney injury (AKI). However, its pathway mechanism in AKI is poorly understood. In this study, we conducted an RNA-sequence analysis of kidneys in AKI and normal mice to explore the pathway mechanism of ferroptosis. Consequently, differentially expressed genes highlighted AcylCoA synthetase long-chain family (ACSL4), a known promotor for ferroptosis. Besides, RT-PCR, Western blot, and immunohistochemical analyses confirmed its upregulation. HIF-1 alpha was downregulated in I/R-AKI mice, and in vitro studies confirmed a negative regulation of HIF-1 alpha on ACSL4. To explore the role of ACSL4 in AKI, we constructed ACSL4 knockout in kidney tubules of mice-as Cdh16Cre-ACSL4F/F mice. Results revealed that ACSL4 knockout significantly reduced ferroptosis and inhibited the functional and pathological injury of AKI mice. Meanwhile, the kidneys of Cdh16Cre-ACSL4F/F mice demonstrated a significantly decreased inflammation and macrophage infiltration. Further, additional explorations were explored to decipher a more thorough understanding of ferroptotic immunogenicity. As a result, neutrophils were not directly recruited by ferroptotic cells, but by ferroptotic cell-induced macrophages. Further, ACSL4 inhibitor rosiglitazone significantly inhibited AKI. Collectively, these data provide novel insights into the AKI pathogenesis, and defined ACSL4 as an effective target in AKI.

Automated summary

This study explored the pathway mechanism of ferroptosis in acute kidney injury (AKI) by conducting RNA-sequence analysis. The results highlighted the important role of AcylCoA synthetase long-chain family (ACSL4) in promoting ferroptosis. Further investigations demonstrated that knockout of ACSL4 reduced ferroptosis and inhibited functional and pathological injury in AKI mice. Additionally, ACSL4 inhibition showed promising results in reducing AKI. This study provides novel insights into the pathogenesis of AKI and identifies ACSL4 as an effective therapeutic target.