4-Octyl itaconate alleviates sepsis-induced liver injury by regulating ferroptosis via the OTUB1/TRAF3 axis.

There are few effective ways to treat sepsis-induced liver damage (SILI). 4-Octyl itaconate (4-OI) demonstrates anti-inflammatory and antioxidant properties; however, its role and underlying mechanism in SILI remain unclear. In this study, a mouse SILI model was established using cecal ligation and puncture (CLP) and consisted of the following experimental groups: Sham, CLP, 4-OI treatment, and a combination of 4-OI and OTUB1 inhibitor treatments. Biochemical, histological, and molecular assays were employed to assess liver damage, inflammation, oxidative stress, and markers associated with ferroptosis. Cell transfection experiments were performed to investigate the interaction between ovarian tumor domain-containing protease 1 (OTUB1) and tumor necrosis factor receptor-associated factor 3 (TRAF3). The results suggested that 4-OI treatment enhanced liver dysfunction and pathological damage, decreased inflammation and oxidative stress, and reversed ferroptosis-associated metabolic dysregulation. From a mechanistic perspective, 4-OI selectively increased the production of the deubiquitinase OTUB1, thereby stabilizing the protein levels of SLC7A11 and GPX4. The protective advantages of 4-OI were offset by the inhibition of OTUB1 or the reduction in TRAF3 expression. This study demonstrated that 4-OI alleviates SILI by suppressing ferroptosis via the OTUB1/TRAF3-mediated deubiquitination of essential proteins, suggesting a possible treatment approach for SILI. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-38612-6.