Glycolytic enzyme PFKFB4 governs lipolysis by promoting de novo lipogenesis to drive the progression of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is among the most aggressive malignancies, marked by high recurrence rates and limited treatment efficacy, especially in HBV-associated HCC (HBV-HCC). This subtype exhibits pronounced metabolic reprogramming, with lipid synthesis playing a pivotal role in driving tumor aggressiveness and therapeutic resistance. However, the molecular mechanisms underlying this metabolic shift remain unclear. In our study, analysis of the LIHC-TCGA database and comparisons between HCC tissues and adjacent peri-tumoral tissues revealed that 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is significantly upregulated in HBV-HCC. Moreover, elevated PFKFB4 expression correlates with poorer prognosis and unfavorable overall survival among HBV-HCC patients. Functional assays demonstrated that PFKFB4 promotes HCC proliferation by enhancing glycolysis and de novo lipid synthesis. Notably, PFKFB4 not only increases glycolytic flux but also upregulates sterol regulatory element-binding protein 1 (SREBP1) expression via its enzymatic activity. Mechanistically, PFKFB4 suppresses phosphorylated AMP-activated protein kinase (p-AMPK) through enhanced aerobic glycolysis, which in turn stimulates the level of SREBP1. Collectively, these findings position PFKFB4 as a critical mediator of metabolic reprogramming in HBV-HCC and a promising therapeutic target.