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SENP2 sensitizes neurons to ferroptosis via deSUMOylation of NCOA4 following cerebral ischemia–reperfusion injury
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DOI：10.1016/j.gendis.2026.102376.png)
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Abstract
En 中文
Ischemic stroke remains one of the leading causes of death and long-term neurological disability worldwide. Increasing evidence indicates that ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, contributes substantially to ischemic brain injury. Ferritinophagy, driven by nuclear receptor coactivator 4 (NCOA4), is considered a pivotal process promoting ferroptosis after cerebral ischemia; however, the upstream mechanisms regulating this pathway are yet to be fully defined. In the present study, using both cell-based and murine models of ischemic brain injury, we found that NCOA4 undergoes SUMOylation and identified sentrin/SUMO-specific protease 2 (SENP2) as an important suppressor of this modification. Mechanistically, SENP2 binds to NCOA4 and removes its SUMO modification, which is associated with reduced HERC2-mediated ubiquitination, increased NCOA4 stability, enhanced ferritinophagy, and exacerbated neuronal ferroptosis following ischemic stroke. In contrast, disrupting the interaction between SENP2 and NCOA4 using a membrane-permeable Tat-NCOA4 peptide maintained NCOA4 SUMOylation, attenuated ferritinophagy-associated ferroptosis, reduced infarct size and cerebral edema, and improved neurological outcomes in mice subjected to transient middle cerebral artery occlusion. Moreover, administration of a high dose of Tat-NCOA4 to nonischemic mice did not produce observable toxicity under the experimental conditions. Collectively, these findings reveal a previously unrecognized mechanism by which NCOA4 SUMOylation regulates neuronal ferroptosis and suggest that targeting SENP2 or the SENP2–NCOA4 axis may represent a promising therapeutic direction for ischemic stroke.
Keywords:
Ferroptosis
Ischemic stroke
NCOA4
SENP2
SUMOylation
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