Background:
Arsenic trioxide (As2O3, AsⅢ) is a first-line treatment for acute promyelocytic leukemia (APL), which has greatly improved the complete remission rate and long-term survival rate of APL patients[1]. However, long-term application of As2O3 can induce cardiotoxicity, including QT prolongation, ventricular arrhythmia, torsades de pointes, and sudden cardiac death[2], which greatly limits the clinical application of As2O3. The key regulatory molecules and mechanisms of As2O3-induced cardiotoxicity have not been fully elucidated. Ferroptosis, as a newly discovered mode of cell death, is involved in regulating various cardiovascular diseases, including drug-induced cardiotoxicity[3]. Studies have shown that the in vivo metabolic process of As2O3 consumes the methyl donor S-adenosylmethionine (SAM), affects the methylation modification level of the body, and mediates the adverse reactions of As2O3[4]. This study aims to explore whether As2O3 consumes SAM to affect methylation modification, thereby inducing myocardial ferroptosis and causing cardiotoxicity, and to investigate its potential molecular mechanism.
Methods:
A randomized controlled trial was conducted to evaluate the cardiotoxic and side effects of APL patients treated with As2O3. The concentration of SAM in the plasma of APL patients treated with As2O3 was determined by liquid chromatography-mass spectrometry (LC-MS/MS). The mechanisms of As2O3-induced cardiotoxicity was determined by detecting differential genes using RNA-seq combined with GSEA analysis. As2O3-induced H3K9me3 site changes were determined by CUT&Tag and CHIP-PCR. The salvage effects of ferroptosis inhibitors, SAM and HMOX1 inhibitors on the As2O3-induced cardiotoxicity were evaluated through in vivo and in vitro experiments. The salvage effect of knockdown As3MT on As2O3-induced cardiotoxicity was evaluated using As3MT knockout mice.
Results:
(1) As2O3 induces cardiotoxicity in the treatment of APL. (2) The content of SAM in the plasma of APL patients is significantly decreased. (3) Ferroptosis mediates the As2O3-induced cardiotoxicity in mice. (4) As3MT consuming SAM to inhibit H3K9me3 mediates As2O3-induced myocardial ferroptosis. (5) As2O3 upregulates HMOX1, causing mitochondrial iron overload and leading to myocardial ferroptosis. (6) As2O3 inhibits H3K9me3-HMOX1 by consuming SAM through As3MT, upregulating HMOX1, and provoking myocardial ferroptosis. (7) Supplementing SAM rescues As2O3-induced myocardial ferroptosis and cardiotoxicity in mice. (8) Knockout of As3MT reverses As2O3-induced myocardial ferroptosis and cardiotoxicity in mice.
Conclusion:
This study indicates that during As2O3 metabolism, As3MT consuming SAM, represses H3K9me3-HMOX1, and upregulates HMOX1, leading to myocardial ferroptosis, resulting in inducing cardiotoxicity. These findings reveal that the As2O3 regulates myocardial ferroptosis by influencing epigenetic modifications, mediates the process of cardiotoxicity in APL patients. It indicated that targeting ferroptosis or influencing metabolic process of arsenic can be effective strategies for As2O3-induced cardiotoxicity during As2O3 treatment of APL.
