In summary, our data have convincingly demonstrated that tubular targeted MANF upregulation promotes mitophagy, improves mitochondrial biogenesis and OXPHOS, and mitigates STING activation, leading to attenuation of tubular injury and fibrosis in ADTKD-UMOD. The gene discussed is STING1; the disease is autosomal dominant medullary cystic kidney disease with or without hyperuricemia.