靶向PRMT5增强B细胞淋巴瘤中的铁死亡

Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric arginine dimethylation of proteins to regulate gene expression. PRMT5 expression is upregulated in B-cell non-Hodgkin lymphomas, including the most common diffuse large B-cell lymphoma (DLBCL) and the currently incurable mantle cell lymphoma (MCL). Ferroptosis is a form of regulated cell death driven by the accumulation of iron-dependent lipid reactive oxygen species (ROS) on cellular membranes, distinguishing it from other types of cell death. This process is initially triggered by the inhibition of system Xc - or GPX4 activity, which ultimately leads to cell death. Lymphoma-related pathways, such as the p53 pathway, MYC, and the PI3K-AKT-mTOR signaling pathway, are involved in the regulation of ferroptosis. We and others have shown that upregulated PRMT5 enhances cell proliferation and survival in lymphoma cells by activating various mechanisms, including the PI3K-AKT signaling pathway and MYC target genes. However, whether PRMT5 is involved in ferroptosis in B-cell lymphoma remains unknown. Therefore, understanding and targeting ferroptosis in B-cell lymphoma is an urgent clinical need. Our lab previously performed PRMT5 knockout RNA sequencing. Re-analysis of the RNA-seq data revealed several metabolic-related pathways affected by PRMT5 knockout in both OCI-Ly7 and TMD8 cells, including the fatty acid metabolism pathway. Treatment of DLBCL and MCL cells with various PRMT5 inhibitors or genetic knockdown alone did not induce lipid peroxidation but enhanced DMF-induced lipid peroxide accumulation. Interestingly, PRMT5 knockout or inhibition in DLBCL and MCL cells increased sensitivity to DMF treatment. Moreover, the combination of DMF and GSK3326595 exhibited a significant synergistic effect. Mechanistically, PRMT5 inhibition reduced system Xc - expression by targeting the PI3K-AKT-MYC signaling pathway. To determine whether PRMT5 inhibition promotes lipid peroxidation in various cell lines in response to DMF and other ferroptosis-inducing agents (FINs), we treated multiple DLBCL and MCL cell lines with different concentrations of the GPX4 inhibitor RSL3 and the SLC7A11 inhibitor Erastin, both alone and in combination with the PRMT5 inhibitor GSK3326595. Both RSL3 and Erastin demonstrated significant synergistic effects across different DLBCL and MCL cell lines. More importantly, a combination of GSK3326695 and DMF achieved a greater anti-tumor effect compared with either drug alone in patient-derived xenograft MCL models. In summary, we demonstrate that targeting PRMT5 through pharmacological inhibition and genetic knockdown sensitizes DLBCL and MCL cells to DMF-induced lipid peroxidation and ferroptosis. These findings provide a rationale for developing a new therapeutic strategy that induces ferroptotic cell death to treat lymphoma patients with relapsed or refractory disease.