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ABSTRACT Ribosomal proteins (RPs), long regarded as essential structural components of the ribosome, are now increasingly appreciated as multifunctional regulators that extend beyond their canonical roles in protein synthesis. They actively modulate key cellular processes, including transcription, DNA damage response, cell cycle progression, and stress signaling, thereby influencing both physiological homeostasis and disease states. Despite substantial advances in structural and functional characterization, the mechanistic underpinnings linking RP dysregulation to human pathogenesis remain incompletely defined, constituting a significant gap in our understanding. This review synthesizes recent evidence illuminating the dual nature of RPs in health and disease, with a particular emphasis on cancer. Under conditions of ribosomal stress, RPs activate tumor‐suppressive pathways, whereas their dysregulation can promote oncogenesis. Beyond cancer, RPs' defects contribute to ribosomopathies, neurodegenerative disorders, and inflammation, highlighting their broad pathophysiological relevance. We also evaluate the translational potential of RPs as diagnostic and prognostic biomarkers, and review emerging therapeutic strategies targeting ribosomal pathways. Finally, we discuss current challenges, such as context‐dependent RP functions, ribosome heterogeneity, and therapeutic specificity. By integrating mechanistic insights with translational prospects, this review positions RPs as pivotal nodes bridging fundamental biology and clinical application, offering a conceptual framework to guide precision medicine efforts in RP‐associated diseases.
Zhang et al. (Mon,) studied this question.