PKM2 lactylation promotes colorectal cancer vasculogenic mimicry and resistance to bevacizumab treatment by facilitating FOSL1 super-enhancer formation [RNA-Seq]

Despite the clinical utility of bevacizumab in advanced colorectal cancer (CRC), resistance remains a major challenge. Here, we unveiled a lactate-mediated mechanism driving vasculogenic mimicry (VM) and bevacizumab resistance through PKM2 lactylation. PKM2 lactylation at K206 by AARS1 promoted PKM2 nuclear translocation and interaction with FOSL1. PKM2 binding facilitated FOSL1-dependent super-enhancer formation and target gene transcription, which contributed to CRC cell VM. Genetic or pharmacological inhibition of PKM2 lactylation disrupted VM and synergized with bevacizumab in patient-derived pre-clinical models, significantly improving therapeutic efficacy. Together, this study reveals lactylation as a metabolic switch linking cancer glycolytic reprogramming to transcriptional rewiring and proposes targeting PKM2 lactylation to enhance the anti-tumor activity of bevacizumab in CRC. Overall design: RNA-seq profiling of PKM2 wildtype (WT) HCT116 cells and their PKM2 K206R mutant cells.