PKM2 Lactylation Promotes Colorectal Cancer Vasculogenic Mimicry and Bevacizumab Resistance by Facilitating FOSL1...

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.

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.