PRMT1 drives oral squamous cell carcinoma progression by activating STAT3 and suppressing ferroptosis via GPX4

Oral squamous cell carcinoma (OSCC) exhibits poor prognosis due to aggression, metastasis, and chemoresistance. Protein Arginine Methyltransferase 1 (PRMT1) and Signal Transducer and Activator of Transcription 3 (STAT3) are implicated in oncogenesis, but their interplay and downstream effects, particularly concerning ferroptosis and immune evasion in OSCC remain unclear.

PRMT1 was significantly upregulated in OSCC tissues and cell lines, correlating with advanced grade, metastasis, and poor patient survival. PRMT1 knockdown inhibited OSCC proliferation, invasion, metastasis, and chemoresistance in vitro and in vivo. Mechanistically, PRMT1 directly interacted with, methylated, and activated STAT3 (increased p-STAT3 and target genes VEGFA, IL-6, c-myc). The PRMT1/STAT3 axis suppressed ferroptosis; PRMT1 knockdown decreased GPX4 expression, increased Fe2 + , ROS, and MDA, and decreased GSH, effects rescued by STAT3 overexpression. STAT3 directly bound and activated the GPX4 promoter. Crucially, inhibiting ferroptosis with liproxstatin-1 reversed the anti-tumor effects (chemosensitization, reduced proliferation/invasion) of PRMT1 knockdown. PRMT1 KO also enhanced anti-PD-1 therapy efficacy in vivo.

PRMT1 drives OSCC aggressiveness by methylating and activating STAT3. This axis promotes chemoresistance and oncogenic phenotypes primarily by suppressing ferroptosis through STAT3-mediated transcriptional upregulation of GPX4. Targeting PRMT1 represents a promising strategy to overcome chemoresistance and inhibit progression in OSCC.