PKM2 Lactylation Promotes Colorectal Cancer Vasculogenic Mimicry and Bevacizumab Resistance by Facilitating FOSL1 Super-enhancer Formation

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. Together, this study reveals lactylation as a metabolic switch linking cancer glycolytic reprogramming to transcriptional rewiring and proposes targeting PKM2 lactylation to enhance the antitumor activity of bevacizumab in colorectal cancer. Significance: PKM2 lactylation mediates vasculogenic mimicry by facilitating FOSL1-dependent super-enhancer formation and represents a potential target to improve the clinical efficacy of bevacizumab in colorectal cancer patients.