XPNPEP3 is a mitochondrial X-prolyl aminopeptidase that functions primarily in mitochondrial protein homeostasis and ciliary biology. As an Xaa-Pro aminopeptidase, it cleaves peptides with proline at the second position (P1') and processes imported mitochondrial matrix proteins, leading to their stabilization 1. XPNPEP3 associates with respiratory chain complex I, where it is required for complex I stability and activity 2. Beyond enzymatic functions, XPNPEP3 serves as an adapter protein that promotes TNFRSF1B-mediated JNK phosphorylation independently of its peptidase activity, potentially inhibiting TNF-induced apoptosis. Clinically, XPNPEP3 mutations cause nephronophthisis-like nephropathy-1 (NPHPL1), a rare ciliopathy characterized by progressive cystic kidney disease 3. Mutations impair complex I function, ciliary length regulation, and predispose to tubular dilation and fibrosis under stress 2. XPNPEP3 deficiency disrupts mitochondrial proteostasis, compromising ATP production critical for high-energy tissues including cardiac muscle 4. Beyond kidney disease, XPNPEP3 represents an emerging link between mitochondrial dysfunction and ciliary pathology. XPNPEP3 expression dysregulation associates with depression and other neuropsychiatric disorders 56, and Wnt/β-catenin-driven upregulation promotes colorectal cancer tumorigenic properties 7.