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Liver sinusoidal endothelial cells (LSECs) play a regulatory role in hepatic stellate cells (HSCs) activation through paracrine signaling; therefore, maintaining the physiological phenotype of LSECs is critical for antifibrotic intervention. Spermidine (SPD) has been recognized for its antifibrotic properties; however, its impact on LSECs' function and the underlying mechanism remains largely unknown. In this study, analysis of NHANES data revealed an inverse association between dietary SPD intake and fibrosis risk. Consistently, in vivo and in vitro models demonstrated that SPD significantly ameliorated LSECs dysfunction and attenuated fibrosis progression. Through an integrative analysis incorporating proteomics, public single-cell datasets, and machine-learning prioritization, we identified LSECs-derived biglycan (BGN) as a principal target of SPD; notably, BGN overexpression diminished the capacity of SPD to restore LSECs function and facilitated HSCs activation. Mechanistically, SPD activated NRF2 to increase UBE2G2 expression, thereby enhancing UBE2G2-dependent ubiquitination and degradation of BGN. UBE2G2 knockdown reversed SPD-induced BGN downregulation, subsequently exacerbating LSECs capillarization and enhancing HSCs activation. Furthermore,\n                    <jats:italic>Bgn<\/jats:italic>\n                    overexpression in the CCl\n                    <jats:sub>4<\/jats:sub>\n                    -induced mouse model markedly attenuated the ability of SPD to improve LSECs dysfunction and its antifibrotic efficacy. In conclusion, our findings uncover a novel mechanism whereby SPD ameliorates LSECs dysfunction and suppresses fibrosis progression by modulating LSECs-derived BGN, suggesting a new therapeutic strategy for liver fibrosis.\n                  <\/jats:p>","DOI":"10.1038\/s41420-026-03129-4","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:55:19Z","timestamp":1778172919000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spermidine suppresses liver fibrosis by remodeling the communication signal between liver sinusoidal endothelial cells and hepatic stellate cells"],"prefix":"10.1038","volume":"12","author":[{"given":"Cheng","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyue","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9340-1728","authenticated-orcid":false,"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8344-9298","authenticated-orcid":false,"given":"Zhi","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"3129_CR1","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41575-023-00807-x","volume":"20","author":"L Hammerich","year":"2023","unstructured":"Hammerich L, Tacke F. 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HYPERLINK \"mailto:yangyangxd95@163.com\"yangyangxd95@163.com. However, according to institutional requirements and to ensure accurate author affiliation indexing, we would like Dr. Yang Yang\u2019s affiliation to be displayed as: Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.","order":9,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The experimental animals were conducted according to the Ethics Committee of Chongqing Medical University (License No. IACUC-SAHCQMU-2025-0142).","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"287"}}