Hepatocyte BPGM Induces RET Lactylation and Macrophage Reprogramming to Promote Tumorigenesis in Hepatocellular Carcinoma

ABSTRACT Aerobic glycolysis is a hallmark of cancer, yet the role of the key glycolytic enzyme bisphosphoglycerate mutase (BPGM) in hepatocellular carcinoma (HCC) progression remains unclear. Here, clinical sample analyses revealed that BPGM expression was upregulated in HCC tissues and associated with poor prognosis. Hepatocyte‐specific Bpgm knockout significantly attenuated DEN‐induced HCC development in mice. Spatial transcriptomics and single‐cell RNA sequencing revealed that hepatocyte‐specific Bpgm knockout reduced the monocyte/macrophage infiltration and decreased M2 polarization of tumor‐associated macrophages. Additionally, BPGM overexpression promoted the proliferation and migration of HCC cells and enhanced intracellular lactate accumulation. Liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) identified ret proto‐oncogene (RET) as a downstream effector that mediated the effects of BPGM on HCC cells. BPGM promoted P300‐mediated lactylation of RET at lysine 549 (K549), which competitively inhibited its ubiquitination, thereby preventing RET protein degradation and enhancing its stability. BPGM in HCC cells also induced both histone lactylation and M2 polarization of macrophages by lactate secretion. This study revealed that BPGM in hepatocytes could enhance RET expression via increasing its lactylation in malignant cells and promote M2 polarization of macrophages, both of which contributed to HCC progression. These findings established that BPGM could act as a potential therapeutic target for HCC.