br Molecular mechanisms and pathways for ferroptosis regulat

Molecular mechanisms and pathways for ferroptosis regulation As to the regulation of lipid peroxidation, iron and related ROS metabolism involved in ferroptosis, many molecular mechanisms and pathways have been presented. It is generally believed that cystine/glutamate antiporter system Xc−, GPX4, and iron metabolism play significant roles in regulating the processes of ferroptosis (Fig. 1) [15], [26]. Besides, MVA pathway [15], HSF1-HSPB1 pathway [27], Nrf2-SLC7A11-HO-1 pathway [28], cysteine dioxygenase 1 [29], lymphoid-specific helicase [30], transsulfuration pathway [31], major Myc/Hypoxia-induced metabolic pathway [32], etc. were also demonstrated to be able to mediate the regulation of ferroptosis processes.
Nanomaterials as inducers of ferroptosis Since ferroptosis was first named by Stockwell in 2012, lots of studies have been conducted to figure out its molecular mechanisms and corresponding signaling pathways, and try to find new inducing reagents to trigger highly efficient ferroptosis for cancer therapy. Up to date, there are varieties of genes, small molecules and nanomaterials elucidated to have the capacity of causing ferroptotic cell death [25], [95], [96], [97], [98], [99]. However, semplice genes or molecule reagents may not elevate the efficiency of the Fenton reaction very well due to the shortage of endogenous iron. In addition, due to the weak selectivity associated with genes and small molecules, how to avoid the unwanted side effects is another hindrance to their clinical use. Under this circumstance, introduction of nanomedicine brings light on developing new ferroptosis inducers for cancer specific therapy. By synthesizing various iron-based nanomaterials that can passively target the tumor sites and release exogenous iron in the acidic lysosome to enhance the efficiency of Fenton reaction, cancer Apoptozole can be killed sufficiently and effectively via ROS accumulation. In this part, we focused on engineering of novel nanomaterials either iron-based or without iron as ferroptosis inducers for high-efficient cancer specific therapy.
Conclusion and future perspectives Cancer therapy remains a great challenge for human beings. Up to date, although there have been various therapeutic strategies studied for efficient cancer treatment, even some of which have been approved for cancer indications, they mainly focused on apoptotic cancer cell death, the major form of cell death [155], [156], [157], [158]. However, the apoptosis-based therapeutic strategies have been discovered not effective enough to achieve satisfactory therapeutic effect on tumors in recent years because of apoptosis evasion and anti-apoptosis caused by the over-expression of apoptosis protein inhibitors and multi-drug resistance (MDR) effect of tumors [159], [160], [161], [162], [163]. Besides, some cancers with RAS mutation show intrinsic apoptosis resistance due to the endogenous apoptosis inhibition implicated in RAS mutation [136], [164], [165]. On this ground, ferroptosis, a new form of nonapoptotic programmed cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels, provides a new therapeutic strategy to overcome apoptotic resistance and MDR in cancer due to its morphological, biochemical, and genetical distinction from apoptosis, various forms of necrosis, and autosis [2], [99]. In comparison with apoptosis and other forms of non-apoptotic cell death, ferroptosis cannot be attenuated by apoptotic inhibitors, deletion of intrinsic apoptotic effectors, small molecule inhibitors of mitochondrial permeability transition pore (MPTP)-dependent necrosis, caspase 1-dependent pyroptosis, or receptor-interacting serine/threonine kinase 1 (RIPK1)-dependent necroptosis [166], [167], [168], [169]. In consideration of these superiorities, ferroptosis is expected to be a very promising strategy for cancer therapy, either by being utilized alone or in combinatorial treatment in the near future.