Norharmane Mitigates Doxorubicin-Induced Heart Failure via PPARγ- Mediated Suppression of Oxidative Stress and Apoptosis

Abstract We studied the cardioprotective effects of norharman (NH), a natural alkaloid, against doxorubicin (DOX)-induced myocardial damage and its mechanism of action through PPARγ signaling. Clinical efficacy is limited by dose-dependent cardiotoxicity (which can lead to cardiomyopathy and heart failure), highlighting the need for safe cardioprotective agents. This study combined in vivo and in vitro experimental designs. C57BL/6 mice were treated with DOX alone or in combination with NH. Cardiac function was analyzed by echocardiography. Serum creatine kinase and lactate dehydrogenase levels were also measured as indicators of myocardial damage. Myocardial fibrosis, inflammation, and oxidative stress were assessed by histological and biochemical analyses. Cultured cardiomyocytes were exposed to DOX ± NH to evaluate cell viability, reactive oxygen species formation, and apoptosis-associated protein expression. The selective PPARγ inhibitor GW9662 was used to determine pathway specificity. DOX significantly reduced myocardial ejection fraction and fractional shortening, increased oxidative stress and damage biomarkers, and induced myocardial fibrosis. NH co-treatment protected cardiac function, reduced oxidative damage, and attenuated fibrosis and inflammation. In cardiomyocytes, NH increased cell viability, inhibited reactive oxygen species production, upregulated Bcl-2, and downregulated Bax, cleaved caspase-3, and TNF-α. GW9662 reversed NH’s protective effects, confirming PPARγ involvement. These results indicate that NH, as a novel PPARγ activator, effectively attenuates DOX-induced oxidative stress and apoptosis, highlighting its potential as a natural therapeutic agent for preventing anthracycline-associated cardiotoxicity.