EF24 targets METTL3 to reprogram m6A methylation and induce ferroptosis: an epitranscriptomic mechanism with therapeutical potential for glioma.

Glioma, the most common primary malignant tumor of the central nervous system, still brings a dismal prognosis, even after stringent standard therapies. This study investigates the RNA epitranscriptomic regulatory mechanism of curcumin analog EF24 in inducing ferroptosis to counter glioma. Both in vitro and in vivo experiments demonstrated that EF24 induces significant ferroptosis and effectively suppresses the growth and metastasis of glioma. Mechanistically, EF24 specifically downregulates the m6A methyltransferase METTL3, a core component of the RNA methylation machinery. More specific, METTL3 recruits an m6A reader YTHDF1 to catalyze methylation at the 3'-UTR region of NRF2 mRNA, forming an m6A-YTHDF1-NRF2 translational enhancement complex that activates downstream antioxidant gene GPX4 expression. EF24 disrupts this complex through suppressing NRF2 mRNA stability and impairing its protein translation, ultimately depleting GPX4 and triggering ferroptosis cascades. For the first time, our study proposes an epitranscriptomic axis of METTL3/YTHDF1/NRF2/GPX4 as a regulator of ferroptosis in glioma, which may be targeted to design an effective and safe therapeutic strategy.