Qu Shuang, Feng Baijie, Xing Mengying, Qiu Yingyi, Ma Longjun, Yang Zhou, Ji Yi, Huang Feng, Wang Yuanrong, Zhou Jingwan, Xu Min, He Jiaxin, Zhou Qinyao, Zhou Xin, Xiong Wenjing, Yao Bing, Liu Ming, Dong Qiantong, Yang Liu, Gu Shouyong
Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Medical Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
Oncogene. 2025 May 30. doi: 10.1038/s41388-025-03457-2.
Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been implicated in a number of human diseases. However, the regulatory mechanisms underlying ferroptosis in colorectal cancer (CRC) remain unclear. In this study, we unravel the pivotal role of PRMT5 in the progression of CRC by promoting ferroptosis resistance. Mechanistically, PRMT5 directly inhibits the transcription of mA demethylase ALKBH5 via histone modifications (H4R3me2s and H3R8me2s), bolstering SLC7A11 mRNA stability and expression, thereby aggravating CRC progression through attenuating ferroptosis. Particularly, our work identifies PRMT5 as a novel lactylation substrate at lysine 240 (PRMT5 K240lac), crucial for sustaining CRC ferroptosis resistance by shaping the ALKBH5/SLC7A11 axis, while mutation disrupting these effects. Overall, our work underscores the significance of PRMT5 K240lac in conferring ferroptosis resistance in CRC, proposing targeted intervention along the PRMT5 K240lac/ALKBH5/SLC7A11 axis as an innovative therapeutic approach in CRC treatment.
铁死亡是一种新发现的程序性细胞死亡类型，其特征是脂质活性氧的铁依赖性积累，这与多种人类疾病有关。然而，结直肠癌（CRC）中铁死亡的调控机制仍不清楚。在本研究中，我们揭示了PRMT5通过促进铁死亡抗性在CRC进展中的关键作用。机制上，PRMT5通过组蛋白修饰（H4R3me2s和H3R8me2s）直接抑制mA去甲基化酶ALKBH5的转录，增强SLC7A11 mRNA的稳定性和表达，从而通过减弱铁死亡来加重CRC进展。特别地，我们的研究确定PRMT5是赖氨酸240（PRMT5 K240lac）处的一种新型乳酰化底物，通过塑造ALKBH5/SLC7A11轴对维持CRC铁死亡抗性至关重要，而突变会破坏这些作用。总体而言，我们的研究强调了PRMT5 K240lac在赋予CRC铁死亡抗性中的重要性，提出沿PRMT5 K240lac/ALKBH5/SLC7A11轴进行靶向干预作为CRC治疗的一种创新治疗方法。
