The SKP2-Substrate Axis in Hematological Malignancies: Mechanisms of Oncogenesis and Opportunities for Targeted...

S-phase kinase-associated protein 2 (SKP2), a key substrate-recognition subunit of the Skp1-Cul1-F-box (SCF) E3 ubiquitin ligase complex, promotes the ubiquitin-proteasome-mediated degradation of tumor suppressors such as p27^Kip1 and p21^(Cip1/Waf1). Through these activities, SKP2 regulates critical cellular processes, including cell cycle progression, apoptosis, metabolic reprogramming, maintenance of cancer stem cell stemness, and contributes to the pathogenesis, therapeutic resistance, and clinical progression of hematological malignancies. Recent advances in protein degradation technologies and regulatory network analysis have highlighted SKP2 and its substrate interactions as promising targets for precision therapies. In this review, we examine the biological functions of SKP2 and regulatory mechanisms governing its substrate spectrum across hematological malignancies, including acute myeloid leukemia, chronic myeloid leukemia, B/NK/T-cell lymphoma, and multiple myeloma. We further review currently available SKP2-targeted therapeutic strategies, including small-molecule inhibitors, molecular glue degraders, and proteolysis-targeting chimeras (PROTACs), and discuss SKP2-related prognostic biomarkers in hematological malignancies. Finally, we outline the key challenges and future directions to guide the development of SKP2-centered therapeutic approaches.