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Nucleus pulposus (NP) cell senescence is a significant pathological manifestation of IVDD. Here, we constructed a hypoxia-induced NP cell model to clarify the mechanisms by which S-palmitoylation is involved in NPC senescence. The IP3R S-palmitoylation of NP cells was significantly reduced under hypoxic conditions, contributing to abnormalities in mitochondria-associated membranes (MAMs). The study found that cellular expression of Bax, Bcl-2, Cleaved-Caspase8, Cleaved-Caspase3, MMP3, and MMP13 was promoted, while COL2 and AGG expression was inhibited. The up-regulated palmitoylation-modifying enzyme DHHC6 can promote IP3R S-palmitoylation modification and regulate GRP75, VDAC1, Drp1, and Mfn2 expression. It can inhibit apoptosis in NP cells, reduce intracellular calcium and ROS levels, elevate mitochondrial membrane potential, and reduce \u03b3-H2AX expression levels. It also inhibited the protein expression levels of hypoxia-induced apoptosis molecules, matrix-degrading enzymes, and up-regulated extracellular matrix protein expression. These results suggested that hypoxia-induced IP3R depalmitoylation might play a role in structural and functional abnormalities in MAMs, which trigger senescence in NP cells.<\/jats:p>","DOI":"10.1371\/journal.pone.0348801","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T17:39:52Z","timestamp":1779471592000},"page":"e0348801","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["S-palmitoylation regulates the function of the mitochondria-associated endoplasmic reticulum membrane to alleviate the senescence of nucleus pulposus 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