Deficiency of m 6 A RNA methylation promotes ZBP1-mediated cell death.

m ⁶ A RNA methylation suppresses the immunostimulatory potential of endogenous RNA. Deficiency of m ⁶ A provokes inflammatory responses and cell death, but the underlying mechanisms remain elusive. Here we showed that the noncoding RNA 7SK gains immunostimulatory potential upon m ⁶ A depletion and subsequently activates the RIG-I/MAVS axis to spark interferon (IFN) signaling cascades. Concomitant excess of IFN and m ⁶ A deficiency synergistically facilitate the formation of RNA G-quadruplexes (rG4) to promote ZBP1-mediated necroptotic cell death. Collectively, our findings delineate a hitherto uncharacterized mechanism that links m ⁶ A dysregulation with ZBP1 activity in triggering inflammatory cell death.