{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:52:28Z","timestamp":1781823148051,"version":"3.54.5"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are critical in secondary spinal cord injury (SCI), but their systematic characterization and link to immune infiltration remain unclear. This study aimed to identify key ERS\/UPR-related genes and their association with the immune microenvironment to find robust biomarkers for SCI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed bulk RNA-seq data (GSE151371) to identify differentially expressed genes (DEGs), followed by pathway enrichment analyses. Machine learning (SVM-RFE) and protein-protein interaction networks were used to screen for hub genes. The identified hub genes were validated using an independent cohort (GSE5296), single-cell sequencing data (GSE213240), and qRT-PCR in a murine SCI model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 17 ERS-related and 27 UPR-related DEGs, primarily enriched in neuron death pathways. SCI samples showed elevated ERS\/UPR phenotype scores that positively correlated with myeloid cell infiltration. PPI analysis pinpointed\n                      <jats:italic>Dnajc3<\/jats:italic>\n                      and\n                      <jats:italic>Hspa5<\/jats:italic>\n                      as central hub genes. However, multi-level validation confirmed that while Hspa5 was consistently and significantly upregulated across all platforms, Dnajc3 did not show significant differential expression in single-cell sequencing and qRT-PCR validation, thereby limiting its credibility as a direct transcriptional biomarker. A diagnostic nomogram incorporating both genes achieved an AUC of 0.745.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      ERS\/UPR activation is a critical component of the post-SCI transcriptomic response and is closely linked to immune remodeling.\n                      <jats:italic>Hspa5<\/jats:italic>\n                      emerges as a robust and dominant hub gene, representing a promising therapeutic target for SCI.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1833119","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:10:23Z","timestamp":1781820623000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative analysis identifies Hspa5 as a key regulator of the ERS\/UPR-immune axis in spinal cord injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Guoyuan","family":"He","sequence":"first","affiliation":[{"name":"School of Clinical Medicine, Ningxia Medical University","place":["Yinchuan, China"]},{"name":"Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aichun","family":"Yang","sequence":"additional","affiliation":[{"name":"The First Clinical College, The First Affiliated Hospital, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hechun","family":"Xia","sequence":"additional","affiliation":[{"name":"Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University","place":["Yinchuan, China"]},{"name":"Department of Neurosurgery, General Hospital of Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/s41393-022-00795-w","article-title":"Epidemiology of traumatic spinal cord injury: a large population-based study","volume":"60","author":"Barbiellini Amidei","year":"2022","journal-title":"Spinal Cord."},{"key":"B2","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1093\/brain\/awp322","article-title":"Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment","volume":"133","author":"Beck","year":"2010","journal-title":"Brain A J. Neurology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1016\/j.cell.2012.11.012","article-title":"Cleaning up: ER-associated degradation to the rescue","volume":"151","author":"Brodsky","year":"2012","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/415092a","article-title":"IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA","volume":"415","author":"Calfon","year":"2002","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1016\/j.cell.2015.05.025","article-title":"ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis","volume":"161","author":"Cubillos-Ruiz","year":"2015","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.yfrne.2009.05.006","article-title":"Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides","volume":"30","author":"Do Rego","year":"2009","journal-title":"Front. Neuroendocrinol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s41598-023-36258-2","article-title":"Opposite modulation of functional recovery following contusive spinal cord injury in mice with oligodendrocyte-selective deletions of Atf4 and Chop\/Ddit3","volume":"13","author":"Gao","year":"2023","journal-title":"Sci. Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1023\/a:1012487302797","article-title":"Gene selection for cancer classification using support vector machines","volume":"46","author":"Guyon","year":"2002","journal-title":"Mach. Learn."},{"key":"B9","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/16729","article-title":"Erratum: protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase","volume":"397","author":"Harding","year":"1999","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e88","DOI":"10.1371\/journal.pgen.0020088","article-title":"Why do hubs tend to be essential in protein networks?","volume":"2","author":"He","year":"2006","journal-title":"Plos Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4222","DOI":"10.1007\/s12035-023-03814-w","article-title":"Targeted therapy of spinal cord injury: inhibition of apoptosis is a promising therapeutic strategy","volume":"61","author":"He","year":"2024","journal-title":"Mol. Neurobiology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The unfolded protein response and cell fate control","volume":"69","author":"Hetz","year":"2018","journal-title":"Mol. Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nrneurol.2017.99","article-title":"ER stress and the unfolded protein response in neurodegeneration","volume":"13","author":"Hetz","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.lfs.2019.04.022","article-title":"GRP78: a cell's response to stress","volume":"226","author":"Ibrahim","year":"2019","journal-title":"Life Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1186\/s12974-021-02186-z","article-title":"D-dopachrome tautomerase activates COX2\/PGE(2) pathway of astrocytes to mediate inflammation following spinal cord injury","volume":"18","author":"Ji","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"B16","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1159\/000492996","article-title":"Local delivery of \u03b2-Elemene improves locomotor functional recovery by alleviating endoplasmic reticulum stress and reducing neuronal apoptosis in rats with spinal cord injury","volume":"49","author":"Jingyu","year":"2018","journal-title":"Cell. Physiology Biochem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/nrm2941","article-title":"The HSP70 chaperone machinery: j proteins as drivers of functional specificity","volume":"11","author":"Kampinga","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1248\/bpb.26.931","article-title":"Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2","volume":"26","author":"Kaneko","year":"2003","journal-title":"Biol. and Pharm. Bull."},{"key":"B19","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3389\/fncel.2019.00248","article-title":"Regeneration of spinal cord connectivity through stem cell transplantation and biomaterial scaffolds","volume":"13","author":"Katoh","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"683","DOI":"10.3171\/2018.10.SPINE18802","article-title":"Neurological recovery following traumatic spinal cord injury: a systematic review and meta-analysis","volume":"30","author":"Khorasanizadeh","year":"2019","journal-title":"J. Neurosurg. Spine"},{"key":"B21","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.cmet.2012.07.007","article-title":"IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress","volume":"16","author":"Lerner","year":"2012","journal-title":"Cell Metab."},{"key":"B22","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1186\/s12906-022-03780-1","article-title":"Ascorbic acid 6-palmitate modulates microglia M1\/M2 polarization in lipopolysaccharide-stimulated BV-2 cells via PERK\/elF2alpha mediated endoplasmic reticulum stress","volume":"22","author":"Li","year":"2022","journal-title":"BMC Complement. Med. Ther."},{"key":"B23","doi-asserted-by":"publisher","first-page":"636","DOI":"10.4103\/1673-5374.266903","article-title":"Unfolded protein response in myelin disorders","volume":"15","author":"Lin","year":"2020","journal-title":"Neural Regen. Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"24881","DOI":"10.1074\/jbc.M004454200","article-title":"Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum","volume":"275","author":"Liu","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.wneu.2021.07.148","article-title":"Inflammatory response to spinal cord injury and its treatment","volume":"155","author":"Liu","year":"2021","journal-title":"World Neurosurg"},{"key":"B26","doi-asserted-by":"publisher","first-page":"6459585","DOI":"10.1155\/2022\/6459585","article-title":"Mitochondrial-endoplasmic reticulum communication-mediated oxidative stress and autophagy","volume":"2022","author":"Liu","year":"2022","journal-title":"Biomed. Res. Int."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3066","DOI":"10.1101\/gad.1250704","article-title":"CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum","volume":"18","author":"Marciniak","year":"2004","journal-title":"Genes Dev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"17022","DOI":"10.3389\/fneur.2019.00282","article-title":"Traumatic spinal cord injury","volume":"3","author":"Marshall","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1128\/MCB.21.4.1249-1259.2001","article-title":"Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state","volume":"21","author":"Mccullough","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e261","DOI":"10.1038\/cddis.2011.132","article-title":"ER stress activates the NLRP3 inflammasome via an UPR-Independent pathway","volume":"3","author":"Menu","year":"2012","journal-title":"Cell Death and Dis"},{"key":"B31","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1042\/BJ20101569","article-title":"Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting","volume":"434","author":"Ni","year":"2011","journal-title":"Biochem. J."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2134","DOI":"10.1016\/j.ymthe.2019.08.009","article-title":"UTX\/KDM6A deletion promotes recovery of spinal cord injury by epigenetically regulating vascular regeneration","volume":"27","author":"Ni","year":"2019","journal-title":"Mol. Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1146\/annurev-pathol-012513-104649","article-title":"The role of endoplasmic reticulum stress in human pathology","volume":"10","author":"Oakes","year":"2015","journal-title":"Annu. Rev. Pathol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1002\/glia.21191","article-title":"Attenuating the endoplasmic reticulum stress response improves functional recovery after spinal cord injury","volume":"59","author":"Ohri","year":"2011","journal-title":"Glia"},{"key":"B35","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1089\/neu.2011.1940","article-title":"Deletion of the pro-apoptotic endoplasmic reticulum stress response effector CHOP does not result in improved locomotor function after severe contusive spinal cord injury","volume":"29","author":"Ohri","year":"2012","journal-title":"J. Neurotrauma"},{"key":"B36","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1089\/neu.2015.3993","article-title":"Activating transcription Factor-6 alpha deletion modulates the endoplasmic reticulum stress response after spinal cord injury but does not affect locomotor recovery","volume":"35","author":"Ohri","year":"2018","journal-title":"J. Neurotrauma"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3951","DOI":"10.3390\/ijms25073951","article-title":"Intranasal administration of GRP78 protein (HSPA5) confers neuroprotection in a lactacystin-induced rat model of parkinson's disease","volume":"25","author":"Pazi","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1111\/j.1471-4159.2007.04671.x","article-title":"Spinal cord injury induces endoplasmic reticulum stress with different cell\u2010type dependent response","volume":"102","author":"Penas","year":"2007","journal-title":"J. Neurochem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.ceb.2010.09.007","article-title":"The critical role of GRP78 in physiologic and pathologic stress","volume":"23","author":"Pfaffenbach","year":"2011","journal-title":"Curr. Opin. Cell Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.neulet.2018.12.006","article-title":"Local application of MDL28170-loaded PCL film improves functional recovery by preserving survival of motor neurons after traumatic spinal cord injury","volume":"694","author":"Shi","year":"2018","journal-title":"Neurosci. Lett."},{"key":"B41","doi-asserted-by":"publisher","first-page":"794580","DOI":"10.3389\/fimmu.2021.794580","article-title":"Endoplasmic reticulum stress-associated neuronal death and innate immune response in neurological diseases","volume":"12","author":"Shi","year":"2021","journal-title":"Front. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e12992","DOI":"10.1111\/cpr.12992","article-title":"Programmed cell death in spinal cord injury pathogenesis and therapy","volume":"54","author":"Shi","year":"2021","journal-title":"Cell Prolif."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3867","DOI":"10.1002\/jcp.26137","article-title":"Crosstalk of ER stress\u2010mediated autophagy and ERphagy: involvement of UPR and the core autophagy machinery","volume":"233","author":"Song","year":"2018","journal-title":"J. Cell. Physiology"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.3390\/ijms24021307","article-title":"Endoplasmic reticulum stress causing apoptosis in a mouse model of an ischemic spinal cord injury","volume":"24","author":"Soni","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e272","DOI":"10.1038\/cddis.2012.8","article-title":"Activation of the unfolded protein response enhances motor recovery after spinal cord injury","volume":"3","author":"Valenzuela","year":"2012","journal-title":"Cell Death Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: from stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"B47","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3892\/etm.2012.745","article-title":"C\/EBP homologous protein (CHOP) mediates neuronal apoptosis in rats with spinal cord injury","volume":"5","author":"Wang","year":"2013","journal-title":"Exp. Ther. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1186\/s12974-017-1002-7","article-title":"Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization","volume":"14","author":"Wang","year":"2017","journal-title":"J. Neuroinflammation"},{"key":"B49","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1007\/s12035-025-05520-1","article-title":"Tetramethylpyrazine promotes functional recovery after spinal cord injury by regulating 5-Methylcytosine RNA modification via the NSUN2-XBP1 axis","volume":"63","author":"Xiao","year":"2026","journal-title":"Mol. Neurobiol."},{"key":"B50","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.devcel.2007.07.018","article-title":"Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6\u03b1 and XBP1","volume":"13","author":"Yamamoto","year":"2007","journal-title":"Dev. Cell"},{"key":"B51","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/S1097-2765(00)00133-7","article-title":"ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs","volume":"6","author":"Ye","year":"2000","journal-title":"Mol. Cell"},{"key":"B52","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/s0092-8674(01)00611-0","article-title":"XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor","volume":"107","author":"Yoshida","year":"2001","journal-title":"Cell"},{"key":"B53","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/s12974-023-02906-7","article-title":"Unbiased multitissue transcriptomic analysis reveals complex neuroendocrine regulatory networks mediated by spinal cord injury-induced immunodeficiency","volume":"20","author":"Zeng","year":"2023","journal-title":"J. Neuroinflammation"},{"key":"B54","first-page":"287","article-title":"Inflammation and apoptosis in spinal cord injury","volume":"135","author":"Zhang","year":"2012","journal-title":"Indian J. Med. Res."},{"key":"B55","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s12974-019-1468-6","article-title":"Macrophage migration inhibitory factor facilitates prostaglandin E(2) production of astrocytes to tune inflammatory milieu following spinal cord injury","volume":"16","author":"Zhang","year":"2019","journal-title":"J. Neuroinflammation"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1833119\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:10:24Z","timestamp":1781820624000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1833119\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":55,"alternative-id":["10.3389\/fgene.2026.1833119"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1833119","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,19]]},"article-number":"1833119"}}