WDR75 (WD repeat domain 75) is a nucleolar protein essential for ribosome biogenesis, specifically functioning as a component of the small subunit (SSU) processome 1. As a ribosome biogenesis factor, WDR75 binds to conserved motifs in the external transcribed spacer region of rRNA to facilitate SSU formation 2. Mechanistically, WDR75 is required for optimal pre-rRNA transcription by supporting physiological levels of RPA194, a key subunit of RNA polymerase I 1. Under nucleolar stress, WDR75 relocalizes to nucleolar caps alongside other canonical nucleolar proteins 1. WDR75 depletion impairs ribosome biogenesis and activates the RPL5/RPL11-dependent p53 stabilization checkpoint, leading to cellular senescence and impaired proliferation 1. Disease relevance includes associations with schizophrenia with tardive dyskinesia through aberrant DNA methylation 3, pancreatic cancer cachexia as a hub gene showing altered expression patterns 4, hepatocellular carcinoma where WDR75 is linked to poor prognosis and immunosuppressive tumor microenvironments 5, and sepsis-induced myopathy as a downregulated hub gene 6. Evolutionary analysis reveals WDR75 undergoes strong purifying selection across mammals, indicating its essential role is under constraint 2.