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While mitochondrial transplantation (MT) is a promising strategy, its therapeutic potency remains limited. This study identifies the transcription factor Engrailed-1 (En-1) as a key regulator of mitochondrial homeostasis and a potential enhancer of MT. En-1 expression is significantly downregulated in SCI\/RI models, whereas its restoration via hypoxic preconditioning or overexpression markedly improves neuronal survival. Mechanistically, En-1 stabilizes mitochondrial membrane potential, attenuates reactive oxygen species (ROS) production, and inhibits apoptosis by transcriptionally upregulating PDGFC. Mitochondria harvested from En-1-overexpressing cells (OE-En1-Mito) exhibit superior bioenergetic profiles and rapid neuronal uptake compared to unmodified mitochondria. In vitro, OE-En1-Mito increased ATP production and antioxidant activity; in vivo, transplantation preserved neuronal integrity and improved motor recovery in SCI\/RI rats. Notably, silencing PDGFC in donor mitochondria abolished these neuroprotective benefits. Thus, En-1-modified MT provides superior neuroprotection for SCI\/RI by leveraging the En-1\/PDGFC axis.<\/jats:p>","DOI":"10.1038\/s42003-026-10171-6","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:53:15Z","timestamp":1778172795000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engrailed-1 potentiates mitochondrial transplant neuroprotection in spinal cord ischemia-reperfusion injury"],"prefix":"10.1038","volume":"9","author":[{"given":"Wei","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxiang","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7937-6363","authenticated-orcid":false,"given":"Enyi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"10171_CR1","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1016\/j.athoracsur.2020.12.028","volume":"113","author":"Z Khachatryan","year":"2022","unstructured":"Khachatryan, Z., Haunschild, J., von Aspern, K., Borger, M. 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