细胞铁死亡的激活在肿瘤治疗中具有广阔的前景。然而，铁死亡同时受到抗铁死亡物质的抑制，包括谷胱甘肽过氧化物酶 4 (GPX4)、二氢乳清酸脱氢酶 (DHODH) 和铁死亡抑制蛋白 1 (FSP1)。因此，同时抑制这三种抗铁死亡物质来激活铁死亡是非常理想的，但也具有挑战性。在这里，我们合理设计了一种负载布奎那（BQR）和利菲西呱（YC-1）的空心铁掺杂SiO2基纳米酶（FeSHS），命名为FeSHS/BQR/YC-1-PEG，用于肿瘤铁死亡激活。 FeSHS 是通过铁离子连续蚀刻 SiO2 纳米粒子而开发的，具有 pH/谷胱甘肽响应性生物降解性，并模仿过氧化物酶、谷胱甘肽氧化酶和 NAD(P)H 氧化酶的活性。具体来说，FeSHS 消耗谷胱甘肽和氧化 NAD(P)H 将抑制 GPX4 的表达，并通过破坏 NAD(P)H/FSP1/泛醌轴来抑制 FSP1。此外，释放的BQR可以抑制DHODH的表达。同时，YC-1 能够通过破坏 HIF-1α/脂滴轴来增加细胞多不饱和脂肪酸 (PUFA)。我们设计的纳米平台在提高铁和 PUFA 水平的同时破坏 GPX4/DHODH/FSP1 抑制途径，在体外和体内均表现出很高的治疗效果。这项工作阐明了合理设计用于铁死亡激活和未来肿瘤治疗的智能纳米平台。

The activation of cellular ferroptosis is promising in tumor therapy. However, ferroptosis is parallelly inhibited by antiferroptotic substances, including glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1). Thus, it is highly desirable, yet challenging, to simultaneously suppress these three antiferroptotic substances for activating ferroptosis. Here, we rationally designed a hollow iron-doped SiO2-based nanozyme (FeSHS) loaded with brequinar (BQR) and lificiguat (YC-1), named FeSHS/BQR/YC-1-PEG, for tumor ferroptosis activation. FeSHS were developed through the continuous etching of SiO2 nanoparticles by iron ions, which exhibit pH/glutathione-responsive biodegradability, along with mimicking the activities of peroxidase, glutathione oxidase, and NAD(P)H oxidase. Specifically, glutathione depletion and NAD(P)H oxidation by FeSHS will suppress the expression of GPX4 and inhibit FSP1 by disrupting the NAD(P)H/FSP1/ubiquinone axis. In addition, the released BQR can suppress the expression of DHODH. Meanwhile, YC-1 is able to increase the cellular polyunsaturated fatty acids (PUFAs) by destroying the HIF-1α/lipid droplet axis. The elevation of levels of iron and PUFAs while simultaneously disrupting the GPX4/DHODH/FSP1 inhibitory pathways by our designed nanoplatform displayed high therapeutic efficacy both in vitro and in vivo. This work elucidates rationally designing smart nanoplatforms for ferroptosis activation and future tumor treatments.