In the current issue of EMBO Molecular Medicine, Xu et al, demonstrate that NF2-deficiency of mesothelioma cells releases an NF2-mediated Hippo-pathway restraint, activates the Yes-associated protein (YAP)–carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD)/dihydroorotate dehydrogenase (DHODH) axis, and drives addiction to high-flux de novo pyrimidine biosynthesis (Xu et al, 2025). The gene discussed is DHODH; the disease is mesothelioma.