Potential modulation of microglial ferroptosis by Linggui Zhugan decoction in Alzheimer's disease through IL-17 and TNF pathways

Alzheimer's Disease (AD) is a neurodegenerative condition marked by cognitive decline and memory loss, with ferroptosis, an iron-dependent form of regulated cell death, emerging as a contributing factor. This study explored the potential modulatory effects of key components of the traditional Chinese medicine (TCM) formula Linggui Zhugan Decoction (LZD) on microglial ferroptosis in AD, focusing on IL-17 and TNF signaling pathways. Using single-cell RNA sequencing, we observed alterations in microglial populations and ferroptosis-related gene expression in AD mice. Network pharmacology and in vitro experiments indicated that LZD components might influence ferroptosis-related pathways, coinciding with reduced IL-17 and TNF levels in Aβ1–42-treated microglia. In vivo, LZD administration was associated with improved behavioral outcomes and modulation of ferroptosis markers. Although our findings suggest a correlation between LZD treatment and attenuation of ferroptosis-associated pathology, further mechanistic validation is necessary to establish causal links. This study provides preliminary evidence supporting the therapeutic potential of TCM in AD via inflammatory pathway modulation. • First evidence that Linggui Zhugan Decoction alleviates AD ferroptosis via IL-17/TNF pathway inhibition. • Key components reverse Aβ1–42-induced microglial damage. • Improves cognition and regulates tau protein in AD mice. • Provides new molecular targets and theoretical basis. • Demonstrates therapeutic potential for AD treatment.