Validation across rigorous preclinical models confirms the therapeutic promise of DHODH targeting and highlights a potent combination strategy: DHODH inhibition specifically synergizes with cisplatin against NF2-deficient mesothelioma, enhancing antitumor efficacy while limiting potential resistance pathways and underscoring the regimen’s robust translational and clinical potential. The gene discussed is DHODH; the disease is mesothelioma.