Abstract
Background: Doxorubicin (Dox) has limited clinical application due to its cardiotoxicity. Berberine (Ber) counteracts Dox-induced myocardial injury. Objectives: This study uncovers molecular mechanisms through which Ber mitigates Dox-induced myocardial damage by modulating the long non-coding RNAs small nucleolar RNA host gene 14 (SNHG14). Methods: To construct Dox-induced cardiotoxicity models in vitro (AC16 cells) and in vivo (male adult rats) for assessing the effects of Ber. Echocardiography was performed to assess the severity of cardiac injury in the rats. RT-qPCR analysis was performed to examine SNHG14 expression. CCK-8, flow cytometry, ELISA and other kits were used to evaluate cell viability, apoptosis, inflammation, oxidative stress and myocardial damage markers. Results: Dox boosted SNHG14 and PDK4 in rat myocardial tissues and cultured cardiomyocytes, while suppressing miR-9-5p. Ber reversed the situation, lowering SNHG14 and PDK4 expression and raising miR-9-5p levels. Mechanistically, SNHG14 acts as a miR-9-5p sponge, which leads to the attenuation of miR-9-5p-mediated inhibition of PDK4, ultimately promoting PDK4 expression. The Ber significantly attenuated Dox-induced diastolic dysfunction in rats. It also attenuated apoptosis, inflammation and oxidative stress in AC16 cells; however, this attenuation was substantially reversed by SNHG14, which was partially abolished by miR-9-5p. Conclusion: Ber may alleviate Dox-induced cardiac toxicity by inhibiting the SNHG14/miR-9-5p/PDK4 axis and reducing the apoptosis, inflammation and oxidative stress in cardiomyocytes.