In the past several months, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐associated infection (coronavirus disease 2019 [COVID‐19]) developed rapidly and has turned into a global pandemic. Although SARS‐CoV‐2 mainly attacks respiratory systems, manifestations of multiple organs have been observed. A great concern was raised about whether COVID‐19 may affect male reproductive functions. In this study, we collected semen specimens from 12 male COVID‐19 patients for virus detection and semen characteristics analysis. No SARS‐CoV‐2 was found in semen specimens. Eight out of 12 patients had normal semen quality. We also compared the sex‐related hormone levels between 119 reproductive‐aged men with SARS‐CoV‐2 infection and 273 age‐matched control men. A higher serum luteinizing hormone (LH) and a lower ratio of testosterone (T) to LH were observed in the COVID‐19 group. Multiple regression analysis indicated that serum T: LH ratio was negatively associated with white blood cell counts and C‐reactive protein levels in COVID‐19 patients. It's the first report about semen assessment and sex‐hormone evaluation in reproductive‐aged male COVID‐19 patients. Although further study is needed to clarify the reasons and underlying mechanisms, our study presents an abnormal sex hormone secretion among COVID‐19 patients, suggesting that attention should be paid to reproductive function evaluation in the follow‐up.

Since SARS-CoV-2 infection was first identified in December 2019, it spread rapidly and a global pandemic of COVID-19 has occurred. ACE2, the receptor for entry into the target cells by SARS-CoV-2, was found to abundantly express in testes, including spermatogonia, Leydig and Sertoli cells. However, there is no clinical evidence about whether SARS-CoV-2 infection can affect male gonadal function so far. In this study, we compared the sex-related hormones between 81 reproductive-aged men with SARS-CoV-2 infection and 100 age-matched healthy men, and found that serum luteinizing hormone (LH) was significantly increased, but the ratio of testosterone (T) to LH and the ratio of follicle stimulating hormone (FSH) to LH were dramatically decreased in males with COVID-19. Besides, multivariable regression analysis indicated that c-reactive protein (CRP) level was significantly associated with serum T:LH ratio in COVID-19 patients. This study provides the first direct evidence about the influence of medical condition of COVID-19 on male sex hormones, alerting more attention to gonadal function evaluation among patients recovered from SARS-CoV-2 infection, especially the reproductive-aged men.

Non-obstructive azoospermia (NOA) is one of the most severe manifestations of male infertility, accounting for up to 70% of azoospermic cases and affecting approximately 1% of the male population. Advances in genomics and epigenetics have transformed our understanding of NOA from a primarily idiopathic condition into a biologically heterogeneous disorder driven by diverse molecular mechanisms. This review synthesizes the current knowledge of the genetic and epigenetic landscape of NOA, integrating chromosomal abnormalities, single-gene mutations, and non-coding RNA (ncRNA) dysregulation. First, we systematically examine classical and emerging chromosomal defects-including karyotype anomalies, Y-chromosome microdeletions, and structural rearrangements-that disrupt meiotic pairing and chromatin organization. Next, we explore syndromic and non-syndromic monogenic mutations affecting meiotic regulators, DNA repair factors, transcription regulators, and chromatin remodelers. Particular emphasis is placed on recently identified genes such as SYCP1, SYCE1 and HORMAD1, whose pathogenic variants are frequently linked to spermatogenic arrest. We then discuss the expanding role of ncRNAs-including microRNAs, PIWI-interacting RNAs, long non-coding RNAs, and circular RNAs-in regulating germ cell apoptosis, transposon silencing, and epigenetic reprogramming. Furthermore, we highlight the translational potential of these molecular insights (including gene variants, ncRNAs and protein) in clinical applications. Genotype-guided sperm retrieval, non-invasive biomarkers, and multi-omic approaches are discussed as promising tools to improve diagnosis and treatment. Moreover, we summarize current and emerging strategies for the treatment and fertility preservation of NOA. Finally, we identify persisting challenges, such as genotypic heterogeneity and incomplete functional validation, and emphasize the need to elucidate interactions between ncRNA and classical genetic pathways to uncover regulatory hierarchies underlying NOA. By integrating molecular genetics with testicular histopathology and clinical phenotypes, this review highlights emerging genetic and ncRNA biomarkers and underscores their potential applications in the clinical management of NOA. Ultimately, a comprehensive understanding of the genetic and epigenetic underpinnings of NOA will be essential for advancing precision diagnostics and improving reproductive outcomes in affected men.

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.