The intricate dance of RNA-binding proteins: unveiling the mechanisms behind male infertility

Abstract BACKGROUND RNA-binding proteins (RBPs) are indispensable for transcriptional and post-transcriptional processes during spermatogenesis, orchestrating germ cell proliferation, differentiation, and maturation. Despite their established importance, the contributions of RBPs in male infertility remain underexplored. Recently, a seminal Science publication reported an RBP atlas of 1744 murine testicular RBPs, 22 loss-of-function variants, and 137 deleterious missense variants identified in 1046 infertile patients, providing unprecedented opportunities to investigate their molecular and clinical relevance. Variants in RBP-related genes associated with azoospermia, oligozoospermia, teratozoospermia, and asthenozoospermia highlight their potential as diagnostic biomarkers and therapeutic targets. However, comprehensive analyses that integrate genetic, functional, and clinical insights are still lacking. OBJECTIVE AND RATIONALE This review aims to systematically analyze the roles of RBPs in male infertility. Leveraging state-of-the-art datasets and experimental insights, it examines pathogenic variants and variants of uncertain significance (VUS), and elucidates the gene–disease relationships (GDRs). Furthermore, it explores known RBP functions across spermatogenesis stages and identifies candidate RBP genes. By integrating these findings, this work provides a comprehensive framework to advance the genetic understanding of RBPs, and their potential as clinical biomarkers and therapeutic targets in male infertility. SEARCH METHODS We searched the PubMed database for articles until 13 July 2025, using the keywords ‘RNA-binding protein’, ‘male infertility’, ‘spermatogenesis’, ‘sperm’, ‘genetic variant’, ‘functional analyses’, and ‘knockout mouse model’. Pathogenic variants and VUS in 1744 RBP-coding genes, retrieved from the ClinVar and PubMed databases, were systematically analyzed to classify GDRs by the International Male Infertility Genomics Consortium database. Functional data from RBP knockout mouse models were assessed to elucidate stage-specific roles in spermatogenesis. Candidate RBP genes lacking knockout mouse models were identified by mining the RBP atlas, alongside data from the Genotype-Tissue Expression, Human Protein Atlas, and Uniprot databases. The clinical potential of RBPs as diagnostic biomarkers and therapeutic targets was also discussed. OUTCOMES Our search generated ∼2000 records, and 331 relevant articles were ultimately included in the final text. Firstly, this review identified 177 pathogenic variants in 62 RBP genes and 91 VUS in 35 RBP genes, 15 of which have been confidently linked to human male infertility. Secondly, functional analyses of 124 RBP knockout mouse models revealed their stage-specific regulatory roles in spermatocytogenesis, spermatidogenesis, and spermiogenesis, offering insights into key processes such as piwi-interacting RNA biogenesis, chromatin remodeling, and RNA stability. Thirdly, 38 RBP genes lacking knockout mouse models were screened as candidate RBP genes in male infertility, underscoring their potential for future functional investigations. Finally, this review discusses the clinical potential of RBPs as biomarkers and therapeutic targets, including RNA-based drugs, small molecules, and gene editing technologies as innovative strategies to address RBP-related male infertility. WIDER IMPLICATIONS This review highlights the role of RBPs in male infertility and offers a framework for integrating genetic, functional, and clinical data. By identifying candidate RBPs and their therapeutic potential, it lays the groundwork for future diagnostic advancements and personalized treatments in reproductive medicine. REGISTRATION NUMBER N/A.