4-Octyl Itaconate

4-Octyl Itaconate (4-OI) is a cell-permeable itaconate derivative. Itaconate and 4-Octyl Itaconate had similar thiol reactivity, making 4-Octyl Itaconate a suitable itaconate surrogate to study its biological function. 4-Octyl Itaconate is reported to alkylate cysteine residues on kelchlike ECH-associated protein 1 (KEAP1) and then activate nuclear factor (erythroid derived 2)-related factor 2 (Nrf2) to exert antioxidant and anti-inflammatory effects. ^[1]. 4-Octyl Itaconate can halt the progress of various diseases, including ischemiareperfusion injury, osteoclast-related diseases, and renal fibrosis, by reducing oxidative stress and modifying the immune response of macrophages to lipopolysaccharide (LPS) ^[2].

The inhibitory effect of 4-octyl itaconate extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)- independent mechanism. In addition, 4-Octyl Itaconate limit host inflammatory responses to SARS-CoV2 infection ^[3].

Treat Vero cells with 4-octyl itaconate enerated before infection with SARS-CoV2 resulted in a 102–104 eduction in SARS-CoV2 RNA levels in a dose dependent manner, while not affecting cell viability, as determined by lactate dehydrogenase (LDH) release assay. The antiviral effect of 4-Octyl Itaconate was also demonstrated in the lung cancer cell line Calu-3, where SARS-CoV2 RNA levels were reduced by >2-logs, while release of progeny virus was reduced by >6-logs. 4-Octyl Itaconate effect SARSCoV2 in primary human airway epithelial (HAE) cultures, also, 4-Octyl Itaconate treatment significantly reduced viral RNA levels. The antiviral effect of 4-Octyl Itaconate was reproduced using a different SARS-CoV-2 isolate ^[3].

4-Octyl Itaconate (50 mg/ kg) were administered to 57BL/6J mice or vehicle 2 h before intraperitoneal injection of LPS (5 mg/kg). 4-Octyl Itaconate treatment significantly prolonged the survival rate and simultaneously decreased the serum levels of IL-1β, IL-6 and lactate in mice induced by LPS. 4-Octyl Itaconate protects mice against experimental lethal endotoxaemia partly by inhibiting cytokine release and lactate production ^[1].

References:
[1] Liao, S. T. et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nat. Commun. 10, 5091, 2019.
[2] Li, Y., Chen, X., Zhang, H., et al. 4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation. Dddt 14, 5547–5558. 2020. doi:10.2147/DDDT.S280922.
[3] Olagnier, D. et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat. Commun. 11, 4938, 2020.