Investigating the multifaceted role of nucleolin in cellular function and Cancer: Structure, Regulation, and therapeutic implications

Nucleolin (NCL), a highly conserved and multifunctional phosphoprotein, is primarily localized in the nucleolus and participates in various cellular compartments, including the nucleoplasm, cytoplasm, and plasma membrane. Initially discovered in the 1970 s, NCL is integral to ribosome biogenesis through its roles in ribosomal RNA transcription, processing, and assembly. Beyond ribosome synthesis, NCL plays critical roles in cellular processes such as DNA and RNA metabolism, chromatin remodeling, and cell cycle regulation, underscoring its essentiality for cell viability. Structurally, NCL comprises multiple functional domains, which facilitates interaction with various kinases and other proteins. NCL’s extensive post-translational modifications influence its localization and function. Importantly, NCL has emerged as a key player in multiple pathologies, particularly cancer, where it contributes to tumor growth, metastasis, and drug resistance. On the cell surface, NCL acts as a co-receptor for growth factors and other ligands, facilitating oncogenic signaling. Additionally, its regulation of non-coding RNAs, stabilization of oncogenic mRNAs, and involvement in immune evasion highlight its potential as a therapeutic target. This review provides an unexplored in-depth overview of NCL’s structure, functions, and modifications, with a focus on its role in cancer biology and its therapeutic implications.