Therapeutic opportunities for ferroptosis in lipopolysaccharides- induced acute kidney injury; Liproxstatin-1 versus N- acetyl cysteine.

Acute kidney injury (AKI) is a fatal condition with high morbidity and mortality rates. Recent studies indicated that ferroptosis is implicated in the pathogenesis of AKI. This suggests that ferroptosis inhibitors deserve more attention as AKI therapeutic options. We explored the comparative effectiveness of liproxstatin-1 (Lip-1) and N- acetyl cysteine (NAC) in mitigating ferroptosis in lipopolysaccharides (LPS)- induced AKI. Herein, mice were exposed to a single intraperitoneal (IP) injection of 10 mg/kg LPS. They were treated either by 10 mg/kg Lip-1 or NAC (total 3 doses of each drug over 6 days). Serum urea, creatinine and malondialdehyde, along with tissue EGR-1, GPX-4 and iron, were assessed. Histological, immuno-fluorescence and ultrastructural studies were conducted as well. Our results elucidated that; Lip-1 possesses significant antiferroptotic effects that modulated the three cornerstones of ferroptosis; MDA, GPX-4 and iron. Additionally, it downregulated EGR-1 and PERK, and upregulated GB3P1, affecting the cellular pathways that relate ferroptosis to endoplasmic reticulum stress (ER stress), stress granules (SGs) formation and lysophagy. The antiferroptotic actions of NAC were less remarkable. In conclusion, our study presents a foundation for therapeutic options directed against ferroptosis in AKI, advocating application of Lip-1 or NAC, with a specific focus on Lip-1.