Small RNA profile alterations as a potential mechanism for sperm quality improvement following varicocelectomy

Varicocele-induced decline in sperm quality is a common cause of male infertility. While varicocelectomy improves semen parameters, the mechanisms remain unclear. Recent studies suggested that small noncoding RNAs (sncRNAs) in sperm play a significant role in male reproductive health. This study investigated whether varicoceles and surgical treatment influence the expression profiles of sperm sncRNAs and explored the related epigenetic mechanisms. This study included 63 infertile males undergoing varicocelectomy. Semen analysis was performed, followed by high-throughput deep sequencing of sperm sncRNAs both before and after surgery. The results indicated that semen parameters improved significantly following varicocelectomy. The expression profiles of sncRNAs were altered, with 10 microRNAs (miRNAs; 3 upregulated: hsa-miR-486-3p, hsa-miR-486-5p, and hsa-miR-874-3p; and 7 downregulated: hsa-miR-132-3p, hsa-miR-202-3p, hsa-miR-34c-5p, hsa-miR-499a-5p, hsa-miR-499b-3p, hsa-miR-520a-3p, and hsa-miR-92b-3p) showing significant changes post-surgery, which correlated with the improvement in sperm quality. Microinjection experiments demonstrated that the abnormally elevated expression of miRNAs in zygotes (miR-132-3p, miR-34c-5p, and miR-520a-3p) may negatively affect early embryonic development. Together, these results suggest that abnormal miRNA expression is a potential epigenetic mechanism underlying varicocele-associated sperm quality impairment. Moreover, the study findings provide evidence that varicocelectomy can relieve this process. Furthermore, the differentially expressed miRNAs may serve as potential predictors for diagnosing different pathological types of infertility and represent new molecular targets for improving fertility in males with varicoceles.