Muller et al. previously demonstrated that the phosphonate compound (1-hydroxy-2-oxopiperidin-3-yl)phosphonic acid (HEX, Fig. 1) selectively inhibits human ENO2, effectively killing ENO1-deleted glioma cells and eliminating intracranial ENO1-deficient tumors in mice.11 Given the 47% sequence similarity between NfENO and human ENO2, and the fact that HEX can permeate the blood-cerebrospinal fluid (CSF) barrier to reach the brain, Milanes and colleagues screened HEX and related phosphonate ENO2 inhibitors against NfENO and N. fowleri trophozoites. Here, ENO1 is linked to glioma.