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Advanced Neurology Ferroptosis in neonatal HIBI

a non-apoptotic mechanism. The group subsequently 11 (SLC7A11) light chain, which mediates its function, and
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found that erastin-treated cells failed to exhibit other a solute carrier family 3 member 2 (SLC3A2) heavy chain,
signs of apoptosis but showed unique morphological which facilitates its transport and membrane expression. 47,49
changes in their mitochondria indicative of mitochondrial Excessive glutamate buildup due to ischemia-reperfusion
dysfunction. These changes were not seen in cells treated injury or other insults inhibits system x , triggering a
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with agents that induce apoptosis, necrosis, or autophagy. decrease in intracellular cysteine. This has been identified
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In addition, ROS accumulation was noted in erastin- as an essential mechanism in ferroptosis, as counteracting
treated cells, and antioxidants protected against erastin- inhibition of system x attenuates erastin-mediated cell
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mediated death, implicating an oxidative mechanism. In death. 31,46,47,51 Cystine is necessary for producing glutathione
a final foundational study, they found that RSL-mediated (GSH), an antioxidant: cystine is reduced to cysteine and
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cell death was iron-dependent, as iron chelators notably incorporated into glutamate-cysteine ligase catalytic
decreased cell death observed in response to erastin, RSL3, subunits. Therefore, intracellular GSH levels decrease
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or RSL5. In summary, before the 2012 study, the Stockwell in response to system x inhibition. 52,53 By depleting
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group had concluded that RSL-mediated cell death is non- GSH through system x , erastin indirectly inactivates
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apoptotic, involves ROS accumulation, and requires iron. glutathione peroxidase-4 (GPX4), a protein that protects
The study integrated these findings to characterize a novel against oxidative stress by preventing membrane lipid
mechanism. 31 peroxidation. 45,54 GPX4 is indirectly inactivated by erastin
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In cultured HT-1080 fibrosarcoma cells, the Stockwell through system xc inhibition, and directly inactivated
group detected an increase in cytosolic and lipid ROS by RSL3. In both cases, GPX4 inactivation promotes
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starting 2 h after erastin treatment, with cell detachment and ferroptosis by stimulating ROS production. GPX4 has
death 4 h later. ROS buildup and cell death were inhibited been deemed an essential regulator of ferroptosis, with
by cotreatment with an iron chelator but enhanced by several studies demonstrating that GPX4 downregulation
exposure to exogenous iron. They concluded that RSL renders cells increasingly susceptible to RSL-mediated
compounds mediate cell death through iron-dependent death, whereas GPX4 upregulation confers increased
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ROS buildup and termed this process ferroptosis. resistance to it. The system x /GSH/GPX4 pathway
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Through microscopy and bioenergetic analysis, the group has been identified as the central mechanism of ferroptosis
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further supported the fact that ferroptosis is a unique regulation.
phenomenon that does not resemble apoptosis, necrosis, Several other signaling molecules modulate the activity
or autophagy. They also identified a small molecule – of this central pathway. 55-59 Nuclear factor erythroid 2–
ferrostatin-1 – as a potent, specific inhibitor of ferroptosis, related factor 2 (NRF2) is a transcription factor that
which prevents erastin-mediated ROS buildup, possibly by restores redox balance under oxidative stress. In addition
acting as a scavenger. In addition, they presented evidence to its role in regulating mitochondrial dysfunction
for the involvement of ferroptosis in cancer cell death and and iron metabolism to protect against ferroptosis, it
excitotoxic neuronal damage. Ferroptosis has since been directly acts on SLC7A11 and GPX4 to upregulate their
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studied by numerous groups and identified to participate in activity. 56,57 Consequently, NRF2 knockdown increases
physiological functions, such as embryonic development, susceptibility to RSL-mediated cell death, whereas NRF2
aging, inflammation, and tumor suppression. 36-38 Its overexpression protects against it. The mechanistic
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important role in various diseases, including myocardial target of rapamycin complex 1 (mTORC1), which consists
infarction, neurodegenerative diseases, acute renal of the protein kinase mTOR and regulatory proteins,
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failure, intestinal ischemia-reperfusion injury, and, also alters activity of this central pathway. On activation
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most relevant to this review, neonatal HIBI, has also been by cystine, mTORC1 promotes the synthesis of GPX4,
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described. protecting against ferroptosis. Therefore, mTORC1 is
dependent on system x activity. mTORC1 inactivation
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2.2. Signaling mechanisms increases the susceptibility of cells to ferroptosis by
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Since the discovery of ferroptosis, research has focused on reducing GPX4 production. The alpha subunit of
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delineating its underlying signaling mechanisms. In the hypoxia-inducible factor-1 (HIF-1α) – a transcription
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instrumental study by the Stockwell group, the cystine/ factor that mediates protective cellular adaptations to
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glutamate antiporter (system x ) was implicated as a key hypoxia – also regulates this central pathway. HIF-1α
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mediator of erastin-induced ferroptosis, a finding that upregulates system x , GSH, and GPX4 activity to protect
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has since been well-supported. 44-47 System x promotes against ferroptosis. 47,58,59 These proteins represent notable
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cystine influx and glutamate efflux under physiological examples, not an exhaustive list, of agents that modulate
conditions. It consists of a solute carrier family 7 member system x /GSH/GPX4 signaling.
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Volume 4 Issue 1 (2025) 28 doi: 10.36922/an.4575