Doxorubicin is considered to be one of the most powerful antitumor agents available in the market. However, its clinical use is restricted as it poses severe cardiotoxicity risk. Research done prior to this study has established that CircITCH is a broad-spectrum tumor-suppressive circular RNA and that its host gene, ITCH (E3 ubiquitin-protein ligase), is involved in doxorubicin-induced cardiotoxicity (DOXIC).

This study aimed to determine the role of CircITCH in DOXIC and further decipher its potential mechanisms. Bioinformatic analysis, luciferase reporter assays, and quantitative polymerase chain reaction showed that SIRT6 (sirtuin 6), BIRC5 (baculoviral IAP repeat-containing 5, Survivin), and ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2, SERCA2a [SR Ca2+-ATPase 2]) were direct targets of miR-330-5p and that the CircITCH/miR-330-5p axis regulated them in DOXIC. Further experiments demonstrated that CircITCH-mediated alleviation of DOXIC depended on the interactions between miR-330-5p and the 3′-UTRs of SIRT6, BIRC5, and ATP2A2 mRNA.

In conclusion, we herein identified the CircITCH-miR-330-5p-SIRT6/BIRC5/ATP2A2 competing endogenous RNA network as a novel target for the prevention and possible treatment of DOXIC. The study findings revealed two promising molecular targets that can be used in therapeutic exploitations for the treatment of DOXIC.