Discovery of 8-hydroxy-tetrahydroquinoline ferroptosis inhibitors for the treatment of acute kidney injury.

Acute kidney injury (AKI) is a severe public health challenge, characterized by high incidence and mortality rates, alongside a lack of effective therapeutic interventions. Emerging evidence highlights kidney tubular ferroptosis as a key driver of AKI pathogenesis. While α-tocopherol, a natural lipid antioxidant, exhibits potent anti-ferroptotic activity, its therapeutic potential remains limited by a lack of structural optimization. Here, we present the discovery of 8-hydroxy-tetrahydroquinoline (compound 6), a rationally designed derivative inspired by α-tocopherol's simplified core structure (6-chromanol), which effectively protects against renal ischemia/reperfusion (I/R) injury by suppressing ferroptosis. Quantum chemistry and reaction kinetics analyses reveal that enhancing p-π conjugation and introducing hydrogen bond donors significantly improve radical trapping activity (RTA), thereby strengthening ferroptosis inhibition. Compound 6 displayed broad-spectrum anti-ferroptotic efficacy across multiple inducers in renal tubular epithelial cells, with nanomolar potency and robust suppression of lipid ROS. Mechanistically, compound 6 neither chelated iron nor altered GPX4 expression, indicating its protection arises via direct peroxyl radical scavenging. In vivo, compound 6 significantly ameliorated renal I/R injury in mice, reducing histological damage, functional impairment, and inflammatory cytokine expression, while decreasing lipid peroxidation biomarkers such as 4-hydroxynonenal. Collectively, this work identifies compound 6 as a promising ferroptosis-targeted therapeutic scaffold for AKI and provides a framework for rational antioxidant design based on natural phenolic structures.