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However, the mechanisms regulating senescence in the intervertebral disc (IVD) and other tissues\/diseases remain poorly understood. Recently, ZNF865 (BLST) was identified as a previously uncharacterized zinc finger protein, that regulates a wide array of genes related to protein processing, cell senescence and DNA damage repair. Here, we show that ZNF865 expression decreases with age and pathology in human and mouse IVD samples. Utilizing CRISPR-guided gene modulation, we show that ZNF865 is necessary for healthy cell function and is a critical protein in regulating senescence and DNA damage in IVD cells, with implications for a wide range of tissues and organs. We also demonstrate that downregulation of ZNF865 induces senescence in asymptomatic human nucleus pulposus (NP) cells. Conversely, restoration in degenerative NP cells mitigates senescence, SASP expression and DNA damage, enhances ECM anabolism, and restores chromatin accessibility and gene expression to a healthy state. In vivo, CRISPRi of ZNF865 induces disc degeneration and painful behaviors. Collectively, our findings establish ZNF865 as a novel regulator of genome stability and a potential therapeutic target for mediating senescence\/DNA damage in aging related diseases.<\/jats:p>","DOI":"10.1101\/2025.06.13.659603","type":"posted-content","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T02:00:10Z","timestamp":1750298410000},"source":"Crossref","is-referenced-by-count":2,"title":["ZNF865 (BLST) a Novel Regulator of DNA Damage and Cell Senescence in Back Pain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7533-8645","authenticated-orcid":false,"given":"Christian","family":"Lewis","sequence":"first","affiliation":[{"name":"University of Utah, Department of Biomedical Engineering, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1720-6545","authenticated-orcid":false,"given":"Hunter","family":"Levis","sequence":"additional","affiliation":[{"name":"University of Utah, Department of Biomedical Engineering, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonah","family":"Holbrook","sequence":"additional","affiliation":[{"name":"University of Utah, Department of Biomedical Engineering, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6570-1789","authenticated-orcid":false,"given":"Jacob T.","family":"Polaski","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy D.","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai, Department of Orthopaedics, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh","family":"Mizels","sequence":"additional","affiliation":[{"name":"University of Utah, Department of Orthopaedic Surgery, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Czachor","sequence":"additional","affiliation":[{"name":"University of Utah, Department of Biomedical Engineering, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7806-6606","authenticated-orcid":false,"given":"Sarah E.","family":"Gullbrand","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Department of Orthopaedic Surgery, Philadelphia, PA"},{"name":"Corporal Michael J. 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