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However, effective treatments remain elusive due to limited knowledge regarding the underlying molecular mechanisms. Itaconic acid, an endogenous metabolite, involved in multiple inflammatory diseases, but its role in sepsis-induced vascular injury remains unclear. The current study investigates the effect of 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconic acid, on sepsis-induced vascular injury and organ damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>An in vitro cell model was established by treating human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) revealed that 4-OI inhibited the LPS-induced increases in TNF-\u03b1, IL-6, and IL-1\u03b2 levels. Cellular reactive oxygen species (ROS) levels, measured using the fluorescent probe DCFH-DA, mitochondrial ROS (mtROS) levels, measured by MitoSOX, and mitochondrial membrane potential (\u0394\u03a8), detected by the fluorescent indicator JC-1, were all reduced following 4-OI treatment. Additionally, mtDNA release, detected by qRT-PCR, were decreased. Mitochondrial morphology, assessed by PK Mito Orange, was preserved by 4-OI treatment. Furthermore, 4-OI suppressed HUVECs apoptosis and pyroptosis, as detected by TUNEL staining and western blotting. 4-OI treatment also significantly inhibited LPS-induced cell adhesion, as shown in THP-1 attachment assay, by decreasing ICAM-1 and VCAM-1 expression. Cell permeability, determined by FITC-Dx-70 leakage, revealed that 4-OI effectively suppressed LPS-induced increases in cell permeability. Furthermore, 4-OI inhibited LPS-induced phosphorylation and internalization of VE-cadherin protein, preserving the adhesion junctions between endothelial cells. Network pharmacology and molecular docking analysis suggested the involvement of TLR4\/MAPK\/NF-\u03baB signaling pathway as a key mechanism by which 4-OI ameliorated sepsis-induced vascular cell inflammation and injury, which was confirmed by western blotting. The in vitro results were subsequently verified in vivo in an LPS-induced sepsis mouse model. 4-OI pretreatment substantially decreased inflammatory cytokine levels in serum and lung tissues, inhibited pulmonary oedema and pulmonary vascular leakage, as evidenced by the wet-to-dry weight ratio and Evans blue staining of lung tissues, and alleviated tissue damage, as shown by histological analysis. Survival analysis indicated that 4-OI post-sepsis treatment improved the overall survival rate in LPS-induced ALI mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>4-OI protects against sepsis-induced vascular injury and tissue damage by suppressing endothelial inflammation, oxidative stress, and preserving endothelial barrier integrity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01160-2","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T06:31:33Z","timestamp":1750055493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["4-Octyl itaconate alleviates endothelial cell inflammation and barrier dysfunction in LPS-induced sepsis via modulating TLR4\/MAPK\/NF-\u03baB signaling"],"prefix":"10.1186","volume":"31","author":[{"given":"Rong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nianhui","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbo","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"issue":"7","key":"1160_CR38","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nri1391","volume":"4","author":"S Akira","year":"2004","unstructured":"Akira S, Takeda K. 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