In conclusion, our studies demonstrated that: (i) UCP2 overexpression positively correlates with PFKFB2 activity; (ii) UCP2-induced PFKFB2 upregulation leads to enhanced glycolysis; (iii) AKT may mediate UCP2-induced PFKFB2 activation; and (iv) targeting UCP2 and/or PFKFB2 may serve as a novel therapeutic approach for UCP2 highly expressed cancers. Here, PFKFB2 is linked to cancer.