PANoptosis in Alzheimer's disease: The expanding landscape of programmed cell death mechanisms and therapeutic interventions.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia in elderly people, marked by the accumulation of amyloid-β plaques and neurofibrillary tangles, resulting in neurodegeneration and cognitive decline. Emerging evidence identifies PANoptosis, a lytic form of programmed cell death that integrates pyroptosis, apoptosis and necroptosis as a central driver of AD progression. PANoptosis is orchestrated by multiprotein PANoptosome complexes such as RIPK1, AIM2, ZBP1 and NLRP12, which are activated by caspases, receptor-interacting protein kinases and innate immune stimuli including pathogen associated molecular pattern and damage associated molecular pattern. In AD, Aβ and tau aggregates activate inflammasomes, trigger mitochondrial dysfunction associated oxidative stress, and provoke chronic neuroinflammation, resulting in sustained PANoptotic cell death. Dysregulation of signalling pathways, including cGAS-STING, PI3K/AKT, JAK/STAT/IRF1, and p38/ERK/JNK MAPK contribute to PANoptosis by enhancing inflammation, free radical generation, mitochondrial damage, synaptic impairment, and BBB disruption. Preclinical studies on compounds like celasterol, magnoflorin, calycosin, and liproxstatin-1, along with clinical trials on the drugs including nicotinamide riboside, barcitinib, dexmeditomidine, and semaglutide, suggest a neuroprotective potential by modulating PANoptotic pathways. This review underscores PANoptosis as a critical pathological mechanism in AD and highlights novel therapeutic avenues aimed at disrupting this cell death program to mitigate AD progression.