Scoparone alleviates cisplatin-induced acute kidney injury by inhibiting 5-lipoxygenase-mediated ferroptosis

Ferroptosis, a regulated form of cell death, plays a critical role in renal tubular epithelial cells during acute kidney injury (AKI). Scoparone, a bioactive coumarin, confers organ protection in cardiovascular, hepatic, and inflammatory disorders. However, its therapeutic potential in AKI and its role in regulating Ferroptosis remain unexplored. This study aimed to investigate the role of scoparone in cisplatin-induced AKI using mouse models and human renal tubular epithelial (HK-2) cells. Integrative analyses, incorporating network pharmacology, bioinformatics, and machine learning, identified arachidonate 5-lipoxygenase (ALOX5) as a key target. In vivo, scoparone treatment markedly improved renal function and preserved histopathological architecture in cisplatin-induced AKI mice. In vitro, scoparone attenuated cisplatin-induced cytotoxicity in HK-2 cells without compromising cisplatin's antitumor efficacy in four human tumor cell lines. Mechanistically, scoparone downregulated ALOX5, suppressed lipid peroxidation, and inhibited Ferroptosis. Pharmacological inhibition of ALOX5 with zileuton recapitulated these protective effects, with no additional benefit from co-treatment. Altogether, the findings of this study show that scoparone ameliorates cisplatin-induced AKI by suppressing ALOX5-mediated Ferroptosis, positioning ALOX5 as a potential therapeutic target and supporting scoparone as a promising therapeutic candidate for AKI management.