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However, the harsh microenvironment of degenerative IVDs increases apoptosis in endogenous and transplanted NPSCs, limiting the effectiveness of NPSC\u2010based therapies. Mitochondria\u2010associated ER membrane (MAM) facilitates communication between mitochondria and ER and is critical for cellular homeostasis. PACS\u20102 is a central regulator of MAM homeostasis. It is found that MAM structure is disrupted in degenerative human and rat IVDs and in NPSCs exposed to an acidic environment, coinciding with reduced PACS\u20102 expression and increased apoptosis. In addition, Pacs\u20102 knockout mice with IDD displayed accelerated degeneration, accompanied by the exacerbation of ER stress, mitochondrial dysfunction, and apoptosis. Mechanistically, PACS\u20102 suppresses phosphorylation and nuclear translocation of the transcription factor SP1, thereby downregulating its downstream target LRRK2. This reduces LRRK2\u2010mediated ubiquitination and degradation of Mfn2 through the JNK pathway, preserving MAM integrity and promoting NPSC survival. In vivo, transplantation of Pacs\u20102\u2013overexpressing NPSCs improved cell survival and enhanced IVD repair in a degenerative model. These findings demonstrate that PACS\u20102 supports NPSC\u2010mediated IVD regeneration by maintaining MAM integrity via the SP1\/LRRK2\/Mfn2 axis, offering potential therapeutic targets for IDD.<\/jats:p>","DOI":"10.1002\/advs.202511781","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T13:30:07Z","timestamp":1762349407000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["PACS\u20102 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1\/LRRK2\/Mfn2 Axis"],"prefix":"10.1002","volume":"13","author":[{"given":"Liang","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Orthopedics and Spine Surgery The First Affiliated Hospital of Anhui Medical University  Hefei 230022 China"},{"name":"Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair The First Affiliated Hospital of Anhui Medical University  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