ArticleInternational endodontic journal2026
Four-Octyl Itaconate Alleviates Enterococcus faecalis-Induced Apical Periodontitis by Inhibiting Macrophage M1 Polarisation.
Article in International endodontic journal, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
aimEnterococcus faecalis is strongly associated with persistent inflammation of the periapical tissue. 4-Octyl itaconate (4-OI), a derivative of itaconate that can permeate the cell membrane, has potent immunomodulatory effects on macrophage polarisation. However, the effect of 4-OI on apical periodontitis induced by the gram-positive bacterium E. faecalis has not yet been reported. This study explored whether 4-OI could alleviate E. faecalis-induced apical periodontitis by regulating macrophage polarisation. METHODOLOGY: A model of apical periodontitis was established in mice by pulp exposure and intra-radicular infection with E. faecalis. 4-OI was then administered intraperitoneally. Periapical bone destruction, periapical inflammation, and macrophage polarisation were assessed. Additionally, RAW264.7 cells were pretreated with 4-OI and exposed to heat-killed E. faecalis (HKEF) in vitro. The expression of polarisation-related markers was examined. The potential role of nuclear factor E2-related 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-OI-mediated polarisation of HKEF-stimulated RAW264.7 cells.
results4-OI treatment reduced periapical bone destruction and periapical inflammation in the mouse model of E. faecalis-induced apical periodontitis. Moreover, 4-OI inhibited macrophage M1 polarisation in the periapical region and inhibited the expression of M1 polarisation-related genes in E. faecalis-infected macrophages. Mechanistically, 4-OI treatment significantly enhanced the expression and nuclear localisation of Nrf2 and its downstream target heme oxygenase-1 in E. faecalis-infected macrophages in vitro. However, suppression of M1 macrophage polarisation by 4-OI was reduced following Nrf2 inhibition.
conclusions4-OI inhibits E. faecalis-induced macrophage M1 polarisation probably by activating the Nrf2 antioxidant system, thereby suppressing experimental apical periodontitis in mice. These findings suggest that 4-OI possesses great potential as a valuable adjunct to conventional root canal therapy in the management of E. faecalis-related refractory apical periodontitis.
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