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Objective <p>To investigate the molecular mechanism by which dexmedetomidine (Dex) alleviates neurological impairment in rats with acute cerebral infarction (ACI) by regulating the HDAC2/GPX4 signaling axis.</p> Methods <p>An ACI rat model was established using the middle cerebral artery occlusion (MCAO) method. Model rats were treated with Dex, the HDAC2 inhibitor SAHA, oe-HDAC2, or the GPX4 inhibitor RSL3. Neurological function was evaluated using neurological deficit scores, while cognitive function was assessed via open field test, three-chamber social interaction test, and novel object recognition test. The enrichment of histone H4K12ac at the GPX4 promoter region was examined by chromatin immunoprecipitation (ChIP) assay.</p> Results <p>ACI rats exhibited aggravated neurological deficits, severe cognitive impairment, and increased cerebral infarction area, accompanied by a significant upregulation of HDAC2 expression in brain tissues. Dex intervention markedly downregulated HDAC2 expression, suppressed inflammatory cytokine release, alleviated brain injury, and improved cognitive dysfunction in ACI rats. Inhibiting HDAC2 activity exerted protective effects similar to those of Dex, whereas HDAC2 overexpression partially reversed the beneficial effects of Dex on cognitive function in ACI rats. Mechanistically, Dex downregulated HDAC2 to increase H4K12ac enrichment at the GPX4 promoter region, thereby promoting the transcriptional expression of GPX4 and suppressing ferroptosis. Moreover, the protective effects of Dex against brain injury and cognitive impairment in ACI rats were partially abrogated by RSL3.</p> Conclusion <p>Dex attenuates neurological impairment and reduces ferroptosis in ACI rats by inhibiting HDAC2 expression, which in turn upregulates H4K12ac enrichment at the GPX4 promoter and facilitates GPX4 transcription.</p>

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Mechanism of Dexmedetomidine Regulating the HDAC2/GPX4 Axis in Neurological Deficits in Rats with Acute Cerebral Infarction

  • 期刊论文

  • 发表日期：

    2026年7月1日

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  • Xiaoqiong Yin,
  • Jiaxing Chen,
  • Lihong Su,
  • Chunyan He,
  • Shuibo Yang,
  • Wei Bai

摘要

Objective

To investigate the molecular mechanism by which dexmedetomidine (Dex) alleviates neurological impairment in rats with acute cerebral infarction (ACI) by regulating the HDAC2/GPX4 signaling axis.

Methods

An ACI rat model was established using the middle cerebral artery occlusion (MCAO) method. Model rats were treated with Dex, the HDAC2 inhibitor SAHA, oe-HDAC2, or the GPX4 inhibitor RSL3. Neurological function was evaluated using neurological deficit scores, while cognitive function was assessed via open field test, three-chamber social interaction test, and novel object recognition test. The enrichment of histone H4K12ac at the GPX4 promoter region was examined by chromatin immunoprecipitation (ChIP) assay.

Results

ACI rats exhibited aggravated neurological deficits, severe cognitive impairment, and increased cerebral infarction area, accompanied by a significant upregulation of HDAC2 expression in brain tissues. Dex intervention markedly downregulated HDAC2 expression, suppressed inflammatory cytokine release, alleviated brain injury, and improved cognitive dysfunction in ACI rats. Inhibiting HDAC2 activity exerted protective effects similar to those of Dex, whereas HDAC2 overexpression partially reversed the beneficial effects of Dex on cognitive function in ACI rats. Mechanistically, Dex downregulated HDAC2 to increase H4K12ac enrichment at the GPX4 promoter region, thereby promoting the transcriptional expression of GPX4 and suppressing ferroptosis. Moreover, the protective effects of Dex against brain injury and cognitive impairment in ACI rats were partially abrogated by RSL3.

Conclusion

Dex attenuates neurological impairment and reduces ferroptosis in ACI rats by inhibiting HDAC2 expression, which in turn upregulates H4K12ac enrichment at the GPX4 promoter and facilitates GPX4 transcription.