HIF-1α exerts a double-edged sword regulatory role in hippocampal neuronal PANoptosis of Alzheimer's disease through HK2/VDAC1/NLRP3 axis and RIPK3 signal

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-1α signaling pathway exerts adouble-edged sword effect on hippocampal neuronal PANoptosis by activating the HK2/VDAC1/NLRP3 axis while concurrently suppressing RIPK3signal. This observation may offer a partial explanation for the double-edged sword role of HIF-1α as both a neuroprotective and neurotoxic factor in AD. Finally, we uncovered that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) currently undergoing phase 3 clinical trials for AD, mitigates hippocampal neuronal PANoptosis by upregulating HIF-1α expression while suppressing its downstream HK2/VDAC1/NLRP3 axis and RIPK3 signal, 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-1α-mediated regulatory mechanisms, offering a promising target for therapeutic intervention.