ULK3 is a serine/threonine protein kinase with diverse cellular regulatory functions. Mechanistically, ULK3 acts as a bifunctional regulator of Sonic hedgehog (SHH) signaling: it negatively regulates SHH signaling by binding SUFU to prevent GLI phosphorylation in the absence of SHH ligand, while positively regulating it upon SHH presence through autophosphorylation and GLI2 activation 1. Beyond hedgehog signaling, ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins, particularly IST1, thereby controlling the abscission checkpoint in response to chromosome 15 and midbody tension 2. Additionally, ULK3 promotes autophagy following cellular senescence. Disease relevance emerges from ULK3's elevated expression in squamous cell carcinomas, where it controls keratinocyte proliferation through regulating histone arginine methyltransferases PRMT1/5 3. In breast cancer, elevated ULK3 expression associates with prolonged recurrence-free survival and inhibits cell proliferation 4. Clinically significant associations were identified through Mendelian randomization linking ULK3 gene expression to breast cancer risk 5. The ULK3 kinase domain exhibits high druggability and conformational plasticity, making it amenable to small-molecule inhibition 6. These findings suggest ULK3 represents a promising therapeutic target across multiple cancer types.