Abstract
Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, plays a pivotal role in ischemia-reperfusion organ injury and other pathological conditions. Despite its emerging significance, the molecular mechanisms controlling ferroptosis remain insufficiently understood, limiting the development of targeted therapeutics. This project aims to bridge this gap by identifying and characterizing novel ferroptosis regulators and evaluating the therapeutic potential of vitamin K analogs as ferroptosis inhibitors in acute kidney injury (AKI). First, a dual high-throughput screening approach—combining small-molecule and CRISPR-Cas9 genetic screens—has identified previously unrecognized ferroptosis-modulating targets. These targets will be validated through computational analysis, gene knockout models, and mechanistic studies in vitro, followed by in vivo evaluation in systemic ferroptosis and ischemia-reperfusion injury models. Additionally, a structure-activity relationship study will optimize vitamin K analogs, identified as potent ferroptosis inhibitors, to enhance their therapeutic potential. Lead compounds will be tested in vitro and in vivo, with direct comparison to established lipophilic radical traps. By integrating molecular discovery with translational validation, this project seeks to uncover novel ferroptosis regulators and therapeutic strategies, providing a foundation for future ferroptosis-targeting interventions in AKI and beyond.
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