RNH1 (ribonuclease/angiogenin inhibitor 1) is a leucine-rich repeat protein that functions as a tight-binding inhibitor of pancreatic ribonucleases and angiogenin (ANG) 1. Under normal conditions, RNH1 localizes to the cytoplasm where it suppresses the cytotoxic tRNA cleavage activity of ANG, protecting cellular RNA stability. Upon cellular stress, RNH1 relocates to the nucleus, simultaneously relieving ANG inhibition in the cytoplasm and blocking ANG's angiogenic activity in the nucleus. Beyond its canonical ribonuclease inhibitory role, RNH1 functions as an inflammasome regulator that dampens excessive innate immune activation by decreasing pro-IL-1β expression and promoting caspase-1 degradation 2. Biallelic RNH1 variants cause acute necrotizing encephalopathy type 2 (ANE2), a severe parainfectious inflammatory brain disease in previously healthy children 3. In colorectal cancer, the antipsychotic drug aripiprazole suppresses tumorigenesis by targeting LAMP2a to degrade RNH1, thereby activating mTOR signaling and inducing autophagy-mediated apoptosis 4. RNH1 protein levels are inversely associated with COVID-19 disease severity in hospitalized patients 2, and the protein's structural scaffold has been repurposed for epitope-focused vaccine design against SARS-CoV-2 variants 5. These findings establish RNH1 as a pleiotropic regulator of translation, immune homeostasis, and cancer metabolism with emerging therapeutic applications.