Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities

Abstract

Lung cancer is the second commonly diagnosed malignancy worldwide and has the highest mortality rate among all cancers. Tremendous efforts have been made to develop novel strategies against lung cancer; however, the overall survival of patients still is low. Uncovering underlying molecular mechanisms of this disease can open up new horizons for its treatment. Ferroptosis is a newly discovered type of programmed cell death that, in an iron-dependent manner, peroxidizes unsaturated phospholipids and results in the accumulation of radical oxygen species. Subsequent oxidative damage caused by ferroptosis contributes to cell death in tumor cells. Therefore, understanding its molecular mechanisms in lung cancer appears as a promising strategy to induce ferroptosis selectively. According to evidence published up to now, significant numbers of research have been done to identify ferroptosis regulators in lung cancer. Therefore, this review aims to provide a comprehensive standpoint of molecular mechanisms of ferroptosis in lung cancer and address these molecules’ prognostic and therapeutic values, hoping that the road for future studies in this field will be paved more efficiently.

Gracillin Shows Potential Efficacy Against Non-Small Cell Lung Cancer Through Inhibiting the mTOR Pathway

“…According to the latest research report, lung cancer has the highest mortality rate among all cancers ( 34 ). As the most classic subtype of lung cancer, NSCLC has malignant metastasis potential and low cure rate ( 35 ).…”

Multifaceted Roles of Ferroptosis in Lung Diseases

“…a System Xc-(xCT) is a cystine/glutamate antiporter consisting of SLC3A2 and SLC7A11, which is accountable for exporting glutamate and importing cysteine. By upregulating SLC3A2 and SLC7A11, lung cancer cells could enhance their antioxidant effect, inhibit the occurrence of ferroptosis, and increase drug resistance to inducers of ferroptosis, such as imidazole ketone erastin (IKE) and cisplatin (DDP) (Huang et al, 2005;Ma et al, 2021;Tabnak et al, 2021;. b The antioxidant enzymes GPXs, GPX8, and GPX4 in particular, have been identified to play an extensive and broad role in the pathological process of cancers (Zhang et al, 2020a).…”

“…b The antioxidant enzymes GPXs, GPX8, and GPX4 in particular, have been identified to play an extensive and broad role in the pathological process of cancers (Zhang et al, 2020a). Overexpression of GPX4 promoted the proliferative capacity of lung cancer cells and inhibited ferroptosis, whereas RSL3 hindered GPX4 activity and limited the proliferation, migration, invasion, and angiogenesis of lung cancer cells (Zhang et al, 2020a;Tabnak et al, 2021). Besides, these antioxidants can protect metastasizing cancer cells in both circulations and the metastatic niche to resist ferroptosis (Liu et al, 2021a).…”

“…The application of erianin (Chen et al, 2020b), sanguinarine (SAG) (Xu et al, 2022), and dihydroisotanshinone I (DT) (Wu et al, 2021) also repressed tumor growth and prevented metastasis in vivo and in vitro. In addition, targeted delivery of ncRNAs is also considered a promising anticancer strategy (Tabnak et al, 2021), and the application of delicate nanotechnology has recently attracted extensive attention due to its specific physicochemical properties (Chen et al, 2021b). Follow-up research can carry out more effective and precise interventions in the above and other regulatory pathways, regulating cellular sensitivity to ferroptosis, inhibiting the growth and metastasis of lung cancer cells, and prolonging the survival of patients.…”

Extracellular HSP90α inhibits ferroptosis through GPX4 in NSCLC cells

“…The newly synthesized nanoparticle 17-DMAG-HMPB@sPP@HA can downregulate the expression of GPX4, while the photothermal effect of this drug accelerates the degradation and release of iron and ferrous ions, reduces the expression of HSP90, and induces ferroptosis in tumor cells [20]. Therefore, combining ferroptosis inhibitors with other therapeutic approaches seems to be an effective strategy for a more potent induction of ferroptosis [21,22]. However, the role of ferroptosis and its chaperone proteins, such as HSPs, has not been fully elucidated.…”