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    • br The signal of ferroptosis ROS generated by extracellular

    2022-05-11


    The signal of ferroptosis ROS generated by extracellular or intracellular stimuli play a fundamental role in cell and tissue injury in a variety of disease states [47]. Ferroptosis is generally considered as a type of ROS-dependent regulated necrosis [48]. Intracellular iron accumulation and lipid peroxidation are two central biochemical events leading to ferroptosis (Fig. 2). Multiple organelles, including mitochondria [[49], [50], [51], [52], [53], [54]], endoplasmic reticulum [[55], [56], [57]], Golgi apparatus [58] and lysosomes [59,60], are involved in the regulation of iron metabolism and redox imbalance in ferroptosis, indicating that an integrated signaling network controls and executes ferroptosis.
    The regulators of ferroptosis
    Role of autophagy in ferroptosis The cellular redox state has a profound effect on autophagy [155]. Lipid peroxidation as well as oxidized lipids can induce MAP1LC3 turnover and autophagosome formation [57,[156], [157], [158]]. In light of a growing body of evidence, excessive autophagy and lysosome activity can promote ferroptosis through iron accumulation or lipid peroxidation, as outlined eicosapentaenoic acid below. The induction of autophagy-dependent ferroptosis has also been suggested as a possible antineoplastic strategy.
    Targeting ferroptosis in cancer Since ferroptosis was described as a type of iron-dependent nonapoptotic cell death, inducing ferroptosis by experimental small-molecule compounds (e.g., erastin, RSL3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) is becoming an attractive antitumor strategy for various types of cancers, especially cancer from iron-rich tissues such as the liver [84,130,[174], [175], [176]], pancreas [57,140,177,178], and eicosapentaenoic acid [[179], [180], [181]]. The induction of ferroptosis is an alternative approach to suppressing apoptosis-resistant tumor growth. Ferroptosis is a complex process that can be pharmacologically targeted at multiple steps, but the antitumor activity of each of these ferroptosis activators is different. Tumor heterogeneity represents an ongoing challenge in the field of therapeutic targeting of ferroptosis. The expression and mutation status of oncogene (e.g., RAS) or tumor suppressor (e.g., TP53) play a context-dependent role in the regulation of ferroptotic cancer cell death [39,44,[88], [89], [90],98,99,119,120,122,123,182,183]. In addition, there is a complex relationship between ferroptosis and other types of cell death, including autophagy-dependent cell death through complex feedback loops. We are currently unable to predict if cancer cells will or won't be ferroptosis-dependent, although certain biomarkers (e.g., ACSL4 and PTGS2 [prostaglandin-endoperoxide synthase 2]) have been identified [78,83]. Of note, these biomarkers are unspecific and may occur in other conditions [184,185]. The inhibition of autophagy may diminish the anticancer activity of ferroptosis inducers. The primary or acquired resistance to ferroptosis are key barriers for tumor therapy. The best way to exploit the novel mechanism of action of ferroptosis activators for anticancer therapy remains to be defined but probably involves combining them with molecule-targeted agents for autophagy. Although certain ferroptosis activators can induce damage-associated molecular patterns (e.g., HMGB1 [high mobility group box 1]) release [186], the impact of ferroptotic cell death in tumor immunity is largely unknown.
    Conclusions and perspectives Research dealing with the fine mechanisms regulating ferroptosis is rapidly growing, although much of the results appear contradictory with regard to the relationship of ferroptosis with other types of RCD. Autophagy has a crucial role in determining the cellular survival or death under various stresses [[187], [188], [189], [190]]. Several studies support the notion that ferroptosis inducers can trigger an excessive activation of autophagy, thereby favoring the induction of cell death. Pharmacological or genetic inactivation of the autophagic machinery therefore blocks ferroptotic cell death, at least in some instances. Most of the reported ferroptosis regulators are also involved in the control of autophagy, although their functions are context dependent. Importantly, lysosomal dysfunction and impaired autophagic flux are involved in the molecular pathogenesis of iron overload and lipotoxicity [[191], [192], [193]]. Moreover, it appears intriguing that FDA-approved autophagy inhibitors such as chloroquine may be advantageously applied to wounds to prevent infection and ferroptosis-dependent tissue injury [82,[194], [195], [196], [197], [198], [199]]. Future studies are required to determine the pathophysiological impact of ferroptosis and ADCD in human disease, especially in tumorigenesis, neurodegeneration, and tissue injury. Defining the metabolic mechanisms governing iron and lipid turnover might lead to the discovery of novel therapeutic strategies.