Emerging mechanisms and targeted therapy of ferroptosis in cancer

Abstract

Ferroptosis is an iron- and lipid reactive oxygen species (ROS)-dependent form of programmed cell death that is distinct from other forms of regulatory cell death at the morphological, biological, and genetic levels. Emerging evidence suggests critical roles for ferroptosis in cell metabolism, the redox status, and various diseases, such as cancers, nervous system diseases, and ischemia-reperfusion injury, with ferroptosis-related proteins. Ferroptosis is inhibited in diverse cancer types and functions as a dynamic tumor suppressor in cancer development, indicating that the regulation of ferroptosis can be utilized as an interventional target for tumor treatment. Small molecules and nanomaterials that reprogram cancer cells to undergo ferroptosis are considered effective drugs for cancer therapy. Here, we systematically summarize the molecular basis of ferroptosis, the suppressive effect of ferroptosis on tumors, the effect of ferroptosis on cellular metabolism and the tumor microenvironment (TME), and ferroptosis-inducing agents for tumor therapeutics. An understanding of the latest progress in ferroptosis could provide references for proposing new potential targets for the treatment of cancers.

Keywords: cancer suppressor; cancer therapy; ferroptosis; ferroptosis-related proteins; iron; lipid ROS.

Graphical abstract

Figure 1

Mechanisms of glutathione-mediated ferroptosis First, the pathways of system Xc−/GSH/GPX4 are shown. Following uptake by system Xc−, cystine is catalyzed to GSH by GCL and GSS. GPX4 converts GSH to GSSH to reduce lipid ROS production and inhibit ferroptosis. Second, the transsulfuration pathway is shown. Methionine is catalyzed to cysteine by transferase, CBS, and CTH to produce GSH. BAP1, ATF3, Beclin1, and p53 inhibit SLC7A11, increasing cystine uptake and leading to ferroptosis.

Figure 2

Mechanisms by which lipid peroxidation and iron metabolism lead to ferroptosis First, AA/AdA is catalyzed by ACSL4, LPCAT3, and LOX to produce PE-AA-OOH/PE-AdA-OOH, inducing ferroptosis. Additionally, through a process mediated by the POR-CYP enzyme system, polyunsaturated (PUFA) phospholipids are converted to lipid peroxides to promote ferroptosis. The MVA pathway affects ferroptosis by regulating Sec-tRNA and CoQ10. Second, iron mediates ferroptosis. Transferrin (TF) binds to the transferrin receptor (TFR) and imports iron into the cell. Fe³⁺ is converted to Fe²⁺ by STEAP3 in endosomes, and then Fe²⁺ is released to the cytosol via DMT1. Free Fe²⁺ induces lipid ROS production by the Fenton reaction. Fe²⁺ is a cofactor of lipoxygenases (LOXs) that produces lipid ROS and induces redundant Fe²⁺ storage in ferritin. Ferroportin (Fpn) controls the intracellular iron concentration by transforming Fe²⁺ to extracellular iron. NCOA4 mediates the autophagic degradation of ferritin, increasing the Fe²⁺ content in the cellular iron pool. The p62/keap1/NRF2 pathway and glutaminolysis also participate in the regulation of ferroptosis. FSP1, GCH1, NRF2, and POR also control ferroptosis.

Figure 3

The effects of cell density and energy stress on ferroptosis First, cell density is associated with ferroptosis. When the cell density is low, the nuclear localization of YAP increases, which increases the expression of target genes, such as ACSL4 and TFP, to increase lipid ROS production. Moreover, when the cell density is low, TAZ is transported from the cytosol to the nucleus, which increases the expression of the target gene EMP1, and then EMP1 triggers lipid ROS production, leading to ferroptosis. Second, ferroptosis is inhibited by energy stress. AMPK is activated under energy stress conditions, and active AMPK suppresses fatty acid synthesis by inhibiting ACC phosphorylation, lending to a decrease in lipid ROS levels.

Figure 4

The effect of ferroptosis in the tumor microenvironment First, lactate in the tumor microenvironment activates HCAR1 receptors on the cytoplasmic membrane of cells and facilitates the MCT1-mediated uptake of lactate to further deactivate AMPK and downregulate the expression of SREBP1 and its target SCD1, thus inhibiting lipid peroxidation. Second, active CD8⁺ T cells release IFNγ to inhibit SLC7A11 expression by activating the STAT1 pathway in cancer cells, thereby inducing tumor cell ferroptosis. Third, ferroptotic cell death releases DAMPs (e.g., HMGB1) or lipid oxidation products (e.g., 4HNE) from immune cells via different intracellular signal transduction pathways.

Figure 5

Ferroptosis-related pathways and inducers Dashed boxes show sets of chemical drugs that inhibit system Xc−, GPX4, GSH synthesis, HMGCR, and CoQ10 production. Iron-based nanomaterials function as nano ferroptosis inducers that incorporate small-molecule ferroptosis inducers into nano delivery vehicles. In acidic lysosomes, ferrous (Fe²⁺) or ferric (Fe³⁺) ions are released to induce lipid peroxidation via the Fenton reaction, resulting in tumor cell ferroptosis.