GNL3 (G protein nucleolar 3) is a nucleolar GTP-binding protein that regulates DNA replication dynamics and stem cell proliferation. Mechanistically, GNL3 prevents excessive DNA resection at stalled replication forks by sequestering the replication initiation factor ORC2 in the nucleolus, thereby limiting origin firing and conserving the RPA pool 1. This function is critical for maintaining genomic stability under replication stress. GNL3 also functions as an RNA-binding protein that regulates downstream genes IL24 and PTN, which contribute to osteoarthritis pathogenesis 2. Additionally, GNL3 is necessary for lithium-induced neural progenitor proliferation, with bipolar disorder-associated genetic variants regulating its expression 34. Clinically, GNL3 is upregulated in multiple cancers. In gastric cancer, high GNL3 expression correlates with poor prognosis in patients with larger tumors 5. In prostate cancer, GNL3 overexpression paradoxically decreases cell migration and invasion 6. GNL3 genetic variants are associated with hand osteoarthritis susceptibility and disease severity 7, and it was identified as a biomarker in hepatic ischemia-reperfusion injury models 8. These findings establish GNL3 as a multifunctional regulator of replication, neuronal development, and disease pathogenesis.