PAR4 exacerbates intracerebral hemorrhage by driving m6A-dependent microglial AIM2 release and neuronal PANoptosis.
5 affiliations
- 1Department of Neurology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China.
- 2Department of Neurology, Affiliated Hospital of Jiujiang University, No. 57 East Road, Xunyang District, Jiujiang City, Jiangxi Province, PR China.
- 3Department of Neurology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China. [email protected].
- 4Institute of Neuroscience, Nanchang University, Nanchang, 330031, Jiangxi Province, PR China. [email protected].
- 5Jiangxi Provincial Clinical Medical Research Center for Neurological Disorders, Nanchang, 330031, Jiangxi Province, PR China. [email protected].
Abstract
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.
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BibTeX
@article{li2026par4,
title = {{PAR4 exacerbates intracerebral hemorrhage by driving m6A-dependent microglial AIM2 release and neuronal PANoptosis.}},
author = {Zhengyu Li and Bing Bao and Xinyu Yang and Jun Min and Zhiping Wu and Weiping Chen and Min Yin},
journal = {Cell biology and toxicology},
year = {2026},
month = aug,
doi = {10.1007/s10565-026-10237-5},
url = {https://europepmc.org/article/MED/42972199},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - PAR4 exacerbates intracerebral hemorrhage by driving m6A-dependent microglial AIM2 release and neuronal PANoptosis.
AU - Zhengyu Li
AU - Bing Bao
AU - Xinyu Yang
AU - Jun Min
AU - Zhiping Wu
AU - Weiping Chen
AU - Min Yin
PY - 2026
DA - 2026/08/05
JO - Cell biology and toxicology
DO - 10.1007/s10565-026-10237-5
UR - https://europepmc.org/article/MED/42972199
AB - 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.
SN - 0742-2091
SN - 1573-6822
ER -