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Epigenetic regulation is critical in IDD pathogenesis. This study explored the roles of SET domain\u2010containing 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\u2010throughput 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\u2010activated receptor alpha (PPAR\u03b1) complex function. This cascade downregulated hypoxia\u2010inducible factor 1\u2010alpha (HIF1\u03b1), impaired glycolytic metabolism, and induced NPCs\u00a0senescence. SETD1A serves as a key epigenetic regulator via the H3K4me3\u2013HELZ2\/PPAR\u03b1\u2013HIF1\u03b1 axis, representing a promising therapeutic target for IDD.<\/jats:p>","DOI":"10.1002\/advs.75105","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T03:51:23Z","timestamp":1775015483000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SETD1A Regulates Glycolysis and Senescence of Nucleus Pulposus Cells via H3K4me3\u2013HELZ2\/PPAR\u03b1\u2010HIF1\u03b1 Axis to Drive Intervertebral Disc Degeneration"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiawei","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Orthopedics Xinqiao Hospital Army Medical University  Chongqing P. R. 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