PRMT5 K240lac confers ferroptosis resistance via ALKBH5/SLC7A11 axis in colorectal cancer.

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 m6A 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.