Discovery of Tetrahydropteridin Analogs as Ferroptosis Inhibitors via Combined Theoretical and Experimental Approaches

Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation and implicated in organ injury and ischemia–reperfusion (I/R) damage. The scarcity of potent ferroptosis inhibitors underscores the need for new discovery strategies. Here, we developed an integrated theoretical–experimental workflow to identify ferroptosis inhibitors beginning with the endogenous antioxidant tetrahydrobiopterin (BH4). Quantum-chemical calculations established tetrahydropteridin as a competent radical-trapping scaffold, whereas molecular-dynamics simulations revealed that native BH4 remains in the aqueous phase and therefore lacks effective anti-ferroptotic activity. Scaffold-based screening of a commercial library yielded several analogs, among which AQ-917/42754485 was predicted to combine favorable antioxidant reactivity with improved membrane accessibility. Consistent with these predictions, AQ-917/42754485 showed strong activity in DPPH and FENIX assays and fully protected HT1080 cells from RSL3-induced ferroptosis. In vivo , AQ-917/42754485 reduced lipid peroxidation and significantly ameliorated renal dysfunction in a mouse kidney I/R model. These findings demonstrate the utility of our workflow and identify AQ-917/42754485 as a promising tetrahydropteridin-based ferroptosis inhibitor.