LBX2 promotes colorectal cancer progression via the glycosylation and lactylation positive feedback.

Colorectal cancer (CRC) ranks as a leading cause of cancer-related mortality worldwide, yet its molecular mechanisms remain incompletely understood. The transcription factor LBX2 regulates morphogenesis of multiple organ systems in vertebrates, yet its role in CRC progression remains poorly understood. In the study, we found that LBX2 knockdown suppresses CRC proliferation in vitro and in vivo. ChIP-seq/RNA-seq identifies GFPT2 as a direct transcriptional target of LBX2. The LBX2/GFPT2 axis elevates UDP-GlcNAc levels and O-GlcNAcylation, promoting Raptor T700 glycosylation. This modification enhances mTORC1 activation by strengthening Raptor-Rag interactions, accelerating glycolysis and lactate production. Accumulated lactate induces histone H4K12 lactylation, which further upregulates LBX2 transcription, forming a positive feedback loop. Clinically, high LBX2 expression correlates with elevated PET-CT SUVmax values (indicating hyperglycolysis) in CRC patients. Patient-derived organoids with high LBX2 show increased sensitivity to the GLUT1 inhibitor. LBX2 thus serves as both a metabolic driver and a potential biomarker for CRC-targeted therapies.