METTL3-mediated m⁶A modification promotes intervertebral disc degeneration

N⁶-methyladenosine (m⁶A) modification is a prevalent RNA modification in epigenetics. METTL3, acting as the principal methyltransferase responsible for catalysing m⁶A, is regarded as a master regulator of this RNA modification. Nonetheless, the complex roles and underlying mechanisms of m⁶A in relation to intervertebral disc degeneration (IDD) are yet to be fully elucidated. In light of this, this study aimed to explore the intricate functions and mechanisms of METTL3-mediated m⁶A modification in IDD.

Our previous batch of RNA sequencing data (GSE167199) and public single-cell data (GSE165722) were utilized to probe the relationship between m⁶A-related genes and IDD. m⁶A quantification, RNA m⁶A immunoblotting, quantitative real-time PCR, western blot and immunofluorescent staining were used to validate the levels of m⁶A modification and expression of m⁶A-related genes in nucleus pulposus (NP) tissues and cells. Moreover, gain- and loss-of-function experiments in NP cells were conducted to explore the impact of METTL3 on IDD. In vivo, the effects of METTL3 inhibition and miR-338-3p suppression on IDD progression were assessed.

A significant association between METTL3-mediated m⁶A modification and IDD was identified. Overexpressing METTL3 induced apoptosis, accelerated senescence and inhibited matrix synthesis in NP cells. Additionally, METTL3-mediated m⁶A modification could expedite the production and maturation of pri-miR-338-3p in NP cells via DGCR8. In vivo, inhibiting METTL3 mitigated IDD progression, while suppressing miR-338-3p notably alleviated IDD during METTL3 overexpression.

This study reveals that targeting METTL3 attenuates IDD progression through the METTL3-m⁶A-miR-338-3p axis, thereby highlighting the therapeutic potential of METTL3 inhibition for IDD. Future studies should prioritize the development of biomaterial delivery systems for METTL3 inhibitors to ensure both therapeutic protection and sustained, site-specific drug release.