ACSL4‐Dependent Lysosomal Lipid Peroxidation Links WTAP‐Mediated m6A Modification to Intervertebral Disc Degeneration

Abstract

ABSTRACT Intervertebral disc degeneration (IVDD) constitutes a leading contributor to the development of low back pain, yet its epigenetic regulation remains unclear. Here, we identify a mechanism by which N6‐methyladenosine (m6A) RNA modification contributes to lysosomal membrane permeabilization (LMP) in IVDD. Single‐cell transcriptomic analysis of human nucleus pulposus (NP) tissues shows an enrichment of lysosomal pathway genes in severely degenerated NP cells, along with LMP and disrupted mitophagy flux. We further show that interleukin‐1β (IL‐1β) induces LMP, disrupts mitophagic flux, and causes mitochondrial dysfunction in NP cells. IL‐1β enhances WTAP, a key part of the m6A methyltransferase complex, essential for m6A methylation of ACSL4 mRNA. The m6A reader IGF2BP2 then binds and stabilizes the modified transcripts, leading to increased ACSL4 expression. Consequently, lysosomal lipid peroxidation is promoted through accumulation of arachidonic acid‐containing phospholipids, resulting in LMP. In a rat model, intradiscal delivery of AAV9‐shWTAP attenuates disc degeneration, with preserved disc height, improved extracellular matrix synthesis, and restored lysosomal function and mitophagy. Our study reveals the WTAP/ACSL4/IGF2BP2 axis as a mediator of IL‐1β‐induced LMP via m6A‐dependent lipid peroxidation, highlighting a potential therapeutic target for IVDD.