HIF1A and hepatocellular carcinoma: Metformin-induced down-regulation of HIF-1a significantly inhibits 6-phosphofructokinase-2, a potent allosteric activator of PFK1, in hepatocellular carcinoma, and studies have confirmed that metformin can inhibit glycolysis via the HIF-1α/PFKFB3/PFK1 pathway.[32] In addition, PFKFB3 significantly upregulated the expression level of HIF-1α in cancer cells.[33] There may be an as yet undefined positive feedback mechanism between PFKFB3 and HIF-1α that can accelerate tumor progression.