Ferroptosis is a type of non-apoptotic regulated cell death that involves excessive iron accumulation and subsequent lipid peroxidation. Although the antioxidant mechanisms of ferroptosis have been extensively studied recently, little is known about the interactions between the different organelles that control ferroptosis. Here, we show that the translocation of lysosomal cysteine protease cathepsin B (CTSB) into the nucleus is an important molecular event that mediates organelle-specific initiation of ferroptosis in human pancreatic cancer cells. Iron-dependent lysosomal membrane permeability triggers the release of CTSB from the lysosome to nucleus during ferroptosis. Mechanistically, nuclear CTSB accumulation causes DNA damage and subsequent activation of the stimulator of interferon response CGAMP interactor 1 (STING1/STING)-dependent DNA sensor pathway, which ultimately leads to autophagy-dependent ferroptosis. Consequently, the genetic inhibition of CTSB-dependent STING1 activation by RNAi prevents ferroptosis in cell culture and animal models. These new findings not only enhance our understanding of the mechanism by which organelles specifically trigger ferroptosis, but also may provide a potential way to enhance the anticancer activity of ferroptosis therapy.

Ferroptosis是一种非凋亡调节性细胞死亡，涉及过度的铁积累和随后的脂质过氧化。尽管近来广泛研究了肥大症的抗氧化机制，但对于控制肥大症的不同细胞器之间的相互作用了解甚少。在这里，我们显示溶酶体半胱氨酸蛋白酶组织蛋白酶B（CTSB）易位到核内是重要的分子事件，它介导人类胰腺癌细胞中肥大症的细胞器特异性起始。铁依赖的溶酶体膜通透性在肥大病期间触发CTSB从溶酶体释放到细胞核。机械上，核CTSB的积累会导致DNA损伤，并随后激活干扰素应答CGAMP相互作用因子1（STING1 / STING）依赖性DNA传感器途径的刺激物，最终导致自噬依赖型肥大病。因此，RNAi对CTSB依赖性STING1激活的遗传抑制作用可防止细胞培养和动物模型中的肥大症。这些新发现不仅增强了我们对细胞器特异性触发肥大作用机理的理解，而且还可能提供增强肥大作用的抗癌活性的潜在途径。