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How the nervous system responds to the cellular stress imposed by nerve injury and adjunct therapies impacts axon regeneration and functional outcomes. Here, we summarize some of the key primarily axonal and neuronal adaptive stress responses and mechanisms that underlie the ability of peripheral neurons to regenerate an axon. This includes activation of the unfolded protein response and endoplasmic reticulum membrane-associated molecules, namely Luman\/CREB3, a transmembrane basic leucine zipper transcription factor that regulates the encoding of beneficial adaptive stress responses that drive the ability of an injured sensory neuron to regenerate their axon. We also highlight an emerging novel non-invasive strategy, therapeutic acute intermittent hypoxia, that imposes a level of beneficial adaptive stress that can alter gene programs induced by the injury to enhance regeneration in a manner akin to the more invasive yet highly effective electrical nerve stimulation. The ability to manipulate and significantly elevate the intrinsic adaptive stress\/repair responses of injured peripheral neurons holds therapeutic promise, with accumulating evidence supporting its clinical use.<\/jats:p>","DOI":"10.3390\/ijms27146327","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:12:38Z","timestamp":1784257958000},"page":"6327","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Beneficially Stressing the Peripheral Nervous System to Repair"],"prefix":"10.3390","volume":"27","author":[{"given":"Valerie M. K.","family":"Verge","sequence":"first","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"},{"name":"Cameco MS Neuroscience Research Centre, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0948-4948","authenticated-orcid":false,"given":"Zhengxin","family":"Ying","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"},{"name":"Cameco MS Neuroscience Research Centre, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafa A.","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"},{"name":"Cameco MS Neuroscience Research Centre, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1094-6778","authenticated-orcid":false,"given":"Justin M.","family":"Naniong","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"},{"name":"Cameco MS Neuroscience Research Centre, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2250-0725","authenticated-orcid":false,"given":"Joelle R.","family":"Nadeau","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"},{"name":"Cameco MS Neuroscience Research Centre, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovan C. D.","family":"Hasmatali","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"},{"name":"Cameco MS Neuroscience Research Centre, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2510-4662","authenticated-orcid":false,"given":"Miles E.","family":"Magno","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"},{"name":"Cameco MS Neuroscience Research Centre, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6818-7156","authenticated-orcid":false,"given":"Vikram","family":"Misra","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology, WCVM, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6426-1651","authenticated-orcid":false,"given":"Gillian D.","family":"Muir","sequence":"additional","affiliation":[{"name":"Cameco MS Neuroscience Research Centre, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada"},{"name":"Department of Veterinary Biomedical Sciences, WCVM, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1016\/j.injury.2005.10.012","article-title":"Regeneration and repair of peripheral nerves","volume":"36","author":"Johnson","year":"2005","journal-title":"Injury"},{"key":"ref_2","first-page":"1","article-title":"Hallmarks of peripheral nerve injury and regeneration","volume":"201","author":"Krishnan","year":"2024","journal-title":"Handb. 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