PRMT5 Inhibition Enhances Ferroptosis in Kidney Cancer Treatment

Ferroptosis, a newly identified form of regulated cell death, has shown potential as a therapeutic target for cancer treatment. A recent study led by Dr. Meng Zhang from the Cancer Institute at Xuzhou Medical University in China, highlights the role of protein arginine methyltransferase 5 (PRMT5) in regulating ferroptosis in renal cell carcinoma (RCC). The findings indicate that inhibiting PRMT5 not only induces ferroptosis but also enhances the efficacy of immunotherapy in treating this prevalent form of kidney cancer.

Renal cell carcinoma accounts for approximately 85% of all kidney cancer cases in adults, yet effective treatment options remain limited. The study, published online on August 1, 2025, in the journal Research, explores how the regulation of the acyl-CoA synthetase family member 4 (ACSL4) protein by PRMT5 influences the ferroptosis pathway in RCC.

Ferroptosis involves lipid peroxidation and the accumulation of iron, leading to cellular membrane rupture and mitochondrial collapse. The process, critical for tumor suppression, offers new avenues for cancer treatment. Previous research has established that ACSL4 plays a key role in mediating this cell death mechanism by binding to polyunsaturated fatty acids and integrating them into cell membranes.

In this latest study, the research team screened around 765 epigenetic compounds to identify novel regulators of ferroptosis in renal cancer cells. The findings reveal that PRMT5 directly regulates the methylation of ACSL4, particularly at the arginine position 549. This methylation process destabilizes the ACSL4 protein, making renal cancer cells resistant to ferroptosis.

Dr. Zhang elaborated on the findings, stating, “Dimethylation of the arginine at position 549 leads to the degradation of ACSL4, thereby increasing the viability of renal cancer cells.” The study demonstrated that inhibiting PRMT5 expression in cancer cells resulted in a significant increase in ferroptosis.

The implications of this research are profound, as inhibiting PRMT5 not only promotes ferroptosis but also enhances the antitumor effects of immunotherapeutic treatments. The team identified a specific PRMT5 inhibitor, GSK3326595, which shows promise as a novel antitumor agent. By combining this inhibitor with a programmed death-1 blockade, the researchers propose a synergistic therapeutic strategy.

Combining multiple treatment modalities has become increasingly important in cancer therapy to overcome resistance and improve overall efficacy. The study suggests that integrating PRMT5 inhibition with immunotherapy could sensitize RCC cells to ferroptosis, potentially leading to better treatment outcomes.

While these findings are promising, further research and clinical trials are necessary to assess the safety and efficacy of this combination therapy in humans. As RCC treatment continues to evolve, understanding the molecular mechanisms that regulate cell death could pave the way for innovative therapeutic strategies.

In summary, the research led by Dr. Zhang and his team opens new avenues for the treatment of renal cell carcinoma by targeting the ferroptosis pathway through PRMT5 inhibition, highlighting the need for continued exploration in this promising area of cancer therapeutics.