Regulation of diabetic disc degeneration: The role of AGEAT/miR-204-5p/Mapk4 axis in nucleus pulposus cells' mitochondrial function and apoptosis.

Chronic low back pain associated with intervertebral disc degeneration (IVDD) is significantly aggravated in patients with diabetes mellitus (DM); however, the underlying molecular mechanisms remain unclear. This study explored the role of the long non-coding RNA AGEAT (AGE-associated transcript) in the pathogenesis of DM-associated IVDD. Whole-transcriptome sequencing of rat nucleus pulposus cells (NPCs) treated with advanced glycation end products (AGEs) revealed a time-dependent upregulation of AGEAT. AGEAT overexpression induced NPC apoptosis, mitochondrial dysfunction, and extracellular matrix (ECM) degradation. Mechanistically, RNA fluorescence in situ hybridization localized AGEAT to the cytoplasm, where it acted as a competing endogenous RNA (ceRNA) by directly binding miR-204-5p, thereby relieving repression of its target Mapk4. Silencing AGEAT via siRNA significantly reduced apoptosis, restored mitochondrial function, and preserved ECM integrity. In vivo, intra-discal injection of AAV-sh-AGEAT in diabetic IVDD rats significantly improved disc integrity, as evidenced by a reduction in MRI Pfirrmann grade and histological preservation of NPC density and collagen II content. Collectively, these findings establish AGEAT as a key ceRNA that exacerbates diabetic IVDD via the miR-204-5p/Mapk4 axis, promoting NPC apoptosis, mitochondrial dysfunction, and ECM degradation. Targeting this pathway-through AGEAT silencing or miR-204-5p activation-represents a promising therapeutic strategy for mitigating diabetes-associated disc degeneration. This study reveals the critical role of the AGEAT/miR-204-5p/Mapk4 axis in the progression of DM-associated IVDD, suggesting a potential therapeutic strategy for its treatment.