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.
Highlights
With 11.4% and 18% of prevalence and total cancer death rate, respectively, lung cancer is the second common cancer and the leading cause of cancer death worldwide [1]
Wohlhieter et al [31] showed that Lung adenocarcinoma (LUAD) tumors with concurrent mutations in serine/threonine kinase 11 (STK11) and KEAP1 were more resistant to ferroptosis since the activity of NRF2 pathway and targets involved in ferroptosis such as SLC7A11 and glutathione peroxidase 4 (GPX4) were increased, leading to worse overall survival and enhanced tumor proliferation both in vivo and in vitro (Figure 2)
Recent evidence has mainly focused on the role of system X−c and GPX4 as main inhibitors of ferroptosis and other regulators and signaling pathways such as NRF2, p53, and Ubiquitin–proteasome system (UPS)
Summary
With 11.4% and 18% of prevalence and total cancer death rate, respectively, lung cancer is the second common cancer and the leading cause of cancer death worldwide [1]. Following treatments with small molecules such as erastin, some morphological changes like chromatin condensation, cytoplasmic and organelle swelling, formation of double-membrane vesicles, shrunken mitochondria, and plasma membrane rupture were observed in affected cells [6]. This process initiates with the accumulation of various proferroptotic molecules contributing to lipid peroxidation through the production of reactive oxygen species (ROS) under the assistance of iron [7]. We aimed to review the role of ferroptosis in lung cancer and provide insights into molecular mechanisms, prognostic and therapeutic importance of ferroptosis regulators
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