Danshensu ameliorates doxorubicin cardiotoxicity by attenuating oxidative stress and JNK-mediated mitochondrial...

Doxorubicin (DOX) is a potent chemotherapeutic widely used in cancer treatment, but its clinical application is limited by dose-dependent cardiotoxicity. The underlying mechanisms involve oxidative stress, mitochondrial dysfunction, and apoptosis; however, effective cardioprotective strategies remain inadequate.

To evaluate the cardioprotective effects of Danshensu (DSS), a bioactive compound from Salvia miltiorrhiza, against DOX-induced cardiotoxicity and to delineate the mechanisms by which it restores DOX-impaired mitochondrial quality control.

Cardiotoxicity models were established in vivo using DOX-treated C57BL/6 J mice and in vitro using neonatal rat cardiomyocytes (NRCMs). The publicly available snRNA-seq dataset GSE292067 was analyzed to delineate DOX-associated transcriptional alterations in human cardiomyocytes. Molecular docking and cellular thermal shift assay were used to identify the targets of DSS. DSS was administered at multiple doses and compared with the FDA-approved cardioprotective agent, dexrazoxane (ICRF-187). Cardiac function was assessed by echocardiography and invasive hemodynamics. Histopathology, immunoblotting, flow cytometry, fluorescence imaging, and mitochondrial functional assays were used to evaluate apoptosis, oxidative stress, mitochondrial dynamics, and mitophagy.

DSS supplementation improved survival, ameliorated ventricular dysfunction, and attenuated cardiac atrophy and fibrosis in DOX-treated mice. In DOX-exposed NRCMs, DSS increased cell viability and area, mitigated oxidative stress, and suppressed apoptosis. Mechanistically, mitochondrial injury-associated pathways were significantly enriched in DOX-treated human cardiomyocytes. DSS directly bonded to JNK and inhibited ROS-stirred c-Jun N-terminal kinase (JNK) phosphorylation, thereby restoring Mfn1/2 expression and limiting Drp1 phosphorylation to rebalance mitochondrial fission-fusion dynamics; It also restrained excessive, Drp1-facilitated and PINK1/Parkin-mediated mitophagy. Collectively, these effects preserved mitochondrial integrity, lowered ROS, and ultimately reduced cardiomyocyte apoptosis.

DSS confers cardioprotection against DOX-induced injury by disrupting the vicious circle formed by ROS and JNK, which mediated impairment of mitochondrial quality control, attenuating oxidative stress, and reducing apoptosis. These findings highlight DSS as a promising therapeutic candidate for mitigating chemotherapy-associated cardiotoxicity.