Furanoeremophilanes from edible wild plants belonging to the Asteraceae family inhibit ferroptosis via suppression of lipid peroxidation.

Ferroptosis is a regulated cell-death pathway caused by iron-dependent lipid peroxidation and is implicated in inflammatory diseases, ischaemic organ injury, and neurodegenerative disorders. Therefore, ferroptosis inhibitors are being explored for therapeutic applications. Furanoeremophilane-type sesquiterpenoids - cacalol (CL), cacalohastin (CH), and dehydrocacalohastin (DCH) - isolated from Cacalia delphiniifolia (C. delphiniifolia) and Cacalia hastata (C. hastata), traditional edible wild plants in Japan, exhibit antioxidative, anti-inflammatory, anti-cancer, and anti-melanogenic properties. In our screening method based on cell viability of cystine-glutamate antiporter xCT-knockout immortalized embryonic fibroblasts (xCTKO-MEFs), we found that C. delphiniifolia and C. hastata extracts inhibit ferroptosis. The ferroptosis-inhibitory effect of these plant extracts was more effective when hexane was used as the extraction solvent than when methanol was used, suggesting that lipophilic components play a key role. CL, CH, and DCH act as potent ferroptosis inhibitors by suppressing lipid peroxidation both in vitro and in non-cellular systems. CL, which inhibits ferroptosis and suppresses lipid peroxidation at the lowest concentration among the tested three compounds, was also found to increase the mRNA expression of ferroptosis/redox-related genes including glutathione peroxidase 4 (GPX4); however, it does not increase GPX4 protein level in xCTKO-MEFs. CL also exhibited a cytoprotective effect against ferroptosis induced by culturing in cystine-free medium or by treatment with erastin and RSL3; however, CL did not protect against cytotoxicity caused by oxidative stress induced by menadione and H2O2 in HeLa cells. These compounds derived from edible wild plants have potential as novel ferroptosis inhibitors and lead compounds for further therapeutic development.