Suppressing ferroptosis: the role of PRMT5-driven ACSL4 methylation in renal carcinoma

Ferroptosis is a newly discovered regulated cell death mechanism, which involves the rupture of the outer membrane of cell and mitochondrial collapse. The mechanism involves lipid peroxidation, a degradation process of lipid which is the main component of the cell membrane. The process is dependent on the accumulation of iron. Recent research works suggest that it plays a pivotal role in tumor suppression, thus providing new opportunities in cancer treatment.

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for 85% of cases. Treatment options for this particular type of cancer are still limited and researchers are exploring effective diagnostic and therapeutic targets for RCC. Understanding how the ferroptosis pathway is regulated in RCC can help in developing a potential therapeutic strategy for the treatment of RCC. Previous studies established the role of acyl-CoA synthetase family member 4 (ACSL4) protein in mediating this cell death mechanism. The protein binds to polyunsaturated fatty acids, incorporates them in the phospholipid bilayer of the cell membrane, and drives the ferroptosis process.

Protein arginine methyltransferase 5 (PRMT5) is another protein of interest involved in RCC tumor progression. PRMT5 regulates methylation, a biochemical process where a methyl group is added to a molecule, such as DNA, RNA, or proteins.

In this study, a research team led by Dr. Meng Zhang from Cancer Institute, Xuzhou Medical University, China, decided to understand the role of PRMT5 and ACSL4 in the ferroptosis regulation of RCC. “Our recent research work revealed that PRMT5-mediated methylation of ALKBH5, a protein involved in RNA metabolism, leads to immune escape in colorectal cancer. We wanted to understand how PRMT5 influences RCC progression and if it affects the ferroptosis process in RCC by regulating ACSL4 methylation,” explains Dr. Zhang, talking about the motivation behind this study. The study was published online in Volume 8 of the journal Research on August 01, 2025.

The researchers used renal cancer cell line to conduct this study. The group also screened around 765 epigenetic compounds to identify the novel regulators involved in ferroptosis of renal cancer cells.  Different assays were conducted to study cell viability, protein expression, and ferroptosis pathway regulation. Patient samples were analyzed to understand RCC prognosis. Some animal model-based studies were also conducted to understand the clinical implications of the findings.

The study revealed that PRMT5 regulates the methylation of ACSL4. “ACSL4 has arginine, a basic amino acid at the 549^th position. PRMT5 regulates the methylation of ACSL4 at this position,” explains Dr. Zhang. Dimethylation of the arginine, a process where two methyl groups are added, destabilizes the ACSL4 protein. The methylated ACSL4 (meR549-ACSL4) binds to UBR5, a protein involved in protein degradation.

As ACSL4 promotes ferroptosis, its degradation makes the renal cancel cells resistant to ferroptosis. “We wanted to understand how PRMT5 affects the ferroptosis process. We inhibited PRMT5 expression in the cancer cells and noticed an increase in ferroptosis,” mentioned Dr. Zhang, while talking about the role of PRMT5. Thus, PRMT5 induces ferroptosis resistance in renal cancer cells, increasing their viability.

Ferroptosis reinforces the antitumor effect of immunotherapeutic treatments. When PRMT5 was inhibited, the researchers noticed an elevation in the ferroptosis process and an improved effect of immunotherapeutic treatment. Additionally, the research team identified a PRMT5 inhibitor called GSK3326595 which could function as a novel antitumor agent. Integrating this newly identified antitumor agent with a programmed death-1 blockade can have potential therapeutic implications.  

Combined therapeutic strategies, often involving the simultaneous application of two or more treatment modalities, are increasingly used to enhance therapeutic efficacy and overcome resistance in various diseases. In RCC, PRMT5 inhibition can be introduced along with immunotherapy strategies to sensitize the RCC cells to ferroptosis and improve the efficiency of the therapy. Further research and clinical trials are needed to assess the safety and efficiency of this combination therapy.

About Research Journal

Launched in 2018, Research is the first journal in the Science Partner Journal (SPJ) program. Research is published by the American Association for the Advancement of Science (AAAS) in association with Science and Technology Review Publishing House. Research publishes fundamental research in the life and physical sciences as well as important findings or issues in engineering and applied science. The journal publishes original research articles, reviews, perspectives, and editorials, with an Impact Factor of 10.7 and a Citescore of 13.3.

Website: https://spj.science.org/journal/research

Sources: https://spj.science.org/doi/10.34133/research.0789