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Background <p>Intracerebral hemorrhage (ICH) is a neurological disorder with high morbidity and mortality. PAR4 has been implicated in ICH and neuroinflammation.</p> Methods <p>The rat model of intracerebral hemorrhage (ICH) was established by injecting collagenase into the brain. TTC staining, H&amp;E staining, and immunofluorescence were used to evaluate the brain tissue. In vitro, rat primary microglia (RPMCs) were isolated and the rat microglial cell line HAPI and the hippocampal neuronal cell line H19-7 were cultured. RNA-seq analysis, Western blot, co-immunoprecipitation, cell immunofluorescence, RIP assay, m<sup>6</sup>A Dot Blot Analysis were performed to investigate the role of PAR4 and its downstream signaling pathways.</p> Results <p>In the ICH rat model, treatment with the PAR4 antagonist inhibited neuronal death and reversed the M1-dominant shift of microglia. PAR4 regulated m<sup>6</sup>A methylation in microglia via KIAA1429-mediated recruitment of methyltransferase complexes. PAR4AP increased JAK2 mRNA m<sup>6</sup>A modification, mRNA and protein levels, and enhanced STAT3 protein phosphorylation. It also increased the expression of inflammatory factors and inflammasome components, with a stronger effect on AIM2 expression. PAR4AP enhanced AIM2 expression in microglial cells through mechanisms dependent on the JAK2/STAT3 signaling pathway and m<sup>6</sup>A modification. PAR4AP-activated microglia induce neuronal PANoptosis via exosome-mediated transfer of AIM2, promoting Pyrin-ZBP1 complex formation. In a rat model of ICH, lentivirus-delivered shRNAs targeting KIAA1429, FMR1, and AIM2, as well as PAR4 inhibition, suppressed PANoptosis in neuronal cells.</p> Conclusion <p>This study provides insights into the role of PAR4 in ICH and its downstream signaling pathways, suggesting potential therapeutic targets for ICH treatment.</p>

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PAR4 exacerbates intracerebral hemorrhage by driving m6A-dependent microglial AIM2 release and neuronal PANoptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Zhengyu Li,
  • Bing Bao,
  • Xinyu Yang,
  • Jun Min,
  • Zhiping Wu,
  • Weiping Chen,
  • Min Yin

摘要

Background

Intracerebral hemorrhage (ICH) is a neurological disorder with high morbidity and mortality. PAR4 has been implicated in ICH and neuroinflammation.

Methods

The rat model of intracerebral hemorrhage (ICH) was established by injecting collagenase into the brain. TTC staining, H&E staining, and immunofluorescence were used to evaluate the brain tissue. In vitro, rat primary microglia (RPMCs) were isolated and the rat microglial cell line HAPI and the hippocampal neuronal cell line H19-7 were cultured. RNA-seq analysis, Western blot, co-immunoprecipitation, cell immunofluorescence, RIP assay, m6A Dot Blot Analysis were performed to investigate the role of PAR4 and its downstream signaling pathways.

Results

In the ICH rat model, treatment with the PAR4 antagonist inhibited neuronal death and reversed the M1-dominant shift of microglia. PAR4 regulated m6A methylation in microglia via KIAA1429-mediated recruitment of methyltransferase complexes. PAR4AP increased JAK2 mRNA m6A modification, mRNA and protein levels, and enhanced STAT3 protein phosphorylation. It also increased the expression of inflammatory factors and inflammasome components, with a stronger effect on AIM2 expression. PAR4AP enhanced AIM2 expression in microglial cells through mechanisms dependent on the JAK2/STAT3 signaling pathway and m6A modification. PAR4AP-activated microglia induce neuronal PANoptosis via exosome-mediated transfer of AIM2, promoting Pyrin-ZBP1 complex formation. In a rat model of ICH, lentivirus-delivered shRNAs targeting KIAA1429, FMR1, and AIM2, as well as PAR4 inhibition, suppressed PANoptosis in neuronal cells.

Conclusion

This study provides insights into the role of PAR4 in ICH and its downstream signaling pathways, suggesting potential therapeutic targets for ICH treatment.