How a Fat-Processing Enzyme Links RNA Modification to Breakdown of Spinal Disc Tissue

N6-methyladenosine (m6A) RNA modification may contribute to lysosomal membrane permeabilization associated with intervertebral disc degeneration (IVDD).

• Severe degeneration of human nucleus pulposus cells is linked to an increase in lysosomal pathway genes and disrupted mitophagy.
• Interleukin-1β (IL-1β) triggers lysosomal membrane permeabilization and mitochondrial dysfunction in nucleus pulposus cells.
• IL-1β enhances the expression of WTAP, which is crucial for the m6A methylation of ACSL4 mRNA.
• The m6A reader IGF2BP2 stabilizes modified ACSL4 transcripts, leading to increased ACSL4 expression.
• Elevated ACSL4 expression promotes lysosomal lipid peroxidation through the accumulation of specific phospholipids, resulting in lysosomal membrane permeabilization.
• In a rat model, targeting WTAP with AAV9-shWTAP reduces disc degeneration and restores lysosomal function.

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