HIF-1 plays a dual regulatory role in hippocampal neuronal PANoptosis in Alzheimer's disease via the HK2/VDAC1/NLRP3 axis and RIPK3 signaling
- Design
- Animal study
- Drugs
- Semaglutide
- Assessment
- Not yet reviewed by a person · added Sep 13, 2026
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Abstract
Extensive neuronal loss in brain regions critical for learning and memory is a hallmark of Alzheimer's disease (AD). PANoptosis, a newly characterized form of programmed cell death, integrates the key features of pyroptosis, apoptosis and necroptosis, and explains the molecular crosstalk among these pathways. However, whether PANoptosis is a new manner for hippocampal neuron death in AD, and the involved regulatory mechanisms remains largely unknown. Here, we demonstrate that PANoptosis is a crucial mechanism driving hippocampal neuronal loss in an AD mouse model. Moreover, we uncovered that the HIF-1 signaling pathway exerts a double-edged sword effect on hippocampal neuronal PANoptosis by activating the HK2/VDAC1/NLRP3 axis while concurrently suppressing RIPK3 signal. This observation may offer a partial explanation for the double-edged sword role of HIF-1 as both a neuroprotective and neurotoxic factor in AD. Finally, we uncovered that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), mitigates hippocampal neuronal PANoptosis by reprograming the double-eged sword effect of HIF-1 mediated by GLP-1R-AMPK signaling pathway, highlighting its potential as a therapeutic avenue for AD. These findings uncover a previously unrecognized role of PANoptosis in AD and provide new insights into the HIF-1-mediated regulatory mechanisms, offering a promising target for therapeutic intervention.