# A Nasal Taxifolin Hydrogel Targets the TLR4/NF-κB/HIF-1α Axis to Suppress Ferroptosis in Alzheimer’s Disease

## TL;DR

A nasal hydrogel containing taxifolin was found to reduce Alzheimer's symptoms by targeting a specific pathway that prevents brain cell death.

## Contribution

This study is the first to show that a nasal taxifolin hydrogel suppresses ferroptosis via the TLR4/NF-κB/HIF-1α axis in Alzheimer’s disease.

## Key findings

- TF-Gel improved cognitive dysfunction and reduced neuroinflammation in an AD mouse model.
- TF-Gel inhibited ferroptosis by reducing ROS and improving mitochondrial function through the TLR4/NF-κB/HIF-1α pathway.
- Co-administration of Erastin abolished TF-Gel's benefits, confirming ferroptosis inhibition as the core mechanism.

## Abstract

In order to further explore new therapeutic targets for Alzheimer’s disease (AD), this study, under the guidance of network pharmacology and molecular docking analysis, focused on the TLR4/NF-κB/HIF-1α signal axis and ferroptosis and verified the mechanism of a nasal taxifolin thermosensitive hydrogel (TF-Gel). In the Okada acid (OA)-induced AD mouse model, intranasal administration of TF-Gel significantly improved cognitive dysfunction and reduced neuroinflammation and oxidative stress. Mechanism studies have shown that TF-Gel effectively reduces the accumulation of reactive oxygen species in the hippocampus, enhances mitochondrial membrane potential, and improves mitochondrial ultrastructure by specifically inhibiting the TLR4/NF-κB/HIF-1α pathway, thereby effectively inhibiting neuronal ferroptosis. Western blot analysis confirmed the regulation of ferroptosis, synaptic function, and apoptosis-related proteins by TF-Gel. Of particular importance, the therapeutic benefits of TF-Gel were completely abolished by co-administration of the ferroptosis inducer Erastin, directly confirming that ferroptosis inhibition is the core link in its neuroprotective effect. This study reveals for the first time that TF-Gel exerts a multi-target neuroprotective effect by precisely regulating the TLR4/NF-κB/HIF-1α axis ferroptosis pathway, providing a new perspective for research into the mechanism and treatment of AD.