Artesunate protects against ocular fibrosis by suppressing fibroblast activation and inducing mitochondria‐dependent ferroptosis

青蒿琥酯 线粒体 药理学 脂质过氧化 成纤维细胞 纤维化 化学 细胞凋亡 程序性细胞死亡 氧化应激 细胞生物学 生物 医学 生物化学 免疫学 病理 体外 恶性疟原虫 疟疾
作者
Jingyuan Liu,Zheng Pan,Boding Tong,Cong Wang,Jiawei Yang,Jingling Zou,Jikuan Jiang,Lusi Zhang,Bing Jiang
出处
期刊:The FASEB Journal [Wiley]
卷期号:37 (6) 被引量:15
标识
DOI:10.1096/fj.202201867r
摘要

Abstract Artesunate, a derivative from extracts of Artemisia annua , has recently been reported to alleviate fibrosis recently. Here, in this study, we sought to determine the anti‐fibrosis effect of artesunate in rabbit glaucoma filtration surgery (GFS) model and illuminate underlying mechanisms. Our results showed that artesunate subconjunctival injection alleviated bleb fibrosis by inhibiting fibroblast activation and inducing ferroptosis. Further mechanistic investigation in primary human ocular fibroblasts (OFs) showed that artesunate abrogated fibroblast activation by inhibiting TGF‐β1/SMAD2/3 and PI3K/Akt pathways and scavenged OFs by inducing mitochondria‐dependent ferroptosis. Mitochondrial dysfunction, mitochondrial fission, and iron‐dependent mitochondrial lipid peroxidation were observed in artesunate‐treated OFs. Besides, mitochondria‐localized antioxidants inhibited artesunate‐induced cell death, suggesting a critical role of mitochondria in artesunate‐induced ferroptosis. Our study also found that expression of mitochondrial GPX4 but no other forms of GPX4 was decreased after artesunate treatment and that mitochondrial GPX4 overexpression rescued artesunate‐induced lipid peroxidation and ferroptosis. Other cellular ferroptosis defense mechanisms, including cellular FSP1 and Nrf2, were also inhibited by artesunate. In conclusion, our study demonstrated that artesunate protects against fibrosis through abrogation of fibroblast activation and induction of mitochondria‐dependent ferroptosis in OFs, which may offer a potential treatment for ocular fibrosis.
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