METTL3-Driven m6A Epigenetic Remodeling of lncRNA-AU020206 Stabilizes SLC7A11 via YTHDC2 Attenuates Apoptosis and Ferroptosis in Cerebral Ischemia/Reperfusion Injury

Cerebral ischemia/reperfusion (I/R) injury is a devastating neurological disorder with limited treatment options. Emerging evidence suggests that the N6-methyladenosine (m6A) modification and its regulatory factors play pivotal roles in the pathophysiology of I/R. This study aimed to elucidate the function of METTL3-mediated m6A modification of the long non-coding RNA (lncRNA) AU020206 in ferroptosis during cerebral I/R injury and to identify potential molecular targets for neuroprotection. A murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) and N2a cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) were established to assess m6A levels and ferroptosis-related changes. Effects of METTL3 overexpression and lncRNA-AU020206 silencing on neuronal apoptosis, inflammation, and ferroptosis were investigated in vitro and in vivo. The interaction between lncRNA-AU020206 and YTHDC2 and the resulting regulation of SLC7A11 mRNA stability and GPX4 expression were evaluated using molecular and biochemical assays. Both MCAO/R mice and OGD/R-treated N2a cells exhibited decreased m6A levels and upregulation of lncRNA-AU020206 accompanied by enhanced ferroptosis. METTL3 overexpression increased the m6A modification of AU020206, promoting its degradation and attenuating neuronal injury, whereas silencing AU020206 or overexpressing YTHDC2 decreased SLC7A11 mRNA stability and enhanced ferroptosis. Restoring the expression of SLC7A11/GPX4 can enhance cell viability, alleviate neuronal apoptosis, and reduce Fe²⁺ overload. Disruption of the METTL3-AU020206-YTHDC2 axis abolished these neuroprotective effects. METTL3-mediated m6A modification of lncRNA-AU020206 restrained ferroptosis and neuronal injury in cerebral I/R by maintaining the stability of the SLC7A11/GPX4 axis via interactions with YTHDC2. Targeting this epitranscriptomic signalling pathway may represent a promising therapeutic strategy for the treatment of ischemic stroke and related neurological disorders.