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  • Introduction High mobility group box HMGB is

    2021-09-18

    Introduction High mobility group box 1 (HMGB1) is a nuclear protein that plays a fundamental role in the regulation of DNA-associated events such as DNA repair, transcription, and replication. HMGB1 can be translocated to the cytosol, plasma membrane, and extracellular space in response to various stresses. In addition to its active secretion by immune cells, HMGB1 is a prototypic damage-associated molecular pattern (DAMP) and can be released by dead, dying, or injured MAFP [1,2]. Once released, HMGB1 can further bind its receptors such as toll-like receptor 4 (TLR4) and advanced glycosylation end-product specific receptor (AGER) to mediate immunity response. Thus, inhibiting the release and extracellular activity of HMGB1 is a potential anti-inflammatory strategy for human disease [3]. Ferroptosis is a newly identified form of regulated cell death (RCD) that can be induced by small-molecule compounds or drugs [4]. Although the molecular mechanism of ferroptosis remains largely unknown, iron-dependent oxidative stress and lipid peroxidation play a key role in its initiation [5]. In particular, the activation of a lipoxygenase-dependent signaling pathway involving acyl-coA synthetase long-chain family member 4 (ACSL4) plays a key role in the generation of lipid hydroperoxides and toxic effect in ferroptosis [6,7]. In contrast, the antioxidant enzyme glutathione peroxidase 4 (GPX4) [8] or nuclear factor, erythroid 2-like 2 (NFE2L2/NRF2) transcription factor [9,10] play a central role in the inhibition of oxidative injury by ferroptosis. Macroautophagy (hereafter referred to as autophagy) is a lysosome-dependent degradation process that is important for balancing cell survival and cell death in response to environmental stress [11]. At molecular levels, autophagy is tightly regulated by autophagy-related (ATG) proteins, which can form various protein complexes with other regulators to control autophagic structures formation. Although increasing evidence indicates that ferroptosis is an autophagy-dependent cell death [12], the mechanism of how autophagic machinery regulates the immune response of ferroptotic cell death remains unidentified.
    Methods
    Results
    Discussion Cell death is a basic biological process involved in development and disease, which is traditionally divided into apoptotic (type 1), autophagic (type 2), and necrotic (type 2) cell death based on morphological features. New contemporary standards have changed from using single morphological features to using a combination of molecular and genetic aspects to classify cell death [17]. In general, cell death is classed as accidental cell death (ACD) or RCD. Unlike ACD, which is uncontrolled, RCD is a tightly controlled process requiring specific induction signaling and effector mechanisms [17]. As our current understanding of the signals and mechanisms of RCD is far from complete, distinguishing between different types of RCD is still challenging. Ferroptosis has been historically defined as an apoptosis-, autophagy-, and necrosis-independent cell death [4]. However, recent genetic studies have shown that ferroptosis requires cellular autophagic machinery to trigger cell death using multiple mechanisms. First, ferritinophagy-mediated ferritin degradation increases intracellular active iron release and subsequent oxidative injury in ferroptosis [18]. Ferritinophagy is a type of selectively autophagy that requires adaptor protein nuclear receptor coactivator 4 (NCOA4) to degrade ferritin in lysosome [18]. Second, lipophagy that is mediated by RAB7A (a member of the RAS oncogene family) can regulate neutral lipid utilization from lipid droplets and leads to lipid peroxidation in ferroptosis [19]. In contrast, increasing lipid storage mediated by tumor protein D52 (TPD52) can limit lipotoxicity in ferroptosis [19]. Third, BECN1, also termed as ATG6 in yeast, is a core regulator of autophagy [20], which can bind solute carrier family 7 member 11 (SLC7A11) to inhibit system xc− activity to cause GSH depletion and ferroptosis [21]. Fourth, lysosomal cell death mediated by signal transducer and activator of transcription 3 (STAT3) contributes to ferroptosis through the upregulation of cathepsin expression and activity [22]. Thus, ferroptosis can be initiated by both autophagy-dependent and -independent pathways.