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As a secretory factor involved in inflammation, pentraxin-3 (PTX3) has been demonstrated to regulate hepatic homeostasis; however, the relationship between PTX3 and cell crosstalk between immune cells and hepatocytes in the liver remains incompletely understood. In this study, we revealed that, compared with WT mice, <jats:italic>Ptx3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice with lipopolysaccharide (LPS)-induced endotoxemia exhibited alleviated liver damage, with reduced serum alanine transaminase and aspartate transaminase levels and an improved survival rate. Mechanistically, RNA-Seq and western blot results revealed that <jats:italic>Ptx3<\/jats:italic> knockdown in hepatocytes increased the expression of <jats:italic>Tfrc<\/jats:italic> and <jats:italic>Ccl20<\/jats:italic>; consequently, <jats:italic>Ptx3<\/jats:italic> deficiency regulated LPS-induced hepatocyte ferroptosis via increased mitochondrial reactive oxygen species and Fe<jats:sup>2+<\/jats:sup> and recruited more macrophages by CCL20\/CCR6 axis to be involved in inflammation and the clearance of harmful substances. Moreover, western blot and immunofluorescence staining confirmed that the NF-\u03baB signaling pathway was upregulated upon LPS treatment in <jats:italic>Ptx3<\/jats:italic>-knockdown macrophages, promoting phagocytosis and polarization toward M1 macrophages. Collectively, our findings show that the absence of <jats:italic>Ptx3<\/jats:italic> can ameliorate sepsis-induced liver injury by regulating hepatocyte ferroptosis and promote the recruitment and polarization of M1 macrophages. These findings offer a key basis for the development of effective treatments for acute infections.<\/jats:p>","DOI":"10.1186\/s43556-024-00227-6","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T06:22:37Z","timestamp":1733984557000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Pentraxin-3 modulates hepatocyte ferroptosis and the innate immune response in LPS-induced liver injury"],"prefix":"10.1186","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3542-1125","authenticated-orcid":false,"given":"Huitong","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaojie","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyun","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baojie","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixiang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfa","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linghui","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6051-7245","authenticated-orcid":false,"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"issue":"8","key":"227_CR1","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.4049\/jimmunol.1901246","volume":"204","author":"Z Wang","year":"2020","unstructured":"Wang Z, Kong L, Tan S, Zhang Y, Song X, Wang T, et al. 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