近日，西安交通大学教授李磊及其团队的最新研究探明了PRMT5介导的精氨酸甲基化稳定GPX4抑制癌症中的铁下垂。2025年3月3日出版的《自然—细胞生物学》杂志发表了这项成果。

在这里，课题组报道了蛋氨酸被代谢成S-腺苷蛋氨酸，它作为甲基供体在保守的精氨酸152 （R152）残基上触发谷胱甘肽过氧化物酶4 （GPX4）的对称二甲基化，并延长GPX4的半衰期。抑制蛋白精氨酸甲基转移酶5 （PRMT5）可以抑制GPX4甲基化，从而降低GPX4蛋白水平，并增加铁中毒诱导剂在体内和体外的敏感性。这种甲基化阻止Cullin1-FBW7 E3连接酶与GPX4结合，从而消除泛素化介导的GPX4降解。

值得注意的是，在无主题肿瘤模型中，将PRMT5抑制剂治疗与紧铁疗法联合使用可显著抑制肿瘤的进展。此外，GPX4水平与FBW7水平呈负相关，在人类癌症患者中预后较差。综上所述，该团队发现PRMT5通过增强GPX4的稳定性来减少肿瘤细胞对铁凋亡的拮抗，从而作为提高癌症治疗疗效的靶点。

研究人员表示，从一个非常规的角度来看，铁下垂的激活已经显示出巨大的癌症治疗潜力，但揭示抑制肿瘤固有铁下垂促进肿瘤发生的机制仍然是一个具有挑战性的任务。

附：英文原文

Title: PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer

Author: Fan, Yizeng, Wang, Yuzhao, Dan, Weichao, Zhang, Yilei, Nie, Li, Ma, Zhiqiang, Zhuang, Yanxin, Liu, Bo, Li, Mengxing, Liu, Tianjie, Wang, Zixi, Ye, Leihong, Wei, Yi, Lei, Yuzeshi, Guo, Chendong, An, Jiale, Wang, Chi, Zhang, Yulin, Zeng, Jin, Wei, Wenyi, Gan, Boyi, Li, Lei

Issue&Volume: 2025-03-03

Abstract: The activation of ferroptosis has shown great potential for cancer therapy from an unconventional perspective, but revealing the mechanisms underlying the suppression of tumour-intrinsic ferroptosis to promote tumorigenesis remains a challenging task. Here we report that methionine is metabolized into S-adenosylmethionine, which functions as a methyl-group donor to trigger symmetric dimethylation of glutathione peroxidase 4 (GPX4) at the conserved arginine 152 (R152) residue, along with a prolonged GPX4 half-life. Inhibition of protein arginine methyltransferase 5 (PRMT5), which catalyses GPX4 methylation, decreases GPX4 protein levels by impeding GPX4 methylation and increasing ferroptosis inducer sensitivity in vitro and in vivo. This methylation prevents Cullin1-FBW7 E3 ligase binding to GPX4, thereby abrogating the ubiquitination-mediated GPX4 degradation. Notably, combining PRMT5 inhibitor treatment with ferroptotic therapies markedly suppresses tumour progression in mouse tumour models. In addition, the levels of GPX4 are negatively correlated with the levels of FBW7 and a poor prognosis in patients with human carcinoma. In summary, we found that PRMT5 functions as a target for improving cancer therapy efficacy, by acting to reduce the counteraction of ferroptosis by tumour cells by means of PRMT5-enhanced GPX4 stability.

DOI: 10.1038/s41556-025-01610-3

Source: https://www.nature.com/articles/s41556-025-01610-3