Knockout of METTL3 promotes neural functional recovery after spinal cord injury in mice via the USP4/YTHDF2 axis

Background Spinal cord injury (SCI) can cause destructive neurological dysfunctions. Objectives The present study investigates the role and mechanism of methyltransferase like 3 (METTL3) in neural functional recovery post-SCI. Results SCI mice showed neurological function impairment, with significantly elevated METTL3 expression and m 6 A content. METTL3 inhibition improved motor and sensory injury in SCI mice, alleviated tissue injury, up-regulated BDNF, GDNF, and IL-10 levels, and down-regulated IL-1β and TNF-α levels. Mechanistically, METTL3 mediated m 6 A modification of USP4 mRNA and enhanced YTHDF2 enrichment on USP4 mRNA, thus reducing USP4 mRNA stability and expression. Combined experiments confirmed that METTL3 exacerbated neurological impairment in SCI mice by reducing USP4 expression. Conclusion METTL3-dominated m 6 A modification enhances YTHDF2 enrichment on USP4 mRNA and thereby reduces USP4 mRNA stability, eventually aggravating neurological impairment in SCI mice.