RNA m⁶A-Regulated circ-ZNF609 Suppression Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating FTO

Cardiac death is a major burden for cancer survivors, yet there is currently no effective treatment for doxorubicin (DOX)-induced cardiotoxicity. Here, we report that circ-ZNF609 knockdown knockdown had cardioprotective effects against DOX-induced cardiomyocyte toxicity. Mechanistically, circ-ZNF609 knockdown alleviated DOX-induced cardiotoxicity through attenuating cardiomyocyte apoptosis, reducing reactive oxygen species production, ameliorating mitochondrial nonheme iron overload. circ-ZNF609 inhibition blocked the elevation of RNA N⁶-methyladenosine (RNA m⁶A) methylation level in DOX-treated mice hearts, whereas m⁶A demethylase fat mass and obesity associated (FTO) acted as the downstream factor of circ-ZNF609. Moreover, the stability of circ-ZNF609 was regulated by RNA m⁶A methylation alteration, and suppression of RNA m⁶A methylation by methyltransferase like 14 (METTL14) modulated the function of circ-ZNF609. These data suggest that circ-ZNF609 inhibition represents a potential therapy for DOX-induced cardiotoxicity.