incidences are increasing year by year. [2] As a newly discovered regulatory cell death, ferroptosis is a type of cell death caused by iron-dependent accumulation of lipid peroxides. [3][4][5] As we all known, normal liver is the important organ to store and metabolize iron. [6] Thus, inducing ferroptosis of liver tumor cells may be a new direction for specific treatment of liver tumors. Unfortunately, Sorafenib is currently the only anti-tumor chemotherapy drug that can treat liver tumors by inducing ferroptosis in clinical, but its drug resistance greatly affects the therapeutic effect. [7,8] Therefore, it is urgent to exploit novel strategies to induce ferroptosis in liver tumors.Briefly, ferroptosis is mainly induced in two modes: One is the classic ferroptosis induction mode, which destroys the membrane protective mechanism of tumor cells to activate ferroptosis by which is mainly managed by the GPX4 pathway. [9,10] GPX4 protein is considered the only glutathione peroxidase (GPXs) family molecule that protects biofilms from hydroperoxidation. [11] There are two main therapeutic methods targeting GPX4 pathway for inducing ferroptosis. The first one is the inactivation and depletion of GPX4 protein. [12] For example, (1S,3R)-RSL3 (RSL3) can covalently bind to the active site of GPX4, thereby mediating ferroptosis regulated by GPX4. [13,14] The second approach is to consume intracellular GSH content. [15] Reduced glutathione, a tripeptide form of antioxidant, can act as a synergistic molecule of GPX4 and assist GPX4 to eliminate lipid ROS. [16,17] Many nanomaterials with the ability to consume GSH have been demonstrated to activate ferroptosis, which provide additional strategies for inducing ferroptosis. [18][19][20] Cu(II) has been widely used for its excellent GSH consumption capacity. [21] Furthermore, another way to induce ferroptosis is named as nonclassical ferroptosis induction mode. Basically, the nonclassical mode is initiated by increasing the Fe 2+ content in tumor cells. [22] For instance, excessive activation of HMOX1 protein, down-regulated ferroportin expression and up-regulated transferrin expression could lead to overload Fe 2+ in tumor cells. [23][24][25] Some exogenous ironcontaining substances (hemin, FeCl 2 , and (NH 4 ) 2 Fe(SO 4 ) 2 ) can cause intracellular iron overloading, which can effectively Liver tumor is difficult to cure for its high degree of malignancy and rapid progression characteristics. Ferroptosis as a new model of inducing cell death is expected to break the treatment bottleneck of liver tumors. Here, a strategy to induce ferroptosis in HepG2 cells with acid-degradable tumor targeted nanosheets Cu-Hemin-PEG-Lactose acid (Cu-Hemin-PEG-LA) is proposed. After highly ingested by HepG2 cells, Cu-Hemin-PEG-LA nanosheets are degraded by weak acid and release Cu(II) and hemin, which consuming intracellular glutathione (GSH) content and increasing the expression of heme oxygenase 1 (HMOX1) protein, respectively. Furthermore, the expression of glutathione peroxidase 4 protein (GPX...
