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

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.