Discovery of THB Derivates as Ferroptosis Inhibitors for the Treatment of Acute Kidney Injury by Targeting VDAC

Acute kidney injury (AKI), a clinical syndrome marked by high morbidity and mortality, remains a significant challenge due to the lack of effective therapeutic options. The accumulation of Fe²⁺ and reactive oxygen species (ROS) in injured renal cells, which triggers ferroptosis, play a key driver in the pathogenesis of AKI. In this study, tetrahydroberberine (THB), a natural product, was identified as a ferroptosis inhibitor that targeted the voltage-dependent anion channel (VDAC). Through structural optimization, a series of THB derivatives were developed, among which 34a exhibited about 100-fold enhanced ferroptosis inhibitory activity. Moreover, 34a significantly reduced ROS, Fe²⁺ and restored glutathione (GSH) below 20 nM. In vivo experiments confirmed that 34a effectively alleviated folic acid-induced AKI, accompanied by a reduction in key kidney injury markers. These results highlight the potential of 12-amino THB derivatives as novel ferroptosis inhibitors and provide promising therapeutic strategies for AKI treatment.