The multidimensional biology of SKP2: mechanisms, pathologies, and emerging therapeutic frontiers

S phase kinase-associated protein 2 (SKP2), the rate-limiting substrate receptor of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, is considered a canonical gatekeeper of cell cycle progression. However, accumulating evidence indicates that SKP2 functions as a multifaceted signaling hub that orchestrates metabolic reprogramming, the DNA damage response, stem cell maintenance, and synaptic plasticity. Dysregulation of these processes contributes to the pathogenesis of many types of human diseases, including cancer. This review provides a comprehensive overview of the diverse biological roles of SKP2, beginning with detailed insights into the assembly and substrate-recognition mechanisms of the Cullin1-SKP2-CKS1 protein complex. Moreover, we explore the functional dichotomy of SKP2, expanding its classic role in K48-linked proteasomal degradation to include noncanonical roles in K63-linked signaling activation. Furthermore, we elucidate the pathogenic implications of SKP2 in malignancies such as castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC), as well as neurodegenerative conditions, including Alzheimer’s disease. More importantly, we evaluate therapeutic approaches targeting SKP2, highlighting the shift from first-generation protein-protein interaction (PPI) inhibitors to next-generation degraders, including the novel induced-proximity degrader SKPer1 and emerging PROTACs. Finally, to bridge the gap to clinical translation, we discuss the remaining druggability challenges and future directions for pharmacological optimization.