Unveiling the mechanistic link between peroxiredoxin inhibition and ferroptosis-like cell death induced by Dinaciclib in Entamoeba histolytica.

Entamoeba histolytica lacks a canonical glutathione-based antioxidant system and primarily relies on the thioredoxin pathway for redox homeostasis, making peroxiredoxin (EhPrx) a critical vulnerability and potential therapeutic target. Through structure-based screening, Dinaciclib was identified as a novel direct inhibitor of EhPrx. Pharmacological targeting of EhPrx by Dinaciclib triggers a ferroptosis-like cell death pathway characterized by oxidative stress and significant accumulation of intracellular iron and lipid peroxides. In contrast, the well-established ferroptosis inducer RSL3 did not induce lipid peroxidation but instead upregulated EhPrx expression, suggesting an adaptive defense mechanism against indirect oxidative stress. Transcriptomic analysis following Dinaciclib treatment revealed widespread dysregulation of genes central to ferroptosis, including those involved in iron, lipid, and cysteine metabolism. Collectively, our results suggest that targeting EhPrx overwhelms the parasite's primary redox defense, leading to iron-driven oxidative cell death. Thus, this study identifies EhPrx as an exploitable target and proposes a distinct mechanism that triggers ferroptosis-like death in E. histolytica.