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However, the effect of 4\u2010OI on apical periodontitis induced by the gram\u2010positive bacterium\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>E. faecalis<\/jats:italic>\n                      <\/jats:styled-content>\n                      has not yet been reported. This study explored whether 4\u2010OI could alleviate\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>E. faecalis<\/jats:italic>\n                      <\/jats:styled-content>\n                      \u2010induced apical periodontitis by regulating macrophage polarisation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>\n                      A model of apical periodontitis was established in mice by pulp exposure and intra\u2010radicular infection with\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>E. faecalis<\/jats:italic>\n                      <\/jats:styled-content>\n                      . 4\u2010OI was then administered intraperitoneally. Periapical bone destruction, periapical inflammation, and macrophage polarisation were assessed. Additionally, RAW264.7 cells were pretreated with 4\u2010OI and exposed to heat\u2010killed\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>E. faecalis<\/jats:italic>\n                      <\/jats:styled-content>\n                      (HKEF) in\u00a0vitro. The expression of polarisation\u2010related markers was examined. The potential role of nuclear factor E2\u2010related factor 2 (Nrf2) signalling was also explored by detecting the expression and nuclear translocation of Nrf2. Finally, genetic and pharmacological interventions targeting Nrf2 were performed to better understand its role in the 4\u2010OI\u2010mediated polarisation of HKEF\u2010stimulated RAW264.7 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      4\u2010OI treatment reduced periapical bone destruction and periapical inflammation in the mouse model of\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>E. faecalis<\/jats:italic>\n                      <\/jats:styled-content>\n                      \u2010induced apical periodontitis. Moreover, 4\u2010OI inhibited macrophage M1 polarisation in the periapical region and inhibited the expression of M1 polarisation\u2010related genes in\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>E. faecalis<\/jats:italic>\n                      <\/jats:styled-content>\n                      \u2010infected macrophages. Mechanistically, 4\u2010OI treatment significantly enhanced the expression and nuclear localisation of Nrf2 and its downstream target heme oxygenase\u20101 in\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>E. faecalis<\/jats:italic>\n                      <\/jats:styled-content>\n                      \u2010infected macrophages in\u00a0vitro. However, suppression of M1 macrophage polarisation by 4\u2010OI was reduced following Nrf2 inhibition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      4\u2010OI inhibits\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>E. faecalis<\/jats:italic>\n                      <\/jats:styled-content>\n                      \u2010induced macrophage M1 polarisation probably by activating the Nrf2 antioxidant system, thereby suppressing experimental apical periodontitis in mice. These findings suggest that 4\u2010OI possesses great potential as a valuable adjunct to conventional root canal therapy in the management of\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">E.<\/jats:styled-content>\n                        faecalis\n                      <\/jats:italic>\n                      \u2010related refractory apical periodontitis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iej.70152","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:53:20Z","timestamp":1774533200000},"page":"1619-1631","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Four\u2010Octyl Itaconate Alleviates\n                    <i>Enterococcus faecalis<\/i>\n                    \u2010Induced Apical Periodontitis by Inhibiting Macrophage\n                    <scp>M1<\/scp>\n                    Polarisation"],"prefix":"10.1111","volume":"59","author":[{"given":"Zilong","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Stomatology, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyuan","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Nanfang Hospital Southern Medical University  Guangzhou China"},{"name":"Haizhu District Stomatological Hospital  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongyang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simin","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Nanfang Hospital Southern Medical University  Guangzhou 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