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Every-other-day fasting (EODF) has shown neuroprotective potential, but the mechanisms underlying its effects in SCI remain unclear. We investigated whether EODF prehabilitation attenuates SCI-associated secondary injury through SREBF1-associated metabolic\u2013immune remodeling. Female C57BL\/6\u00a0J mice underwent EODF for 4\u00a0weeks before SCI induction, and adeno-associated virus-mediated SREBF1 knockdown was used to assess the functional contribution of SREBF1. EODF was well tolerated, significantly improved locomotor recovery, reduced lesion cavity formation, and attenuated histopathological damage after SCI. EODF also had stage-dependent effects on SREBF1 expression, suppressing its aberrant early protein elevation while promoting coordinated regulation at later stages. In parallel, EODF partially restored altered omega-3 and omega-6 fatty acid profiles, attenuated TLR4\/MyD88 signaling, reduced TNF-\u03b1, increased IL-10, shifted macrophage\/microglia-associated markers toward a less proinflammatory profile, and reduced the proportion of TUNEL-positive cells. These protective effects were markedly attenuated by SREBF1 knockdown. Overall, our findings indicate that EODF prehabilitation mitigates SCI-associated secondary injury and support SREBF1-associated metabolic\u2013immune remodeling as a functionally relevant mechanism underlying this protection. The results further suggest that temporal regulation of metabolic\u2013inflammatory coupling may contribute to spinal cord resilience after injury.<\/jats:p>","DOI":"10.1007\/s12035-026-06139-6","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:58:39Z","timestamp":1787003919000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Every-Other-Day Fasting Prehabilitation Attenuates Secondary Injury Following Spinal Cord Injury and Is Associated with Stage-Dependent SREBP1-Related Metabolic\u2013Immune Remodeling"],"prefix":"10.1007","volume":"63","author":[{"given":"Yinuo","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nianyi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"issue":"6","key":"6139_CR1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.18468","volume":"7","author":"RH Jaffe","year":"2024","unstructured":"Jaffe RH, Coyte PC, Chan BC, Hancock-Howard RL, Malhotra AK, Ladha K, Wilson JR, Witiw CD (2024) Traumatic cervical spinal cord injury and income and employment status. 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