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

Lu Chen; Xingang Sun; Han Zhang; Xuan Zhang; Mairedan Muhetarijiang; Zuoshi Wen; Chenxi Li; Mengjia Chen; Zhangquan Ying; Shuai Yuan; Liangrong Zheng; Ting Chen

doi:10.1038/s41416-026-03376-3

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

Br J Cancer. 2026 Apr 6. doi: 10.1038/s41416-026-03376-3. Online ahead of print.

Authors

Lu Chen^#^{1

2}, Xingang Sun^#³, Han Zhang¹, Xuan Zhang¹, Mairedan Muhetarijiang¹, Zuoshi Wen¹, Chenxi Li¹, Mengjia Chen¹, Zhangquan Ying¹, Shuai Yuan⁴, Liangrong Zheng⁵, Ting Chen⁶

Affiliations

¹ Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
² Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
³ Department of Cardiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang Province, China.
⁴ Department of Echocardiography and Vascular Ultrasound Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
⁵ Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China. 1191066@zju.edu.cn.
⁶ Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China. ct010151452@zju.edu.cn.

^# Contributed equally.

PMID: 41942611
DOI: 10.1038/s41416-026-03376-3

Abstract

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.