AUTHOR=Li Weili , Cao Jing , Wang Xiaoping , Zhang Yawen , Sun Qianbin , Jiang Yanyan , Yao Junkai , Li Chun , Wang Yong , Wang Wei 

TITLE=Ferruginol Restores SIRT1-PGC-1α-Mediated Mitochondrial Biogenesis and Fatty Acid Oxidation for the Treatment of DOX-Induced Cardiotoxicity

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.773834

DOI=10.3389/fphar.2021.773834

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Doxorubicin (DOX), a broad-spectrum chemotherapy drug, has life-threatening cardiotoxicity. Therefore, searching cardioprotective drugs for DOX-induced cardiotoxicity (DIC) is urgently needed.</p><p><bold>Objectives:</bold> This study aimed to explore cardioprotective effect and specific mechanism by which Ferruginol (FGL) attenuated DIC <italic>in vivo</italic> and <italic>in vitro</italic>.</p><p><bold>Methods:</bold> We evaluated the cardioprotection of FGL and performed high-throughput RNA-Seq on a DIC mouse. Whereafter, multiple methods, including western blot, RT-qPCR, a transmission electron microscope, CO-IP, immunofluorescence, and other staining methods, and antagonist of SIRT1 and PGC-1α were utilized to confirm the cardioprotection and molecular mechanism of FGL.</p><p><bold>Results:</bold> FGL-exerted cardioprotection manifested as enhanced cardiac function and reduced structural damage and apoptosis. The transcriptome and other results revealed that FGL facilitated PGC-1α-mediated mitochondrial biogenesis and fatty acid oxidation (MB and FAO) by increasing the expression of PGC-1α and concurrently promoting the expression of SIRT1-enhancing deacetylase SIRT1 deacetylating and activating PGC-1α.</p><p><bold>Conclusions:</bold> These results documented that FGL exerted cardioprotective effects restoring MB&amp;FAO via the SIRT1–PGC-1α axis.</p>