Double-stranded RNA adenosine deaminases suppress ferroptosis through regulating SCD1.

Double-stranded RNA adenosine deaminases 1 and 2 (ADAR1/2) are enzymes that convert adenosine to inosine (A-to-I), a major RNA editing event. A-to-I editing is strongly correlated with cancer progression and drug resistance. While the role of ADAR1/2 in apoptosis regulation in certain cancer types is well-characterized, their potential involvement in ferroptosis has not been explored. In this study, we report that ADAR1/2 are upregulated in cervical, breast, and colon cancers but have no impact on drug-induced apoptosis. Depletion of ADAR1/2 resulted in increased lipid droplets and downregulated Stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme that protects cells from lipid peroxidation and ferroptosis. ADAR1/2 and SCD1 expressions are positively correlated at both mRNA and protein levels in cancers with elevated ADAR1/2. Cells depleted of ADAR1/2 were sensitized to RSL3-induced ferroptosis. Furthermore, cells stably overexpressing wild-type ADAR1 (WT) remained resistant to ferroptosis with strong SCD1 expression, whereas cells with an RNA editing-inactive mutant (EAA) were sensitive with diminished SCD1 levels. WT cells became susceptible to RSL3-induced ferroptosis when SCD1 was depleted. These results indicate that ADAR1/2 suppress ferroptotic cell death via RNA editing activity, specifically through SCD1 regulation. Collectively, our findings highlight the suppressive role of ADAR1/2 in ferroptosis and reveal a novel function of ADAR1/2 in regulating this process. These results suggest that targeting ADAR1/2 could offer a promising strategy to overcome chemotherapeutic resistance in cancers with elevated RNA editing.