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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Cyclophosphamide (CP) is a widely used alkylating agent, but its clinical use is limited by drug-induced liver injury (DILI). This study evaluated whether SP-3, a defined polysaccharide from Saposhnikovia divaricata, ameliorates established CP-induced liver injury after injury induction. BALB\/c mice received CP (80 mg\/kg\/day, days 0\u20133), followed by oral SP-3 (50, 100, or 200 mg\/kg\/day, days 4\u201310). Serum biochemistry, histopathology, TUNEL staining, immunohistochemistry, transcriptomics, untargeted metabolomics, RT-qPCR, and PPAR\u03b1 protein expression were assessed. CP caused hepatic injury characterized by increased ALT and AST, histological damage, increased DNA-fragmentation signal, lipid peroxidation, inflammatory-marker expression, and impaired systemic antioxidant indices. SP-3 attenuated these endpoint injury indices, with the medium and high doses showing broadly comparable responses. Multi-omics analyses indicated that SP-3 treatment was associated with partial normalization of lipid metabolism-related transcripts and glycerophospholipid\/fatty acid-related metabolites. PPAR signaling emerged as an enriched pathway, and SP-3 partly restored hepatic PPAR\u03b1 mRNA and protein expression. Collectively, these data support the post-injury therapeutic efficacy of SP-3 against CP-induced liver injury, highlighting its potential role in modulating PPAR\u03b1-related lipid metabolic homeostasis as a promising strategy for drug-induced liver injury management.<\/jats:p>","DOI":"10.3390\/ijms27156841","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:55:11Z","timestamp":1785419711000},"page":"6841","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SP-3 Ameliorates Established Cyclophosphamide-Induced Liver Injury and Is Associated with PPAR-Related Transcriptional and Lipid-Metabolic Changes"],"prefix":"10.3390","volume":"27","author":[{"given":"Caiyi","family":"Ke","sequence":"first","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuechun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaihe","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leixin","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2706-9051","authenticated-orcid":false,"given":"Qun","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/nrclinonc.2009.146","article-title":"Cyclophosphamide and cancer: Golden anniversary","volume":"6","author":"Emadi","year":"2009","journal-title":"Nat. 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