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<p>Ischemic stroke (IS) constitutes a leading driver of mortality and morbidity worldwide, with neuronal apoptosis representing a key pathological process. Accordingly, our objective was to delve into the implications of a novel signaling axis of the m6A methyltransferase METTL7B, lncRNA-MIR22HG, and JARID2 in driving neuronal apoptosis throughout cerebral ischemia/reperfusion (I/R) injury (CIRI). Mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and N2a cells exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) were, respectively, established as in vivo and in vitro I/R models. METTL7B was markedly up-regulated after I/R and enhanced the m6A methylation and stability of lncRNA-MIR22HG, significantly prolonging its transcript half-life and amplifying its biological effects on neuronal fate. Stabilized lncRNA-MIR22HG suppressed the ubiquitin-mediated degradation of JARID2, thereby increasing JARID2 abundance and activity. Elevated JARID2 promoted the assembly of the p53/p300/MDM2 transcriptional complex, which in turn up-regulated the levels of pro-apoptotic genes, ultimately exacerbating neuronal apoptosis alongside ischemic brain injury. Functionally, METTL7B overexpression aggravated neurological deficits, infarct volume, and neuronal apoptosis in vivo, whereas METTL7B knockdown alleviated ischemic damage and conferred robust neuroprotection. Collectively, these findings define a novel METTL7B/lncRNA-MIR22HG/JARID2 signaling axis that integrates RNA methylation, lncRNA stabilization, proteostasis, and transcriptional activation of apoptosis, and highlight METTL7B as a potential novel target for therapeutic strategies aimed at preventing and treating ischemic stroke.</p> Graphical Abstract <p><b>Schematic illustration of the METTL7B/lncRNA-MIR22HG/JARID2 signaling axis during cerebral ischemia/reperfusion injury.</b> Ischemic stress up-regulates METTL7B, which enhances m6A methylation and stabilizes MIR22HG. Stabilized lncRNA-MIR22HG prevents ubiquitin-mediated degradation of JARID2, promoting its accumulation. Elevated JARID2 facilitates the assembly of the p53/p300/MDM2 transcriptional complex, leading to transcriptional activation of pro-apoptotic genes (Bax, Puma, Noxa) and aggravation of neuronal apoptosis during I/R injury.</p> <p>1. METTL7B stabilizes lncRNA-MIR22HG, enhancing neuronal apoptosis in cerebral ischemia/reperfusion injury.</p> <p>2. MIR22HG prevents the ubiquitin-mediated degradation of JARID2, promoting the p53/p300/MDM2 complex.</p> <p>3. METTL7B upregulation exacerbates infarct volume, neuronal apoptosis, and neurological deficits.</p> <p>4. Knockdown of METTL7B offers neuroprotection, highlighting it as a potential therapeutic target.</p> <p></p>

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METTL7B-stabilized lncRNA-MIR22HG to drive p53-mediated neuronal apoptosis via the ubiquitinating JARID2 in cerebral ischemia/reperfusion injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月5日

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  • Hao Zhang,
  • Meng Li,
  • Yilin Wu,
  • Xiaoou Sun

摘要

Ischemic stroke (IS) constitutes a leading driver of mortality and morbidity worldwide, with neuronal apoptosis representing a key pathological process. Accordingly, our objective was to delve into the implications of a novel signaling axis of the m6A methyltransferase METTL7B, lncRNA-MIR22HG, and JARID2 in driving neuronal apoptosis throughout cerebral ischemia/reperfusion (I/R) injury (CIRI). Mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and N2a cells exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) were, respectively, established as in vivo and in vitro I/R models. METTL7B was markedly up-regulated after I/R and enhanced the m6A methylation and stability of lncRNA-MIR22HG, significantly prolonging its transcript half-life and amplifying its biological effects on neuronal fate. Stabilized lncRNA-MIR22HG suppressed the ubiquitin-mediated degradation of JARID2, thereby increasing JARID2 abundance and activity. Elevated JARID2 promoted the assembly of the p53/p300/MDM2 transcriptional complex, which in turn up-regulated the levels of pro-apoptotic genes, ultimately exacerbating neuronal apoptosis alongside ischemic brain injury. Functionally, METTL7B overexpression aggravated neurological deficits, infarct volume, and neuronal apoptosis in vivo, whereas METTL7B knockdown alleviated ischemic damage and conferred robust neuroprotection. Collectively, these findings define a novel METTL7B/lncRNA-MIR22HG/JARID2 signaling axis that integrates RNA methylation, lncRNA stabilization, proteostasis, and transcriptional activation of apoptosis, and highlight METTL7B as a potential novel target for therapeutic strategies aimed at preventing and treating ischemic stroke.

Graphical Abstract

Schematic illustration of the METTL7B/lncRNA-MIR22HG/JARID2 signaling axis during cerebral ischemia/reperfusion injury. Ischemic stress up-regulates METTL7B, which enhances m6A methylation and stabilizes MIR22HG. Stabilized lncRNA-MIR22HG prevents ubiquitin-mediated degradation of JARID2, promoting its accumulation. Elevated JARID2 facilitates the assembly of the p53/p300/MDM2 transcriptional complex, leading to transcriptional activation of pro-apoptotic genes (Bax, Puma, Noxa) and aggravation of neuronal apoptosis during I/R injury.

1. METTL7B stabilizes lncRNA-MIR22HG, enhancing neuronal apoptosis in cerebral ischemia/reperfusion injury.

2. MIR22HG prevents the ubiquitin-mediated degradation of JARID2, promoting the p53/p300/MDM2 complex.

3. METTL7B upregulation exacerbates infarct volume, neuronal apoptosis, and neurological deficits.

4. Knockdown of METTL7B offers neuroprotection, highlighting it as a potential therapeutic target.