The m⁶A methyltransferase METTL3 in intervertebral disc degeneration: from molecular mechanisms to therapeutic...

Intervertebral disc degeneration (IDD) is the fundamental pathological process underlying low back pain, a major cause leading to disability worldwide. As the most prevalent methylation modification in eukaryotic RNA molecules, N6-methyladenosine (m⁶A) is involved in various diseases and cellular processes by regulating RNA fate. Methyltransferase-like protein 3 (METTL3) is the sole catalytic component of the methyltransferase complex and mediates m⁶A deposition on target RNAs. METTL3 is ubiquitously expressed and modulated by a variety of factors at the transcriptional and post-transcriptional levels. METTL3 expression is significantly increased in degenerative nucleus pulposus tissue and shows a positive correlation with degeneration degree. Importantly, recent studies have demonstrated that METTL3-mediated m⁶A modification is able to promote the progression of IDD through multiple approaches, including extracellular matrix metabolism imbalance, inflammatory response, nucleus pulposus cell senescence and apoptosis, and mitochondrial dysfunction. Thus, METTL3 could represent a promising therapeutic target for IDD. This review systematically summarizes the latest advances regarding the role of METTL3 in IDD and underlying molecular mechanisms, and also highlights its potential translational implications.