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Four‐Octyl Itaconate Alleviates Enterococcus faecalis ‐Induced Apical Periodontitis by Inhibiting Macrophage M1 Polarisation

Year: 2026

Type: article

Abstract: AIM: Enterococcus 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. RESULTS: 4-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. CONCLUSIONS: 4-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.

Source: International Endodontic Journal

DOI: 10.1111/iej.70152