# MST1 promotes microglial pyroptosis and neuroinflammation in alzheimer’s disease by regulating the novel DPP8/NLRP1/Caspase-1/GSDMD-N axis

## TL;DR

This study shows that MST1 promotes brain inflammation in Alzheimer’s disease by activating a specific pathway in microglial cells, suggesting that targeting MST1 could be a new treatment strategy.

## Contribution

The paper identifies a novel MST1-regulated DPP8/NLRP1/Caspase-1/GSDMD-N axis in microglial pyroptosis and neuroinflammation in Alzheimer’s disease.

## Key findings

- MST1 is activated in AD patients and 5xFAD mice, linking it to microglial pyroptosis and inflammation.
- Knocking down MST1 reduces cognitive deficits, neurodegeneration, and inflammation in 5xFAD mice.
- MST1 regulates DPP8 to modulate the NLRP1/Caspase-1/GSDMD-N axis, inhibiting microglial pyroptosis.

## Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) induced disruption of brain homeostasis, leading to neuronal damage and cognitive impairment. Increasing evidence confirms that microglia-driven neuroinflammation serves as a core mechanism driving the progression of AD. Mammalian Ste20-like kinase 1 (MST1) plays a crucial regulatory role in apoptosis, immune inflammation, and oxidative stress. Our team’s previous research revealed that MST1 regulates mitochondrial oxidative stress in neurons, contributing to the pathogenesis of AD. Here, we show that MST1 is activated as p-MST1 in the peripheral blood of AD patients, the serum of 5xFAD mice, and the hippocampal and cortical brain tissues of 5xFAD mice, an effect which was associated with microglial pyroptosis under chronic inflammatory stimulation. Knocking down MST1 in hippocampal and cortical tissues of 5xFAD mice improved cognitive deficits, reduced p-tau protein levels, and alleviated neurodegeneration and neuroinflammatory responses. Concurrently, MST1 knockdown suppressed abnormal microglial activation, decreased inflammatory cytokine release, and ultimately mitigated microglial pyroptosis. Mechanistically, we found that MST1 knockdown modulated DPP8 protein expression, thereby regulating the NLRP1/Caspase-1/GSDMD-N signaling axis to inhibit microglial pyroptosis and attenuate neuroimmune inflammation. In summary, MST1 knockdown improved AD disease progression by preventing disruption to the immune-inflammatory homeostasis of microglia. Therefore, we propose targeting MST1 as a promising therapeutic strategy to halt neuroinflammation and progression in Alzheimer’s disease.

Schematic diagram illustrating the mechanism by which MST1-mediated regulation of DPP8 drives microglial pyroptosis via the NLRP1/Caspase-1/GSDMD-N axis in Alzheimer's disease.

Schematic diagram illustrating the mechanism by which MST1-mediated regulation of DPP8 drives microglial pyroptosis via the NLRP1/Caspase-1/GSDMD-N axis in Alzheimer's disease.

The online version contains supplementary material available at 10.1186/s12974-026-03732-3.