Uncovering the neuroprotective mechanisms of the food–medicine homologous Zhengchan Formula in APP/PS1 mice: Mitophagy–mediated inhibition of NLRP3 inflammasome activation

Food–medicine homologous formulas with long-term dietary safety have gained attention as functional food interventions for age-related diseases. Alzheimer's disease (AD) lacks effective and safe therapeutic options, highlighting the need for sustainable dietary strategies. Zhengchan Formula (ZCF), a classical food–medicine homologous prescription, remains poorly understood in terms of its chemical composition and mechanisms in AD. In this study, the chemical constituents of ZCF were comprehensively characterized using UPLC–QTOF–MS/MS. Dietary administration of ZCF significantly improved cognitive function and reduced neuronal damage in APP/PS1 transgenic mice. Mechanistically, ZCF enhanced mitochondrial quality control by activating mitophagy, suppressed NLRP3 inflammasome–mediated neuroinflammation, and modulated gut microbiota composition and short-chain fatty acid production. Importantly, pharmacological inhibition of autophagy abolished the beneficial effects of ZCF on neuroinflammation and gut microbial homeostasis, indicating a central role of mitophagy. These findings support ZCF as a promising functional food–based intervention for the dietary management of AD.