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The endoplasmic reticulum (ER) and mitochondria are crucial regulators of the cell death signaling pathway, and their involvement in IVDD has been reported. However, the specific role of ER stress (ERS) and ER\u2010mitochondria interaction in compression\u2010induced programmed necrosis of NP cells remains unknown. Our studies revealed that compression enhanced ERS and the association between ER and mitochondria in NP cells. Suppression of ERS via 4\u2010phenylbutyrate (4\u2010PBA) or ER\u2010mitochondrial Ca<jats:sup>2+<\/jats:sup> crosstalk by inhibiting the inositol 1,4,5\u2010trisphosphate receptor, glucose\u2010regulated protein 75, voltage\u2010dependent anion\u2010selective channel 1 complex (IP<jats:sub>3<\/jats:sub>R\u2013GRP75\u2013VDAC1 complex) protected NP cells against programmed necrosis related to the poly(ADP\u2010ribose) polymerase (PARP) apoptosis\u2010inducing factor (AIF) pathway. Moreover, excessive reactive oxygen species are critical activators of ERS, leading to mitochondrial Ca<jats:sup>2+<\/jats:sup> accumulation and consequent programmed necrosis. These data indicate that ERS and ER\u2010mitochondrial Ca<jats:sup>2+<\/jats:sup> crosstalk may be potential therapeutic targets for the treatment of IVDD\u2010associated disorders. These findings provide new insights into the molecular mechanisms underlying IVDD and may provide novel therapeutic targets.<\/jats:p>","DOI":"10.1155\/2021\/8810698","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T02:50:06Z","timestamp":1615949406000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Reactive Oxygen Species Regulate Endoplasmic Reticulum Stress and ER\u2010Mitochondrial Ca<sup>2+<\/sup> Crosstalk to Promote Programmed Necrosis of Rat Nucleus Pulposus Cells under 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