SETD1A Regulates Glycolysis and Senescence of Nucleus Pulposus Cells via H3K4me3–HELZ2/PPARα‐HIF1α Axis to Drive Intervertebral Disc Degeneration

Intervertebral disc degeneration (IDD) is a major cause of lower back pain, but its molecular mechanisms remain unclear. Epigenetic regulation is critical in IDD pathogenesis. This study explored the roles of SET domain-containing 1A (SETD1A) and histone H3 lysine 4 trimethylation (H3K4me3) in IDD. Using human nucleus pulposus (NP) tissues, animal models, cultured nucleus pulposus cells (NPCs), and high-throughput sequencing, we found that H3K4me3 was significantly decreased in degenerative NP tissues. H3K4me3 loss promoted NPC senescence, and SETD1A acted as a key upstream regulator. SETD1A knockdown accelerated NPCs senescence and aggravated IDD, whereas SETD1A overexpression exerted protective effects. Mechanistically, SETD1A downregulation reduced H3K4me3 enrichment at the helicase with zinc finger 2 (HELZ2) promoter, inhibiting HELZ2 transcription and HELZ2/peroxisome proliferator-activated receptor alpha (PPARα) complex function. This cascade downregulated hypoxia-inducible factor 1-alpha (HIF1α), impaired glycolytic metabolism, and induced NPCs senescence. SETD1A serves as a key epigenetic regulator via the H3K4me3-HELZ2/PPARα-HIF1α axis, representing a promising therapeutic target for IDD.