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This study untangles the synergistic multi-mechanistic effects of the natural flavonoid apigenin in ameliorating this pathological process. Utilizing a murine sepsis model and Caco-2 cell line, we systematically investigated the impact of apigenin on intestinal barrier function. Apigenin treatment (50\u00a0mg\/kg) markedly improved intestinal barrier integrity, as shown by reduced serum FITC-dextran levels and restored expression of tight junction proteins Occludin, Claudin-1, and ZO-1. The compound simultaneously attenuated systemic inflammation by lowering IL-6 and TNF-\u03b1 levels. Network pharmacology and molecular docking identified AKT1 and MMP-9 as key molecular targets of apigenin, which was experimentally validated through observed suppression of MMP-9 and COX-2 protein expression. These results demonstrate apigenin\u2019s capacity to preserve intestinal barrier function during sepsis through coordinated anti-inflammatory and barrier-repair mechanisms.<\/jats:p>","DOI":"10.1186\/s12876-025-04196-0","type":"journal-article","created":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T09:45:54Z","timestamp":1756547154000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Apigenin mitigates intestinal barrier dysfunction in sepsis by modulating the AKT signaling pathway"],"prefix":"10.1186","volume":"25","author":[{"given":"Zheng","family":"Lijun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Liping","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Dandan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Wenjie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Renjie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Xueyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che","family":"Wenqing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"issue":"2","key":"4196_CR1","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1093\/ndt\/gfx076","volume":"33","author":"JW Song","year":"2018","unstructured":"Song JW, Zullo J, Lipphardt M, Dragovich M, Zhang FX, Fu B, et al. 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