Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis.

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis and limited therapeutic options. Leukemic stem cells (LSCs), which drive disease progression and confer resistance to therapy, pose a significant challenge to conventional treatment strategies. In this study, we identified and characterized the inhibitory mechanisms of TH37, a small molecule derived from traditional Chinese medicine, which selectively targets AML blasts and LSCs. Our analyses identified peroxiredoxin 1 (PRDX1), an enzyme that catalyzes the breakdown of hydrogen peroxide (a reactive oxygen species), as the primary molecular target of TH37. We demonstrated that TH37 directly interacts with PRDX1, inhibiting its enzymatic activity and thereby elevating intracellular reactive oxygen species levels in AML cells. PRDX1 was found to be overexpressed in AML, and its expression correlated with poor prognosis and the activation of AML- and cancer-associated pathways. Targeting PRDX1, either through lentiviral short-hairpin RNA-mediated silencing or TH37 treatment, induced apoptosis, reduced colony formation, and impaired the engraftment and growth of AML cells in immunodeficient mouse models. Furthermore, TH37 synergized with conventional chemotherapeutic agent to significantly reduce the viability and colony-forming capacity of AML cells. These findings demonstrate the critical role of PRDX1 in AML pathogenesis and highlight its potential as a key therapeutic target to improve clinical outcomes for AML patients.