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<p>Ferroptosis is a pathogenesis of stroke. Succinylation is a promising therapeutic target for stroke. This study aimed to investigate the impact of succinyltransferase HAT1 in the progression of ischemic stroke and the underlying mechanism. HT-22 cells were stimulated by oxygen glucose deprivation to induce cell death. Mice received middle cerebral artery occlusion (MCAO) to generate a model. Ferroptosis was evaluated using propidium iodide staining and by measuring key indicators, including glutathione (GSH) levels, intracellular Fe²⁺ concentration, reactive oxygen species (ROS) levels, and ferroptosis-related protein levels. Brain infarction was observed using 2,3,5-Triphenyltetrazolium staining. The succinylation of transferrin receptor (TFRC) was measured using immunoprecipitation and western blotting. The results showed that HAT1 expression was downregulated in OGD-related HT-22 cell ferroptosis. Overexpression of HAT1 promoted the viability, as well as inhibited inflammatory response and ferroptosis of OGD-induced cells. Moreover, HAT1 ameliorated neurological dysfunction, brain infarction, and ferroptosis in the brain of MCAO mice. Additionally, we identified a novel mechanism whereby HAT1 interacted with TFRC and promoted its succinylation at K384 and K626 sites, establishing a previously unrecognized post-translational regulatory axis. Overexpression of TFRC or mutants of TFRC at succinylation sites abrogated the effect on cell phenotype induced by HAT1. In conclusion, HAT1 suppresses ferroptosis by promoting TFRC succinylation, thereby attenuating ischemic brain injury. These findings provide a potential therapeutic target for ischemic stroke.</p>

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HAT1 Protects Against Cerebral Ischemia Injury by Inhibiting TFRC-Mediated Ferroptosis

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Yue Dou,
  • Changjiang Deng,
  • Hongmei Yue,
  • Xiang Xie

摘要

Ferroptosis is a pathogenesis of stroke. Succinylation is a promising therapeutic target for stroke. This study aimed to investigate the impact of succinyltransferase HAT1 in the progression of ischemic stroke and the underlying mechanism. HT-22 cells were stimulated by oxygen glucose deprivation to induce cell death. Mice received middle cerebral artery occlusion (MCAO) to generate a model. Ferroptosis was evaluated using propidium iodide staining and by measuring key indicators, including glutathione (GSH) levels, intracellular Fe²⁺ concentration, reactive oxygen species (ROS) levels, and ferroptosis-related protein levels. Brain infarction was observed using 2,3,5-Triphenyltetrazolium staining. The succinylation of transferrin receptor (TFRC) was measured using immunoprecipitation and western blotting. The results showed that HAT1 expression was downregulated in OGD-related HT-22 cell ferroptosis. Overexpression of HAT1 promoted the viability, as well as inhibited inflammatory response and ferroptosis of OGD-induced cells. Moreover, HAT1 ameliorated neurological dysfunction, brain infarction, and ferroptosis in the brain of MCAO mice. Additionally, we identified a novel mechanism whereby HAT1 interacted with TFRC and promoted its succinylation at K384 and K626 sites, establishing a previously unrecognized post-translational regulatory axis. Overexpression of TFRC or mutants of TFRC at succinylation sites abrogated the effect on cell phenotype induced by HAT1. In conclusion, HAT1 suppresses ferroptosis by promoting TFRC succinylation, thereby attenuating ischemic brain injury. These findings provide a potential therapeutic target for ischemic stroke.