N6-methyladenosine and intervertebral disc degeneration: Advances in detection and pathological insights

Abstract

Intervertebral disc (IVD) degeneration (IDD) is a progressive condition characterized by the deterioration of the intervertebral discs, which serve as cushions between the vertebrae in the spinal column. This degeneration is often associated with aging and can be influenced by various factors, including genetics, mechanical stress, and lifestyle choices. N⁶-methyladenosine (m⁶A) modification has emerged as a critical post-transcriptional regulatory mechanism that influences various biological processes, including cellular differentiation, proliferation, and response to stress. Recent studies suggest that m⁶A modification play significant roles in the pathophysiology of IDD. The dysregulation of m⁶A methylation is linked to the altered expression of genes involved in inflammation, oxidative stress, extracellular matrix remodeling, regulated cell death including apoptosis, autophagy, pyroptosis and ferroptosis, all of which contribute to the IDD. In this review, we summarize the advanced detection technology of m⁶A and the roles of m⁶A in pathological process of IDD, to provide new insights into the molecular mechanisms underlying IDD and identify novel therapeutic targets for intervention.

The translational potential of this article: This work underscores the diagnostic and therapeutic potential of targeting m⁶A mechanism in IDD. Clinically, m6A regulators may serve as biomarkers for early IDD detection or progression monitoring. Therapeutically, small-molecule modulators of m⁶A writers/erasers or RNA-based strategies could restore ECM homeostasis, mitigate inflammation, and prevent IVD cell death. Furthermore, advanced m⁶A mapping technologies may enable personalized interventions by decoding patient-specific epitranscriptomic profiles. These insights bridge molecular mechanisms to clinical innovation, offering novel avenues for IDD treatment and regenerative therapies.

Keywords: Cellular metabolism; Extracellular matrix metabolism; Intervertebral disc degeneration; Oxidative stress; Regulated cell death; m6A modification.

Graphical abstract

Fig. 1

Schematic diagram of healthy IVD, degenerated IVD, and pathological microenvironment.

Fig. 2

The composition and function mechanism of m⁶A methylation. m⁶A methylation, a highly conserved RNA modification mechanism, is dynamically regulated by three key protein groups: writers (including METTL3, METTL14, WTAP, ZC3H13, VIRMA, RBM15 and so on.) that catalyze methylation; erasers (FTO and ALKBH5) responsible for demethylation; readers (YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3) that recognize m⁶A marks and mediate downstream effects on RNA fate. This modification system orchestrates multiple RNA bioprocesses, including RNA splicing, transcript processing, translation efficiency modulation, and degradation control, through its dynamic and reversible regulatory network.

Fig. 3

Schematic diagrams of the mechanism of m⁶A methylation detection based on antibody method. (A) m⁶A-seq/MeRIP-seq technology. (B) m⁶A-seq technology. (C) m⁶A-miCLIP-seq technology. (D) m⁶A-LAIC-seq technology.

Fig. 4

Schematic diagrams of the mechanism of m⁶A methylation detection based on chemical method. (A) m⁶A-seal-seq technology. (B) m⁶A-SAC-seq technology. (C) m⁶A-Lable-seq technology. (D) m⁶A-GLORI-seq technology.

Fig. 5

Schematic diagrams of the mechanism of m⁶A methylation detection based on enzymatic method. (A) m⁶A-MAZTER-seq technology. (B) m⁶A-REF-seq technology. (C) m⁶A-DART-seq technology.

Fig. 6

Functions of m⁶A and IDD links on inflammation, oxidative stress, ECM metabolism, regulated cell death, cell senescence, and signal pathway. In different biological processes, various m⁶A methyltransferases or demethylases undergo changes, which subsequently affect downstream molecular alterations and ultimately influence the progression of IDD. (a) Functions of m⁶A and IDD links on inflammation. The characteristic of IDD is the elevated levels of inflammatory cytokines TNF-α, IL-6 and IL-1β secreted by IVD cells themselves. (b) Functions of m⁶A and IDD links on oxidative stress. (c) Functions of m⁶A and IDD links on ECM metabolism. (d) Functions of m⁶A and IDD links on regulated cell death. (e) Functions of m⁶A and IDD links on cell senescence. (f) Functions of m⁶A and IDD links on signal pathway. The red arrow indicates upregulation of molecular expression, while the green arrow indicates downregulation of molecular expression.