Clusterin interference decreases cerebral ischemia/reperfusion injury by suppressing TFR1-dependent ferroptosis.

Authors

Xiaoping Zhou, Helan Yuan, Weilong Huang, Guanlin Huang, Xinyun Ye, Hongzhi Gao

Published in

Brain research bulletin. Pages 112160. Oct 06, 2026. Epub Oct 06, 2026.

Abstract

Ferroptosis plays a crucial role in the pathological process of cerebral ischemia-reperfusion (I/R) injury, but the specific regulatory mechanism of Clusterin in this process remains unclear. This study aims to investigate whether interfering with Clusterin can alleviate cerebral I/R injury by regulating neuronal ferroptosis. A cerebral I/R injury mouse model was established and the adeno-associated virus (AAV-sh-Clusterin) was stereotactically injected into the brain. Brain tissue damage was evaluated using TTC and HE staining. The expressions of blood-brain barrier proteins (Occludin, ZO-1) and inflammatory factors (IL-1β, TNF-α, IL-6) were detected. Downstream differentially expressed genes were analyzed through mRNA transcriptome sequencing. The expression changes of iron death-related indicators (Fe2+, MDA, GSH, NRF2, GPX4, ACSL4, SLC7A11) were evaluated by means of biochemical methods and WB/qPCR. Subsequently, an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model of HT22 cells was constructed to analyze the effects of Clusterin interference on the proliferation and ferroptosis of HT22 cells. The interaction between Clusterin and TFR1 was detected, and a rescue experiment was carried out by overexpressing TFR1. Clusterin was significantly upregulated in both in vitro and in vivo models. Interference with Clusterin effectively reduced the volume of cerebral infarction, upregulated the expressions of Occludin and ZO-1, and inhibited the inflammatory response. Besides, interference with Clusterin significantly decreased the ferroptosis level in mouse brain tissue. There is a protein interaction between Clusterin and TFR1, and the rescue experiment indicated that overexpression of TFR1 could counteract the inhibitory effect of sh-Clusterin on ferroptosis and the proliferation protection effect of HT22 cells. In summary, interfering with Clusterin by inhibiting TFR1-dependent neuronal ferroptosis significantly mitigates neuronal damage and inflammatory responses induced by cerebral I/R.

PMID:
42838389
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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