A review on the research progress of traditional Chinese medicine with anti-cancer effect targeting ferroptosis

Abstract

Ferroptosis is a non-apoptotic form of regulated cell death characterized by iron-dependent lipid peroxidation. It can be triggered by various mechanisms, including the glutathione peroxidase 4 (GPX4)-glutathione (GSH) axis, iron metabolism, lipid metabolism, the GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, and the ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 axis. The redox balance is disrupted when ferroptosis occurs in cells, which is fatal to cancer cells. Additionally, some tumor-associated genes are involved in ferroptosis. Hence, targeting ferroptosis might be an effective strategy for treating cancer. Several small-molecule compounds exhibit anti-tumor effects through ferroptosis, including sorafenib and altretamine, which induce ferroptosis by inhibiting System-Xc and GPX4 respectively, but many problems, such as poor druggability, still exist. Some studies have shown that many traditional Chinese medicine (TCM) induce ferroptosis by inhibiting GPX4, solute carrier family 7 member 11 (SLC7A11), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2), or by increasing the expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4), transferrin (TF), and transferrin receptor 1 (TFR1). These changes can lead to the lysosomal degradation of ferritin, accumulation of iron, lipid peroxidation and the production of reactive oxygen species (ROS), which in turn can promote anti-tumor activities or synergistic effects with chemotherapeutic drugs. In this study, we elucidated the underlying mechanisms of ferroptosis, and the anti-tumor pharmacology of TCM targeting ferroptosis including prescriptions, Chinese herbs, extracts, and natural compounds. Our findings might act as valuable reference for research on anti-tumor drugs targeting ferroptosis, especially those drugs developed from TCM.

Keywords: Anti-tumor; Ferroptosis; Mechanisms; Traditional Chinese medicine.

Fig. 1

Schematic diagram of the mechanism of ferroptosis. Transferrin, transferrin receptor 1, and other iron metabolism-related proteins regulate ferroptosis by affecting the labile iron pool (LIP). p53 positively controls ferroptosis by inhibiting System-Xc and activating spermidine/spermine N1-acetyltransferase 1 (SAT1) and ALOX1, negatively regulating ferroptosis by controlling p21 and blocking dipeptidyl peptidase-4 (DPP4). System-Xc influences the synthesis of GSH, which interacts with GPX4 to protect cells from lipid peroxidation damage and ferroptosis. ACSL4 and LPCAT3 are involved in the synthesis of PUFA-CoA into PUFA-PLs, which can cause ferroptosis when oxidized to PL-PUFA-OOH. Mitochondrial respiration and its associated products also induce ferroptosis by lipid peroxidation

Fig. 2

TCM targeting ferroptosis against cancer. ACP the root of Actinidia chinensis Planch, LBP Lycium barbarum polysaccharide, FZKA Fuzhengkang'ai decoction, YQHY Yiqi Huayu decoction. Oleanolic acid, ruscogenin and other compounds induce ferroptosis by affecting iron metabolism. Nobiletin, tagitinin C and other compounds act on the p62-Keap1-Nrf2pathway to lead to ferroptosis. Scutellaria barbata, dihydroisotanshinone I and other Chinese medicine result in ferroptosis by functioning in GPX4-GSH axis. Tanshinone IIA, gambogic acid and curcumin induce ferroptosis by modulating p53. Atractylodin and others cause lipidperoxidation by activating ACSL4