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Background <p>Isoquercitrin (ISO), a neuroprotective flavonoid, alleviates ischemic stroke (IS) by inhibiting ferroptosis. In present study, we explored the mechanism of ISO attenuates neuronal ferroptosis in IS.</p> Methods <p>HT22 cells and primary neurons underwent oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic in vitro IS. Dual‑luciferase reporter assays detected luciferase activity. H3K9 acetylation levels at the RBM15 promoter were assessed by ChIP. The m6A modification of SLC25A28 mRNA was analyzed by MeRIP. The binding of RBM15 and IGF2BP3 to SLC25A28 mRNA was examined via RIP. Lipid and intracellular ROS levels were measured by C11-BODIPY and DCFH-DA staining. The levels of ferroptosis-related indicators were determined with commercial kits. Cell viability was examined using the CCK-8 assay. In vivo, the middle cerebral artery occlusion (MCAO) rat model was used to explore the effect of ISO.</p> Results <p>ISO protected against OGD/R-induced ferroptosis and restored viability. ISO inhibited neuronal ferroptosis by reducing RBM15 expression. ISO suppressed RBM15 via SIRT1-mediated H3K9 deacetylation. Subsequently, RBM15 promoted m6A modification of SLC25A28 mRNA to enhance its stability. Reversal of ISO-mediated ferroptosis suppression by SLC25A28 overexpression was partly counteracted by RBM15 knockdown. In the MCAO model, ISO reduced infarct volume, lowered MDA levels, and restored GPX4 expression, which were partly reversed by RBM15 overexpression.</p> Conclusion <p>ISO promoted SIRT1-mediated H3K9 deacetylation at the RBM15 promoter to suppress its transcription. RBM15 downregulation inhibited SLC25A28 stability by m6A-IGF2BP3-dependent, ultimately attenuating neuronal ferroptosis in IS.</p>

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Isoquercitrin suppresses neuronal ferroptosis in ischemic stroke via SIRT1-mediated deacetylation of H3K9 at the RBM15 promoter

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Shichang Cai,
  • Siqi Zhou,
  • Yicheng Wang,
  • Zhen Li,
  • Hongzhu Long,
  • Yiping Chen,
  • Meichun Wu,
  • Xiuping Li

摘要

Background

Isoquercitrin (ISO), a neuroprotective flavonoid, alleviates ischemic stroke (IS) by inhibiting ferroptosis. In present study, we explored the mechanism of ISO attenuates neuronal ferroptosis in IS.

Methods

HT22 cells and primary neurons underwent oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic in vitro IS. Dual‑luciferase reporter assays detected luciferase activity. H3K9 acetylation levels at the RBM15 promoter were assessed by ChIP. The m6A modification of SLC25A28 mRNA was analyzed by MeRIP. The binding of RBM15 and IGF2BP3 to SLC25A28 mRNA was examined via RIP. Lipid and intracellular ROS levels were measured by C11-BODIPY and DCFH-DA staining. The levels of ferroptosis-related indicators were determined with commercial kits. Cell viability was examined using the CCK-8 assay. In vivo, the middle cerebral artery occlusion (MCAO) rat model was used to explore the effect of ISO.

Results

ISO protected against OGD/R-induced ferroptosis and restored viability. ISO inhibited neuronal ferroptosis by reducing RBM15 expression. ISO suppressed RBM15 via SIRT1-mediated H3K9 deacetylation. Subsequently, RBM15 promoted m6A modification of SLC25A28 mRNA to enhance its stability. Reversal of ISO-mediated ferroptosis suppression by SLC25A28 overexpression was partly counteracted by RBM15 knockdown. In the MCAO model, ISO reduced infarct volume, lowered MDA levels, and restored GPX4 expression, which were partly reversed by RBM15 overexpression.

Conclusion

ISO promoted SIRT1-mediated H3K9 deacetylation at the RBM15 promoter to suppress its transcription. RBM15 downregulation inhibited SLC25A28 stability by m6A-IGF2BP3-dependent, ultimately attenuating neuronal ferroptosis in IS.