Enhancer collapse dictates PKHD1 silencing and centrosome-mediated chromosomal instability and metastasis in clear cell renal cell carcinoma.

Chromosomal instability (CIN) drives clear cell renal cell carcinoma (ccRCC) progression, yet its upstream triggers remain elusive. To identify key drivers governing renal genomic integrity, we integrated machine learning-driven screening with Mendelian randomization analysis to prioritize candidates associated with both CIN and clinical outcomes. This computational pipeline identified Polycystic Kidney and Hepatic Disease 1 (PKHD1) as a top candidate and a crucial guardian of the renal genome. Through single-cell and spatial transcriptomics, combined with functional assays in ccRCC cell lines and clinical cohort validation, we characterized the expression dynamics and biological function of PKHD1. Mechanistically, PKHD1 localizes to the centrosome, where it maintains the CEP97-CP110 complex. Depletion of PKHD1 leads to the loss of CP110 at the centrosome, thereby triggering both CIN and epithelial-to-mesenchymal transition (EMT). We further demonstrate that PKHD1 is silenced in ccRCC through the epigenetic inactivation of a distal 800-kb enhancer, which physically interacts with the PKHD1 gene within a shared topologically associating domain (TAD). Collectively, this study establishes a novel link between 3D genomic regulation and centrosome homeostasis, identifying the loss of the PKHD1-CEP97-CP110 axis as a pivotal event in kidney cancer progression and a potential biomarker for aggressive disease.