Dysregulation of the Upb1-3-ureidopropionate Pathway Impairs Fatty Acid Metabolism and Exacerbates Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a prevalent clinical syndrome associated with high mortality and lacking effective therapies, largely due to incomplete understanding of its pathogenic mechanisms. Proximal tubular epithelial cells (PTECs), with their high metabolic demand, represent the primary targets of injury in AKI. We identified β-ureidopropionase 1 (Upb1), a key enzyme in pyrimidine catabolism, as being specifically enriched in PTECs but markedly downregulated upon AKI. Genetic silencing of Upb1 exacerbated IR-induced AKI. Targeted metabolomics revealed that loss of renal Upb1 drives accumulation of 3-ureidopropionate (3-UPA), a pyrimidine catabolic intermediate. Integrated multi-omics analyses and functional validation demonstrated that 3-UPA impairs fatty acid oxidation through DNMT1-mediated DNA methylation, leading to mitochondrial structural and functional defects. Transcription factor analysis further revealed that myeloid ecotropic viral integration site 1 (Meis1) transcriptionally represses Upb1. Tubule-specific Meis1 overexpression aggravated folic acid (FA)- and ischemia/reperfusion injury (IR)-induced AKI, whereas pharmacological inhibition of Meis1 alleviated tubular damage. Notably, Meis1 overexpression induced marked 3-UPA accumulation, reinforcing its role as an upstream regulator of this metabolic axis. Collectively, these results demonstrate that Meis1/Upb1/3-UPA axis exerted a detrimental role in AKI, and targeting this axis (inhibiting Meis1 or activating Upb1) has therapeutic potential for AKI.