# Tetrahydrocurcumin Ameliorates Cerebral Ischemia–Reperfusion Injury and Restores Blood–Brain Barrier Dysfunction by Inhibiting Ferroptosis

## TL;DR

Tetrahydrocurcumin (THC) protects against brain injury after stroke by reducing cell death and restoring the blood-brain barrier through a specific signaling pathway.

## Contribution

This study reveals that THC alleviates cerebral ischemia–reperfusion injury by inhibiting ferroptosis via the Keap1/Nrf2 pathway.

## Key findings

- THC reduces infarct volume, BBB disruption, and neurological deficits in a mouse stroke model.
- THC inhibits ferroptosis by upregulating GPX4, xCT, and FTH1 and decreasing lipid peroxidation and iron accumulation.
- THC activates the Keap1/Nrf2 pathway, and its protective effects are reversed by an Nrf2 inhibitor.

## Abstract

Cerebral ischemia–reperfusion (I/R) injury is a major consequence of ischemic stroke, leading to blood–brain barrier (BBB) disruption, neuroinflammation, and neuronal death. Recent studies suggest that tetrahydrocurcumin (THC), a natural compound, may have neuroprotective effects in ischemic stroke. However, the underlying mechanisms remain unclear. This study aims to investigate THC's neuroprotective effects in cerebral I/R injury and explore its potential mechanisms.

A middle cerebral artery occlusion (MCAO) model was used to induce ischemia–reperfusion injury in mice. Bioinformatics analysis identified key genes involved in ferroptosis. THC's effects were assessed by evaluating infarct volume, BBB permeability, and ferroptosis‐related markers (GPX4, xCT, FTH1). Molecular mechanisms were explored using an Nrf2‐specific inhibitor (ML385) and molecular docking analysis.

THC treatment significantly reduced infarct volume, alleviated BBB disruption, and improved neurological function. It inhibited ferroptosis by upregulating the expression of GPX4, xCT, and FTH1, and by decreasing lipid peroxidation and iron accumulation. THC promoted Nrf2 nuclear translocation, which in turn activated the downstream antioxidant pathway. Molecular docking analysis revealed that THC binds to Keap1, promoting Nrf2 dissociation and nuclear translocation. ML385 reversed THC's protective effects, confirming the involvement of the Keap1/Nrf2 signaling pathway.

THC inhibits ferroptosis through the activation of the Keap1/Nrf2 signaling pathway, significantly improving BBB dysfunction and alleviating neurological deficits following cerebral ischemia–reperfusion. These findings suggest that THC could serve as a potential therapeutic agent for ischemic stroke, providing a novel approach for the treatment of cerebral ischemia–reperfusion injury through ferroptosis modulation.

Tetrahydrocurcumin (THC) inhibits ferroptosis and restores blood–brain barrier (BBB) function by activating the Keap1/Nrf2 signaling pathway, thereby alleviating neurological dysfunction induced by cerebral ischemia–reperfusion.