Lithospermic Acid Improves Doxorubicin‐Induced Cardiomyopathy Through Sirtuin‐3‐Mediated Deacetylation of p53

Doxorubicin (Dox)-induced cardiomyopathy (DIC) is characterized by significant myocardial damage that can progress to dilated cardiomyopathy and potentially lead to heart failure. The rate of mortality due to heart disease in patients undergoing cancer chemotherapy has even surpassed that caused by tumor recurrence. However, there is a lack of effective treatments for DIC in clinical practice. Lithospermic acid (LA), a polycyclic phenolic carboxylic acid isolated from the traditional Chinese herb Salvia miltiorrhiza , exhibits superior efficacy in inhibiting oxidative stress damage across various diseases. This study aimed to assess the therapeutic potential of LA in alleviating cardiac injury and elucidate its potential molecular mechanisms in DIC. Male C57BL/6J mice were randomly divided into four groups: saline control, saline with LA, Dox, and LA combined with Dox. A mouse cardiomyocyte cell line HL-1, along with human embryonic stem cells-derived cardiomyocytes, was utilized to investigate the therapeutic potential of LA on Dox-induced cardiomyocyte injury in vitro. Supplementation with exogenous LA mitigated Dox-induced cardiac atrophy, cardiac fibrosis, and ventricular remodeling while preserving cardiac function. LA reduced Dox-induced abnormal cardiomyocyte apoptosis and excessive oxidative stress both in vitro and in vivo. Dox promoted the acetylation of p53 by decreasing the expression of sirtuin-3 (SIRT3), which triggered continuous oxidative stress and apoptosis. LA enhanced the deacetylation of p53 and subsequently inhibited the activation of the p53 signaling pathway by directly targeting SIRT3. Knockdown of SIRT3 eliminated the beneficial effects of LA against Dox. LA serves as a beneficial treatment for Dox-induced pathological cardiac injury and remodeling by targeting SIRT3, thereby enhancing the deacetylation of p53. This study provides novel insights into the potential of LA as a promising drug candidate for cardio-protection.