PPARα alleviates iron overload-induced ferroptosis in mouse liver

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 PPAR alpha suppresses ferroptosis by promoting the expression of glutathione peroxidase 4 (Gpx4) and by inhibiting the expression of the plasma iron carrier TRF. PPAR alpha directly induces Gpx4 expression by binding to a PPR alpha element within intron 3. PPAR alpha knockout mice develop more severe iron accumulation and ferroptosis in the liver when fed a high-iron diet than wild-type mice. Ferrous iron (Fe2+) triggers ferroptosis via Fenton reactions and ROS accumulation. We further find that a rhodamine-based turn-on fluorescent probe(probel) is suitable for the in uiuo detection of Fe2+. Probe1 displays high selectivity towards Fe2+, and exhibits a stable response for Fe2+ with a concentration of 20 mu M in tissue. Our data thus show that PPAR alpha activation alleviates iron overload-induced ferroptosis in mouse livers through Gpx4 and TRF, suggesting that PPAR alpha 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 Fe2+ in uiuo.

Automated summary

This study reveals that PPAR alpha can suppress ferroptosis by promoting the expression of Gpx4 and inhibiting TRF. The activation of PPAR alpha may alleviate iron overload-induced ferroptosis and provide a promising therapeutic target for drug discovery in ferroptosis-related tissue injuries. Additionally, a fluorescent probe for the detection of Fe2+ has been identified.