RACK1: A multifunctional scaffold protein involved in signal transduction, ribosomal regulation, and Cancer...

RACK1 (receptor for activated C kinase 1) is a highly conserved WD40 repeat family scaffold protein. As a central signaling hub, it regulates cell proliferation, migration, apoptosis, and stress responses by binding key molecules like protein kinase C, Src kinases, and integrin β-subunits. Additionally, RACK1 acts as a ribosomal protein, associating with the 40S subunit to modulate translational stalling and ubiquitination, influencing ribosome function and protein synthesis. RACK1 shows significantly down- or up-regulated in different tumors, highlighting its complex bidirectional signaling role. These effects are mediated through regulation of oncogenic pathways, apoptosis induction, metastasis inhibition, and modulation of metabolic and immune microenvironments. Therefore, the enthusiasm for RACK1-targeted therapeutic strategy is growing and placed RACK1 under the spotlight of oncology. This manuscript, to our knowledge, is the first review to summarize the role of RACK1 in pan-cancers via analysis of comprehensive gene information, and targeted inhibitors. Specifically, we introduce the structure of RACK1 and discuss the current understanding of its mechanism as a central signaling hub that coordinates diverse pathways to regulate cell proliferation, migration, apoptosis, and stress responses. This review outlines the potential therapeutic applications for targeting RACK1 and may contribute to the development of effective RACK1 inhibitors within the strategy of structure-based drug discovery of cancer therapy.