ArticleJournal of orthopaedic surgery and research2026
HDAC9 drives intervertebral disc degeneration by potentiating STAT1-mediated senescence and inflammation.
Article in Journal of orthopaedic surgery and research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundIntervertebral disc degeneration is a leading cause of chronic low back pain, characterized by cellular senescence, extracellular matrix disintegration, and chronic inflammation. However, the key epigenetic regulators that orchestrate senescence and the resultant inflammatory cascade in disc degeneration remain poorly understood.
objectiveThis study aimed to investigate the pathological role and molecular mechanism of HDAC9 in IDD.
methodsWe analyzed HDAC9 expression in aged degenerative discs. Using siRNA-mediated knockdown in primary cells, we assessed senescence, ECM, and inflammation. The mechanism was probed via co-immunoprecipitation, transcriptomics, and ELISA.
resultsHDAC9 expression was significantly upregulated in aged degenerative discs, correlating with enhanced cellular senescence and tissue destruction. Transcriptomic analysis revealed a profound pro-inflammatory and senescent signature in aged discs, with marked activation of the STAT1 signaling pathway. Knockdown of HDAC9 in aged cells attenuated senescence, reduced the expression of senescence markers and matrix catabolic enzyme, rescued proliferation deficits, and mitigated oxidative stress. Mechanistically, HDAC9 physically interacted with STAT1, and its knockdown decreased STAT1 phosphorylation. Both HDAC9 and STAT1 knockdown significantly suppressed the secretion of IL-6, TNF-α. Furthermore, classical STAT1 target genes were upregulated in aged discs.
conclusionOur findings demonstrate that HDAC9 is a critical epigenetic driver of age-related IDD. It promotes cellular senescence and a pro-inflammatory microenvironment by interacting with and activating the STAT1 signaling pathway. Targeting the HDAC9-STAT1 axis may represent a novel therapeutic strategy for mitigating disc degeneration.
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