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Here, the antibacterial and anti-inflammatory activities of 2K4L in macrophages, <jats:italic>C. elegans<\/jats:italic> and mice were investigated. The results demonstrated that 2K4L could enter THP-1 cells to kill a multidrug-resistant <jats:italic>Acinetobacter baumannii<\/jats:italic> strain (MRAB 0227) and a sensitive <jats:italic>A. baumannii<\/jats:italic> strain (AB 22933), as well as reduce proinflammatory responses induced by MRAB 0227 by inhibiting NF-\u03baB signaling pathway. Similarly, 2K4L exhibited strong bactericidal activity against <jats:italic>A. baumannii<\/jats:italic> uptake into <jats:italic>C. elegans<\/jats:italic>, extending the lifespan and healthspan of the nematodes. Meanwhile, 2K4L alleviated the oxidative stress response by inhibiting the expression of core genes in the p38 MAPK\/PMK-1 signaling pathway and downregulating the phosphorylation level of p38, thereby protecting the nematodes from damage by <jats:italic>A. baumannii<\/jats:italic>. Finally, in an LPS-induced septic model, 2K4L enhanced the survival of septic mice and decreased the production of proinflammatory cytokines by inhibiting the signaling protein expression of the MAPK and NF-\u03baB signaling pathways and protecting LPS-induced septic mice from a lethal inflammatory response. In conclusion, 2K4L ameliorated LPS-induced inflammation both in vitro and in vivo.<\/jats:p>","DOI":"10.1038\/s41598-024-64511-9","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T06:03:54Z","timestamp":1719900234000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Antimicrobial peptide 2K4L inhibits the inflammatory response in macrophages and Caenorhabditis elegans and protects against LPS-induced septic shock in mice"],"prefix":"10.1038","volume":"14","author":[{"given":"Fangyu","family":"Ji","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoxu","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dejing","family":"Shang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"issue":"10","key":"64511_CR1","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1038\/nri2634","volume":"9","author":"R Medzhitov","year":"2009","unstructured":"Medzhitov, R. & Horng, T. 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