PPARα Alleviates Iron Overload-induced Ferroptosis in Mouse Liver

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2022 Jun 15

PMID 35703725

Authors

Guowei Xing

Lihua Meng

Shiyao Cao

Shenghui Liu

Jiayan Wu

Qian Li

Wendong Huang

Lisheng Zhang

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is an iron-dependent form of non-apoptotic cell death implicated in liver, brain, kidney, and heart pathology. How ferroptosis is regulated remains poorly understood. Here, we show that PPARα suppresses ferroptosis by promoting the expression of glutathione peroxidase 4 (Gpx4) and by inhibiting the expression of the plasma iron carrier TRF. PPARα directly induces Gpx4 expression by binding to a PPRE element within intron 3. PPARα knockout mice develop more severe iron accumulation and ferroptosis in the liver when fed a high-iron diet than wild-type mice. Ferrous iron (Fe ) triggers ferroptosis via Fenton reactions and ROS accumulation. We further find that a rhodamine-based "turn-on" fluorescent probe(probe1) is suitable for the in vivo detection of Fe . Probe1 displays high selectivity towards Fe , and exhibits a stable response for Fe with a concentration of 20 μM in tissue. Our data thus show that PPARα activation alleviates iron overload-induced ferroptosis in mouse livers through Gpx4 and TRF, suggesting that PPARα may be a promising therapeutic target for drug discovery in ferroptosis-related tissue injuries. Moreover, we identified a fluorescent probe that specifically labels ferrous ions and can be used to monitor Fe in vivo.

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