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Objective <p>Through the Forkhead box protein M1 (FOXM1)/Signal Transducer and Activator of Transcription 3 (STAT3)/P2X7 receptor (P2X7R) signaling pathway, this study sought to determine whether Special AT-rich sequence-binding protein 2 (SATB2) controls hippocampal inflammation and, in turn, impacts the development of post-traumatic stress disorder (PTSD).</p> Methods <p>The GSE66151 dataset was subjected to bioinformatics analysis in order to identify differentially expressed genes and build regulatory networks. Stereotaxic lentiviral injections were used in in vivo experiments to overexpress SATB2 or knock down P2X7R in C57BL/6J mice. PTSD traits were evaluated using behavioral tests such as the open-field test (OFT), elevated plus maze (EPM), whisker stimulation response, and conditioned fear trials. Pharmacological therapies including FOXM1 inhibitors (TH), STAT3 activators (TFA), and P2X7R antagonists (AD) were used in mechanistic investigations to break down signaling pathways. Western blotting (WB) and RT-qPCR were used to measure the amounts of protein and mRNA. Furthermore, protein interactions and FOXM1 methylation status were clarified by chromatin immunoprecipitation combined with fluorescent quantitative PCR (CHIP-qPCR) and methylation-specific PCR (MSP), while P2X7R and ionized calcium-binding adapter molecule 1 (IBA1) localization were evaluated by immunofluorescence assays.</p> Results <p>SATB2 and FOXM1 have a favorable correlation with synaptic plasticity pathways, according to a bioinformatics study. Behavioral findings showed that whereas P2X7R knockdown corrected these negative effects, SATB2 overexpression markedly increased fear memory, anxiety-like behaviors, and defensive responses. Mechanistically, CHIP-qPCR and MSP tests showed that SATB2 and FOXM1 interacted physically, with SATB2 causing the FOXM1 promoter to become demethylated in order to activate its transcription. A downstream STAT3/TET3 signaling cascade was set off by this activation, which resulted in an excessive release of inflammatory cytokines and an increase in P2X7R expression. Compensation experiments demonstrated that FOXM1 inhibitors (TH) and P2X7R inhibitors (AD) attenuated these inflammatory responses and restored methylation levels at the FOXM1 promoter, while STAT3 activators (TFA) counteracted the protective effects of FOXM1 inhibition. Furthermore, immunofluorescence confirmed that SATB2 promotes the upregulation of IBA1 and P2X7R.</p> Conclusion <p>SATB2 accelerates PTSD by inducing hippocampal inflammation via the FOXM1/STAT3/P2X7R signaling pathway. These findings provide a novel molecular mechanism for PTSD pathogenesis and suggest potential therapeutic targets.</p>

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SATB2 accelerates post-traumatic stress disorder (PTSD) via increased FOXM1/STAT3/P2X7R signaling-induced inflammation in the hippocampus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月20日

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  • Cui Zhao,
  • Jian Zhou,
  • Chi Zhang,
  • Yi Xue,
  • Zongying Liang,
  • Jimeng Cui

摘要

Objective

Through the Forkhead box protein M1 (FOXM1)/Signal Transducer and Activator of Transcription 3 (STAT3)/P2X7 receptor (P2X7R) signaling pathway, this study sought to determine whether Special AT-rich sequence-binding protein 2 (SATB2) controls hippocampal inflammation and, in turn, impacts the development of post-traumatic stress disorder (PTSD).

Methods

The GSE66151 dataset was subjected to bioinformatics analysis in order to identify differentially expressed genes and build regulatory networks. Stereotaxic lentiviral injections were used in in vivo experiments to overexpress SATB2 or knock down P2X7R in C57BL/6J mice. PTSD traits were evaluated using behavioral tests such as the open-field test (OFT), elevated plus maze (EPM), whisker stimulation response, and conditioned fear trials. Pharmacological therapies including FOXM1 inhibitors (TH), STAT3 activators (TFA), and P2X7R antagonists (AD) were used in mechanistic investigations to break down signaling pathways. Western blotting (WB) and RT-qPCR were used to measure the amounts of protein and mRNA. Furthermore, protein interactions and FOXM1 methylation status were clarified by chromatin immunoprecipitation combined with fluorescent quantitative PCR (CHIP-qPCR) and methylation-specific PCR (MSP), while P2X7R and ionized calcium-binding adapter molecule 1 (IBA1) localization were evaluated by immunofluorescence assays.

Results

SATB2 and FOXM1 have a favorable correlation with synaptic plasticity pathways, according to a bioinformatics study. Behavioral findings showed that whereas P2X7R knockdown corrected these negative effects, SATB2 overexpression markedly increased fear memory, anxiety-like behaviors, and defensive responses. Mechanistically, CHIP-qPCR and MSP tests showed that SATB2 and FOXM1 interacted physically, with SATB2 causing the FOXM1 promoter to become demethylated in order to activate its transcription. A downstream STAT3/TET3 signaling cascade was set off by this activation, which resulted in an excessive release of inflammatory cytokines and an increase in P2X7R expression. Compensation experiments demonstrated that FOXM1 inhibitors (TH) and P2X7R inhibitors (AD) attenuated these inflammatory responses and restored methylation levels at the FOXM1 promoter, while STAT3 activators (TFA) counteracted the protective effects of FOXM1 inhibition. Furthermore, immunofluorescence confirmed that SATB2 promotes the upregulation of IBA1 and P2X7R.

Conclusion

SATB2 accelerates PTSD by inducing hippocampal inflammation via the FOXM1/STAT3/P2X7R signaling pathway. These findings provide a novel molecular mechanism for PTSD pathogenesis and suggest potential therapeutic targets.