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Endoplasmic reticulum (ER) homeostasis is essential to counteract neuronal apoptosis. ER stress, an integral part of ER homeostasis, was observed in a rat model of chronic cervical cord compression in our previous study. However, the correlation between ER homeostasis and CSM remains unknown. The antioxidant melatonin is known to exert therapeutic effects in acute spinal cord injury, but the specific effects and their potential mechanisms in the pathological processes of CSM require further exploration. The present study hypothesized that ER homeostasis is essential for neuronal apoptosis in the CSM and that melatonin maintains this homeostasis. The results showed that ER stress led to neuronal apoptosis in rats with chronic cervical cord compression. Conversely, melatonin attenuates protein kinase R\u2010like ER kinase\u2010eukaryotic initiation factor 2\u03b1\u2010C\/EBP\u2010homologous protein, inositol\u2010requiring enzyme 1, and transcription factor 6 signaling pathways to release ER stress and prevents Bax translocation to the mitochondrion, thereby promoting motor recovery and protecting neurons in vivo. It also rescued primary rat cortical neurons from ER stress\u2010induced glutamate toxicity in vitro. Moreover, melatonin remodels the ER morphology and restores homeostasis via ER\u2010phagy in injured neurons. FAM134B, CCPG1, RTN3, and Sec. 62 are four known ER\u2010phagy receptors. In this study, Sec. 62 was identified as a key melatonin factor in promoting ER\u2010phagy and restoring ER homeostasis in damaged neurons in vivo and in vitro. In conclusion, melatonin suppresses neuronal apoptosis by reducing ER stress and promoting ER\u2010phagy to restore ER morphology and homeostasis. The current results suggested that melatonin is a promising treatment for CSM owing to its restorative effect on ER homeostasis; however, well\u2010designed randomized controlled trials must be carried out to further investigate its clinical effects.<\/jats:p>","DOI":"10.1111\/jpi.12859","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T02:49:52Z","timestamp":1675392592000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Melatonin restores endoplasmic reticulum homeostasis to protect injured neurons in a rat model of chronic cervical cord compression"],"prefix":"10.1111","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0410-7900","authenticated-orcid":false,"given":"Min","family":"Yao","sequence":"first","affiliation":[{"name":"Spine Disease Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine Shanghai China"},{"name":"Key Laboratory of 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