Abstract
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.