FOSL1 upregulation contributes to ischemia/reperfusion-induced acute kidney injury by regulating GPX4-dependent ferroptosis.
TL;DR
Results suggest that FOSL1 inhibition alleviates I/R-induced AKI by enhancing ferroptosis resistance through GPX4 transcriptional regulation.
Abstract
Fos-like antigen 1 (FOSL1) has been implicated in the pathology of acute kidney injury (AKI), but its specific mechanism remains unclear. In this study, we investigated the role of FOSL1 in the regulation of ferroptosis and inflammation in the context of ischemia-reperfusion (I/R)-induced AKI. Our results showed that renal I/R resulted in renal injury as evidenced by renal tissue damage and decreased renal function accompanied by increased FOSL1 expression, all of which was effectively restored by FOSL1 knockout (KO) in mice. FOSL1 KO downregulated the levels of pro-inflammatory cytokines and the number of CD4+ T cells in I/R mice model. Furthermore, FOSL1 KO decreased ROS, MDA, and Fe²⁺ levels, elevated GSH levels, and normalized the expression of the acyl-CoA synthetase long-chain family member 4 (ACSL4)/glutathione peroxidase 4 (GPX4) axis. Consistent with the in vivo results, FOSL1 inhibition suppressed HK-2 cell ferroptosis induced by oxygen-glucose deprivation and reoxygenation (OGD/R), erastin, or co-culture with CD4+ T cells. Notably, GPX4 knockdown (KD) in HK-2 cells reversed the ferroptosis-resistant effect mediated by FOSL1 KD, suggesting that GPX4 is a key downstream molecule of FOSL1. Besides, dual-luciferase reporter (DLR) and chromatin immunoprecipitation (ChIP) assays further confirmed that FOSL1 directly binds to the GPX4 promoter to repress its transcription. Collectively, these results suggest that FOSL1 inhibition alleviates I/R-induced AKI by enhancing ferroptosis resistance through GPX4 transcriptional regulation.