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PIM-1 exacerbates sepsis-associated encephalopathy via promoting microglia NLRP3 inflammasome activation

Xiaomeng Ji1, Jingquan Dong2, Wenting Zhu1

  • 1Institute of Neuroscience, Department of Neurosurgery, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, 222000, China; Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.

Free Radical Biology & Medicine
|October 2, 2025
PubMed
Abstract

Insights

PIM-1 kinase drives sepsis-associated encephalopathy (SAE) by activating microglia and neuroinflammation. Inhibiting PIM-1 with urolithin B offers a potential therapeutic strategy for SAE, improving cognitive function.

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, leading to mortality and cognitive deficits.
  • Microglial mitochondrial reactive oxygen species (mtROS) and NLRP3 inflammasome activation are key drivers of SAE pathogenesis.
  • The role of PIM-1 kinase in SAE, despite its known regulation of mtROS and NLRP3, was not well understood.

Purpose of the Study:

  • To investigate the role of PIM-1 in the development of SAE.
  • To explore the therapeutic potential of PIM-1 inhibition in SAE.

Main Methods:

  • Established a mouse model of SAE using cecal ligation and puncture (CLP).
  • Utilized in vitro models of activated microglia (BV-2 cells) with siRNA interference and RNA-seq.
  • Screened Urolithin B (UB) as a PIM-1 inhibitor via molecular docking and evaluated its efficacy in vivo and in vitro.

Main Results:

  • PIM-1 was upregulated in SAE models and correlated with brain damage.
  • PIM-1 knockdown reduced microglial activation and inflammatory cytokine release.
  • PIM-1 inhibition by UB ameliorated SAE, reduced neuronal damage, and improved cognitive impairment by modulating the mtROS/NLRP3 pathway.

Conclusions:

  • PIM-1 plays a critical role in SAE progression by mediating microglial activation and neuroinflammation.
  • Targeting PIM-1, particularly with urolithin B, demonstrates significant therapeutic potential for SAE.
Keywords:
NLRP3PIM-1Sepsis-associated encephalopathyUBmtROS

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