Design, Synthesis, and Evaluation of Indolizine Derivatives as Nonclassical Ferroptosis Inhibitors with Efficacy in Acute Liver Injury and Ischemic Stroke Models.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Inhibiting ferroptosis has emerged as a promising therapeutic strategy, but existing inhibitors suffer from limited chemical diversity and suboptimal drug-likeness. Here, we report 1,3-disubstituted indolizine derivatives as novel noncanonical ferroptosis inhibitors. Through phenotypic screening and SAR optimization, we identified D12 (3-(2-methylbenzoyl)indolizine-1-yl acetate). D12 exhibits nanomolar potency (EC50 = 39.7 nM) in RSL3/erastin-induced PC12 cells, outperforming Fer-1. Mechanistically, D12 acts independently of iron chelation, radical trapping, or direct Nrf2 activation; instead, it alleviates oxidative stress and lipid peroxidation upstream. Compared to Fer-1, D12 displays improved metabolic stability, markedly higher systemic exposure, and robust brain penetration (brain/plasma ratio = 6.31). In vivo, D12 attenuates acetaminophen-induced liver injury and cerebral ischemia-reperfusion injury. These findings establish D12 as a mechanistically distinct, drug-like preclinical candidate and. highlight the indolizine scaffold as a promising new chemotype for ferroptosis-targeted drug discovery.