Prdx2 suppresses the erythroid differentiation by modulating the ROS-JNK1 signaling axis

Erythroleukemia is a rare but aggressive subtype of acute myeloid leukemia with a poor prognosis and limited therapeutic options. Impaired erythroid differentiation is a hallmark of this disease, yet the underlying molecular mechanisms remain incompletely understood. Peroxiredoxin 2 (PRDX2), a key antioxidant enzyme involved in maintaining cellular redox homeostasis, has been implicated in various solid tumors, but its role in erythroleukemia pathogenesis has not been explored. In this study, we employed single-cell RNA sequencing (scRNA-seq) to profile the bone marrow microenvironment of Friend murine leukemia virus (F-MuLV)-induced erythroleukemia mice. Integrated analysis identified PRDX2 as a significantly upregulated molecule across multiple malignant cell populations. Elevated PRDX2 expression in leukemic bone marrow was accompanied by decreased intracellular reactive oxygen species (ROS) levels, suggesting a potential link between PRDX2-mediated redox regulation and erythroleukemia progression. Functional assays in human erythroleukemia cell lines K562 and HEL demonstrated that PRDX2 knockdown inhibited cell accumulation, increased apoptosis, and promoted erythroid differentiation. Mechanistically, PRDX2 knockdown elevated ROS levels, and treatment with the ROS inhibitor N-acetylcysteine (NAC) reversed both ROS elevation and differentiation. Furthermore, PRDX2 depletion selectively activated the JNK1 pathway, with no changes in p38, ERK, or mTOR signaling. NAC treatment reversed JNK1 activation, indicating that ROS modulates differentiation through JNK1. Consistently, treatment with a JNK1 inhibitor reversed the differentiation induced by PRDX2 knockdown, confirming that JNK1 activation is functionally required. Collectively, our findings establish PRDX2 as a critical regulator of erythroid differentiation blockade and identify PRDX2 as a promising pharmacologically actionable target for differentiation-based therapy in erythroleukemia.