Arachidonate lipoxygenase 5 metabolism axis promoting ferroptosis: a potential druggable target for doxorubicin-induced cardiomyopathy

BACKGROUND: Doxorubicin (Dox) is a widely-used anthracycline drug for various cancers, but its clinical application is limited due to cardiotoxicity. Targeting ferroptosis is a new and effective strategy for treating Dox-induced cardiomyopathy (DIC). The arachidonate lipoxygenase 5 (ALOX5) metabolism axis is closely linked to ferroptosis, but its role in DIC remains unknown. METHODS: In vivo and in vitro DIC models were established to investigate the role of the ALOX5 metabolism axis in DIC and to clarify the underlying mechanism using genetic and pharmacological approaches. RESULTS: Our findings revealed that ALOX5 and 5-hydroxyicosatetraenoic acid (5-HETE) levels were increased in DIC. Overexpression of Alox5 exacerbated Dox-induced cardiac dysfunction and myocardial injury, whereas pharmacological inhibition and genetic knockdown of ALOX5 alleviated these effects by modulating ferroptosis. Mechanistically, elevated ALOX5 catalyzed the metabolism of arachidonic acid to generate 5-HETE, which facilitated NRF2 ubiquitination-dependent degradation via PI3K/AKT/GSK-3β signaling, thereby contributing to cardiomyocyte ferroptosis. CONCLUSIONS: This study suggests that targeting cardiomyocyte ferroptosis mediated by the ALOX5 metabolism axis may represent a therapeutic strategy for DIC.