Inhibition of oxidative stress and ferroptosis is currently considered to be a promising therapeutic approach for neurodegenerative diseases. Herpotrichones, a class of compounds derived from insect symbionts, have shown potential for neuroprotective activity with low toxicity. However, the specific mechanisms through which herpotrichones exert their neuroprotective effects remain to be fully elucidated. In this study, the natural [4 + 2] adducts herpotrichone A (He-A) and its new analogues were isolated from the isopod-associated fungus Herpotrichia sp. SF09 and exhibited significantly protective effects in H2O2-, 6-OHDA-, and RSL3-stimulated PC12 cells and LPS-stimulated BV-2 cells. Moreover, He-A was able to relieve ferroptotic cell death in RSL3-stimulated PC12 cells and 6-OHDA-induced zebrafish larvae. Interestingly, He-A can activate antioxidant elements and modulate the SLC7A11 pathway without capturing oxidic free radical and chelating iron. These findings highlight He-A as a novel hit that protects against ferroptosis-like neuronal damage in the treatment of neurodegenerative diseases.
Keywords: Nrf2; SLC7A11; ferroptosis; herpotrichones; lipid ROS; neuroprotective effect.