Lactylation of EIF4A3 mediates sustained circPTK2 biogenesis to drive prostate cancer metastasis

Enhanced glycolysis leads to pathological lactate accumulation and promotes malignant tumor progression through protein lactylation. However, the mechanisms by which lactylation enhances RNA processing to drive prostate cancer metastasis remain unclear. Specifically, we found that pathologically accumulated lactate induces the synthesis of a novel circRNA, circPTK2 (hsa_circ_0135904), which is highly expressed in PCa and predicts poor patient prognosis. Functionally, lactylated EIF4A3-induced circPTK2 promotes PCa metastasis in vitro and in vivo. Mechanistically, we revealed that lactylated EIF4A3 interacts with the flanking introns of exons 16-20 on PTK2 pre-mRNA to trigger sustained circPTK2 biogenesis. Subsequently, circPTK2 upregulates the expression of SLC4A4 by directly sponging miR-582-5p, which in turn activates the PI3K/AKT signaling pathway to drive the epithelial-mesenchymal transition (EMT) and metastasis of PCa. Crucially, SLC4A4-mediated intracellular pH (pH_i) homeostasis promotes intracellular lactate accumulation, thereby enhancing EIF4A3 lactylation and establishing a positive regulatory axis. Importantly, circPTK2 overexpression significantly accelerated subcutaneous tumor growth and facilitated lung metastasis in PCa mouse models. Our findings identify a novel mechanism by which lactate metabolism drives circRNA biogenesis, where the lactylation of EIF4A3 promotes the aberrant synthesis of circPTK2. Furthermore, we characterized a unique mechanism involving a lactylation-driven EIF4A3/circPTK2/SLC4A4 positive regulatory axis that promotes distant metastasis in PCa. Targeting this lactylation-mediated axis represents a promising therapeutic strategy for metastatic disease.