癌细胞通常表现出“铁成瘾”表型，这导致它们容易受到铁死亡诱导剂的影响。铁死亡是一种新发现的由铁依赖性脂质过氧化引起的程序性细胞死亡形式。在本研究中，pacidusin B 是一种来自大戟科 Phyllanthus Acidus (L.) Skeels 的二氢胨型三萜类化合物，可诱导 HT1080 人纤维肉瘤细胞系铁死亡。用pacidusin B 处理的细胞表现出铁死亡的形态学特征“膨胀”表型。在 pacidusin B 处理的细胞中也观察到了铁死亡的生化特征。氧化应激和内质网应激在 pacidusin B 诱导的铁死亡中发挥重要作用。 PERK-Nrf2-HO-1信号通路的激活导致铁过载，而GPX4的抑制进一步使癌细胞对铁死亡敏感。此外，分子对接研究表明，pacidusin B 与铁死亡诱导剂erastin 对接在 xCT 中的同一口袋中。这些结果表明，pacidusin B 通过诱导 ER 介导的铁死亡细胞发挥抗癌作用。© 2024。作者。

Cancer cells generally exhibit 'iron addiction' phenotypes, which contribute to their vulnerability to ferroptosis inducers. Ferroptosis is a newly discovered form of programmed cell death caused by iron-dependent lipid peroxidation. In the present study, pacidusin B, a dichapetalin-type triterpenoid from Phyllanthus acidus (L.) Skeels (Euphorbiaceae), induces ferroptosis in the HT1080 human fibrosarcoma cell line. Cells treated with pacidusin B exhibited the morphological characteristic 'ballooning' phenotype of ferroptosis. The biochemical hallmarks of ferroptosis were also observed in pacidusin B-treated cells. Both oxidative stress and ER stress play significant roles in pacidusin B-induced ferroptosis. The activation of the PERK-Nrf2-HO-1 signaling pathway led to iron overload, while inhibition of GPX4 further sensitized cancer cells to ferroptosis. Furthermore, the molecular docking study showed that pacidusin B docked in the same pocket in xCT as the ferroptosis inducer erastin. These results revealed that pacidusin B exerts anticancer effects via inducing ER-mediated ferroptotic cell death.© 2024. The Author(s).