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Bull."],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Activation of spinal cord neural stem cells (NSCs) and subsequent neurogenesis holds a promising alternative for spinal cord injury (SCI) repair. Our previous study demonstrated that complement C3a, derived from reactive astrocytes, inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1 (UCHL1)-proteasome system post-SCI. However, the potential molecular mechanism by which C3a modulates NSC activation\n                    <jats:italic>via<\/jats:italic>\n                    this pathway remains unclear. Here, we revealed that C3a\/C3a receptor (C3aR) signaling activated NF-\u03baB p65, which in turn inhibited Nrf2 activity and UCHL1 expression, resulting in diminished proteasome activity and the accumulation of protein aggregates, and ultimately impaired NSC activation. Both knockdown of NF-\u03baB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity\n                    <jats:italic>in vitro<\/jats:italic>\n                    , promoting NSC activation by enhancing protein aggregate clearance. Mechanistically, we found that NF-\u03baB p65 regulated Nrf2 activity through a dual mechanism: (1) promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2; (2) inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation. Using the dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) analysis, we further identified UCHL1 as a direct transcriptional target of Nrf2. Importantly,\n                    <jats:italic>in vivo<\/jats:italic>\n                    experiments using SCI mice confirmed that either C3aR blockade, NF-\u03baB p65 knockdown, or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation. Together, this study uncovers the C3a-NF-\u03baB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI. This may provide novel molecular targets and intervention strategies for SCI repair.\n                  <\/jats:p>","DOI":"10.1007\/s12264-025-01488-z","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T18:51:39Z","timestamp":1759517499000},"page":"153-174","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Complement C3a Suppresses Spinal Cord Neural Stem Cell Activation by Inhibiting UCHL1 via the NF-\u03baB p65\/Nrf2 Pathway"],"prefix":"10.1007","volume":"42","author":[{"given":"Lu","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YaQin","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1525-9969","authenticated-orcid":false,"given":"Feng-Quan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2664-8254","authenticated-orcid":false,"given":"David Y. 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