人参皂苷Rh3（GRh3）是一种半天然产物，通过化学处理从中药中分离得到，对人类肿瘤具有强烈的抗肿瘤活性。然而，它的抗肿瘤作用仍需阐明。本研究旨在从焦痂性死亡和铁死亡的角度探究GRh3的肿瘤抑制活性机制。GRh3通过激活气体孔径蛋白D（GSDMD）依赖的焦痂性死亡和抑制溶质载体家族7成员11 (SLC7A11)，从而通过Stat3/p53/NRF2轴激活铁死亡来消除结直肠癌（CRC）细胞。GRh3抑制核因子红细胞生成2相关因子2（NRF2）进入细胞核，导致血红素加氧酶1（HO-1）表达下降，进而促进NOD样受体热蛋白结构域相关蛋白3（NLRP3）和半胱氨酸天冬酶1（caspase-1）表达。最后，caspase-1激活GSDMD依赖的焦痂性死亡。此外，GRh3有效阻止NRF2进入细胞核，抑制SLC7A11，导致谷胱甘肽（GSH）的耗尽和铁、脂质活性氧（ROS）和丙二醛（MDA）的积累，最终导致CRC细胞的铁死亡。此外，GRh3在体外和裸鼠模型中有效抑制CRC细胞的增殖。总之，GRh3通过Stat3/p53/NRF2轴在CRC细胞中触发焦痂性细胞死亡和铁死亡，对正常细胞的危害最小，显示出巨大的抗癌潜力。

Ginsenoside Rh3 (GRh3) is a seminatural product obtained by chemical processing after isolation from Chinese herbal medicine that has strong antitumor activity against human tumors. However, its antitumor role remains to be elucidated. The aim of this study is to explore the mechanisms underlying the tumor suppressive activity of GRh3 from the perspective of pyroptosis and ferroptosis. GRh3 eliminates colorectal cancer (CRC) cells by activating gasdermin D (GSDMD)-dependent pyroptosis and suppressing solute carrier family 7 member 11 (SLC7A11), resulting in ferroptosis activation through the Stat3/p53/NRF2 axis. GRh3 suppresses nuclear factor erythroid 2-related factor 2 (NRF2) entry into the nucleus, leading to the decrease of heme oxygenase 1 (HO-1) expression, which in turn promotes NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and caspase-1 expression. Finally, caspase-1 activates GSDMD-dependent pyroptosis. Furthermore, GRh3 prevents NRF2 from entering the nucleus, which suppresses SLC7A11, causing the depletion of glutathione (GSH) and accumulation of iron, lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and eventually leading to ferroptosis in CRC cells. In addition, GRh3 effectively inhibits the proliferation of CRC cells in vitro and in nude mouse models. Collectively, GRh3 triggers pyroptotic cell death and ferroptotic cell death in CRC cells via the Stat3/p53/NRF2 axis with minimal harm to normal cells, showing great anticancer potential.