p53 regulates glucose metabolic reprogramming in MASLD-related hepatocellular carcinoma via modulating mitochondrial pyruvate carriers.

Abstract

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a leading cause of hepatocellular carcinoma (HCC), yet the molecular mechanisms linking metabolic reprogramming to MASLD-related HCC (MASLD-HCC) remain unclear. This study aimed to elucidate the role of p53 in regulating glucose metabolism via the mitochondrial pyruvate carrier (MPC) axis and its impact on MASLD-HCC progression. METHODS: A MASLD-HCC mouse model and a high-fat-induced HepG2, Huh7, Hep3B cell model were established. Serum biomarkers, liver histopathology, and tumor characteristics were analyzed. p53 activity and expression was modulated using Nutlin-3, Pifithrin-α (PFT-α), and TP53 overexpression plasmids, while MPC pathway involvement was validated using the MPC inhibitor UK-5099 and MPC1 overexpression plasmids. Techniques included Western blot, qPCR, CCK-8 assays, Oil Red O (ORO) staining, and functional assays for proliferation and migration. RESULTS: During the disease progression from MASLD to HCC, p53 expression is upregulated in vivo and in vitro models, promoting glucose metabolic reprogramming by enhancing glycolysis and suppressing gluconeogenesis. This metabolic shift is mediated through the p53-PUMA axis, which downregulates MPC. Moreover, both pharmacological and genetic modulation of MPC reversed the effects of p53 on glycolysis, lipid accumulation, tumor cell migration, and clonogenic potential. CONCLUSIONS: TP53 drives metabolic reprogramming in MASLD-HCC via the PUMA-MPC axis, promoting glycolysis-dependent tumor progression. This challenges the conventional tumor-suppressive role of p53, highlighting its context-dependent pro-tumorigenic function under metabolic stress. Targeting the p53-PUMA-MPC pathway may provide potential targets for precision therapy.