Abstract：
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.
摘要：
目前，抑制氧化应激和铁死亡被认为是神经退行性疾病的有希望的治疗方法。Herpotrichones,一类来源于昆虫共生体的化合物,具有低毒性的神经保护活性。然而,Herpotrichones发挥神经保护作用的具体机制仍有待完全阐明。在这项研究中,从等足类动物相关真菌Herpotrichiasp中分离出天然[42]加合物HerpotriconeA（He-A）及其新类似物。SF09并在H2O2-中表现出显着的保护作用，6-OHDA-,和RSL3刺激的PC12细胞和LPS刺激的BV-2细胞。此外，He-A能够减轻RSL3刺激的PC12细胞和6-OHDA诱导的斑马鱼幼虫中的铁细胞死亡。有趣的是,He-A可以激活抗氧化剂元素并调节SLC7A11途径，而不会捕获氧化自由基和螯合铁。这些发现强调了He-A作为一种新颖的打击，可以在神经退行性疾病的治疗中防止铁性凋亡样神经元损伤。
