PRMT1 and YBX1 Cooperatively Transcriptionally Activate GPX4 to Inhibit Ferroptosis and Promote Breast Cancer Progression.

Ferroptosis, a regulated form of cell death driven by lipid peroxide accumulation, is crucial in tumor development and controlled by Glutathione Peroxidase 4 (GPX4). Targeting ferroptosis offers a promising cancer therapy approach but remains challenging. Here we show that Protein Arginine Methyltransferase 1 (PRMT1) is highly expressed in breast cancer and forms a transcriptional activation complex with Y-box binding protein 1 (YBX1). This complex binds the GPX4 promoter, suppressing ferroptosis and promoting breast cancer growth and metastasis. YBX1 recruits PRMT1 independently of its enzymatic activity, while PRMT1's methyltransferase function activates transcription via H4R3me2a modification. Combined treatment with MS023 (a type I PRMT inhibitor targeting PRMT1) and SU056 (a YBX1 inhibitor) synergistically decreases GPX4 expression, enhances ferroptosis, and suppresses tumor growth. These findings establish the PRMT1-YBX1-GPX4 axis as a previously unrecognized transcriptional regulatory module and a promising therapeutic target for breast cancer.