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Toxicology and applied pharmacology

Toxicology and applied pharmacology

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NFE2L2 protects against Sorafenib-induced Ferroptosis and cardiotoxicity by activating the HO1/ferritin pathway

Published:28 August 2025 DOI: 10.1016/j.taap.2025.117537
Hui Jiang , Yan Su , Yinglong Hou , Cong Wang

Abstract

Sorafenib, a tyrosine kinase inhibitor, has demonstrated efficacy in the treatment of hepatocellular carcinoma and clear cell renal carcinoma. However, its clinical application is limited by cardiotoxicity. Here, we show that NFE2L2, a transcription factor that regulates oxidative stress and iron homeostasis, mitigates Sorafenib-induced cardiotoxicity. Sorafenib increases NFE2L2 expression in cardiomyocytes, while ferroptosis inhibitors such as ferrostatin-1 (Fer-1) and deferoxamine (DFO) attenuate this effect, indicating that ferroptosis is involved in NFE2L2 activation. Further studies revealed that NFE2L2 knockdown exacerbates Sorafenib-induced cardiomyocyte ferroptosis, which is characterized by increased lipid peroxidation and reactive oxygen species (ROS) production. Conversely, NFE2L2 agonist sulforaphane (SFN) mitigated Sorafenib-induced ferroptosis. Mechanistically, NFE2L2 activates the heme oxygenase-1 (HO-1)/ferritin axis, which alleviates oxidative stress and promotes iron homeostasis in cardiomyocytes, thereby mitigating Sorafenib-induced ferroptosis. Interestingly, Sorafenib activates NFE2L2 via the endoplasmic reticulum (ER) stress-related kinase EIF2AK3, rather than the SQSTM1-KEAP1 pathway. This finding reveals a novel role for ER stress-dependent pathways in counteracting Sorafenib-induced cardiotoxicity. Finally, we found that SFN alleviates Sorafenib-induced cardiotoxicity in vivo, providing a new therapeutic strategy for managing drug-induced cardiac injury. Taken together, these data suggest that NFE2L2 and its downstream pathways, including the HO-1/ferritin axis, may represent promising therapeutic targets for mitigating Sorafenib-induced cardiotoxicity. Further investigation of NFE2L2 agonists could enhance the safety of Sorafenib therapy.

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