Fan et al. describe DF-003, an alpha-kinase 1 (ALPK1) inhibitor that targets the root cause of the rare genetic disease ROSAH syndrome, demonstrating the ability of DF-003 to inhibit ocular inflammatory pathology in ROSAH model mice. Here, ALPK1 is linked to retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome.