La lactilazione di PKM2 promuove la mimetizzazione vascolare del cancro colorettale e la resistenza al bevacizumab facilitando la formazione del super-attivatore FOSL1.

UNLABELLED: Despite the clinical utility of bevacizumab in advanced colorectal cancer, resistance remains a major challenge. In this study, 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 colorectal cancer cell VM. Genetic or pharmacologic inhibition of PKM2 lactylation disrupted VM and synergized with bevacizumab in patient-derived preclinical models, significantly improving therapeutic efficacy. Tog