Hypoxia‐Induced PRMT1 Lactylation Drives Vimentin Arginine Asymmetric Dimethylation in Tumor Metastasis

Metastasis contributes to around 90% of cancer mortality, but effective strategies to disrupt metastatic cascades remain elusive. Hypoxia-driven epithelial-mesenchymal transition (EMT) promotes cancer cell spread, yet the post-translational mechanisms governing cytoskeletal reprogramming here remain incompletely defined. This study reports a hypoxia-inducible post-translational modification cascade: under hypoxia, protein arginine methyltransferase 1 (PRMT1) is lactylated at evolutionarily conserved residues K134/K145, enhancing its methyltransferase activity to catalyze the asymmetric dimethylation (aDMA) of vimentin at R64. This modification drives vimentin filament assembly, cytoskeletal remodeling, and metastasis in preclinical models. shPRMT1 or vimentin R64K mutation (methylation-deficient) abrogates hypoxia-enhanced migration in vitro and metastasis in vivo. Hypoxia reduces the protein levels of HDAC8 (PRMT1's delactylase), boosting PRMT1 lactylation. PRMT1 K134R/K145R mutants (lactylation - deficient) lose the ability to bind vimentin and fail to rescue filament formation. In triple-negative breast cancer (TNBC), vimentin R64 aDMA levels correlate with advanced tumor stage and poor patient survival. PRMT1 inhibitor MS023 reduces xenograft metastasis with low toxicity. These findings establish a hypoxia-PRMT1-vimentin axis, identifying vimentin R64 aDMA as a metastatic regulator. Inhibiting PRMT1 represents a promising anti-metastasis strategy.