The dried rhizome of Acorus tatarinowii Schott (ATR) is the most widely used traditional Chinese medicine for the treatment of dementia due to its effect of opening orifices and eliminating phlegm (Kai-Qiao-Huo-Tan in Chinese), reviving the mind and enhancing intelligence (Xing-Shen-Yi-Zhi in Chinese), but its mechanism remains not fully understood.

To reveal the mechanism of ATR in the treatment of Alzheimer's disease (AD), which is a major type of dementia.

The effects of ATR on cognitive function and neuronal loss in APP/PS1 mice were evaluated by the novel object recognition test, nesting test, hematoxylin-eosin staining, and Nissl staining. The underlying mechanisms were studied by serum metabolomics, transcriptomics, network pharmacology, RT-PCR, Western blot, immunofluorescence, and immunohistochemistry.

ATR significantly improved cognitive function, neuronal loss, and altered lipid metabolism in APP/PS1 mice. In β-amyloid (Aβ)_1-42 and ferric citrate (FC)-induced HT22?cells, ATR significantly improved the cell viability, reduced the intracellular free iron, reactive oxygen species, and lipid peroxidation, and transcriptome analysis showed that the mechanism was related to ferroptosis and iron metabolism. Network pharmacology analysis indicated that ATR may regulate Nrf2 signaling. Both in vitro and in vivo results showed that ATR increased the mRNA and protein expression of Nrf2 and GPX4. ATR also reduced brain iron deposition, downregulated TFR1, and upregulated FPN1 expression in APP/PS1 mice.

ATR ameliorated AD by improving iron metabolism and inhibiting neuronal ferroptosis through activation of the Nrf2/GPX4 axis, which provided modern medical evidence for the use of ATR to improve AD.