The interaction between ferroptosis and lipid metabolism in cancer

Abstract

Ferroptosis is a new form of programmed cell death characterized by the accumulation of iron-dependent lethal lipid peroxides. Recent discoveries have focused on alterations that occur in lipid metabolism during ferroptosis and have provided intriguing insights into the interplay between ferroptosis and lipid metabolism in cancer. Their interaction regulates the initiation, development, metastasis, therapy resistance of cancer, as well as the tumor immunity, which offers several potential strategies for cancer treatment. This review is a brief overview of the features characterizing the interaction between ferroptosis and lipid metabolism, and highlights the significance of this interaction in cancer.

Fig. 1. Mechanisms of ferroptosis.

The excessive production and failure of elimination of LPO are key causes of ferroptosis. The pathways of eliminating LPO includes system ${\mathrm{x}}_{\mathrm{c}}^{\text{-}}$/GSH/GPX4 axis and NADPH/FSP1/CoQ₁₀ axis. The cystine ingested by system ${\mathrm{x}}_{\mathrm{c}}^{\text{-}}$ is catalyzed to GSH by γ-GCS and GSS. GPX4 converts GSH to GSSH to reduce LPO and inhibit ferroptosis. FSP1 catalyzes CoQ₁₀ to ubiquinol by NADPH, which acts as a lipophilic radical scavenger that reduces LPO. The PUFA-OOH is the main source of LPO. Main peroxidation target PUFAs are AA/AdA mainly present in the endoplasmic reticulum compartment. After catalyzed by ACSL4, LPCAT3, and 15-LOX, AA/AdA is converted to PE-AA-OOH/PE-AdA-OOH to promote ferroptosis. The Fenton reaction mediated by Fe²⁺ produces a large number of HO• to promote the peroxidation of PUFA. P53 transcriptionally inhibits SLC7A11, leading to the production of 12-LOX-mediated PUFU-OOH upon ROS stress. In addition, transsulfuration pathway, MVA pathway and glutaminolysis also participate in the regulation of ferroptosis

Fig. 2. The interaction of ferroptosis and lipid metabolism in tumor biology.

ACSL4, 15-LOX, and GPX4 are key factors involved in ferroptosis and lipid metabolism that regulate tumor initiation, development, invasion, metastasis, chemoresistance, and radioresistance. GPX4 and ZEB1 are associated with high mesenchymal state to contribute to tumor chemoresistance. Both GPX4 and 15-LOX can activate Nrf2 to inhibit the expression of VCAM-1 that contribute to tumor metastasis and angiogenesis. The transcription factor Nrf2 is a key regulator of antioxidant response that suppress ferroptosis to enhance tumor chemoresistance and radioresistance. EGLN1/3 and c-Myc can directly activate the expression of LSH by suppressing HIF-1α, and the elevated LSH upregulates genes involved in lipid metabolism, such as SCD1 and FADS2 to suppress ferroptosis and promote tumor initiation and development

Fig. 3. The interaction of ferroptosis and lipid metabolism in modulating tumor immunity.

With the catalysis of ACSL4, LPCAT3, and 15-LOX, AA/AdA is oxidized to LPO that initiate ferroptosis. Some AA/AdA metabolites e.g., HETEs released from ferroptotic cancer cells activate antitumor immunity, while other lipids e.g., PGE₂ suppress immunity to promote tumor cell evasion. Immune cells also regulate the ferroptosis of cancer cells. Immunotherapy-activated CD8⁺ T cells induce the ferroptosis of cancer cells by releasing IFNγ to downregulate the system ${\mathrm{x}}_{\mathrm{c}}^{\text{-}}$. Thus, GSH level in tumor cells is not enough to eliminate LPO by GPX4, which leads to ferroptosis. Under certain conditions, immune cells including T cells, B cells, macrophages also undergo ferroptosis, which will modulate the tumor immunity