RGS14 binding to GNAI3 regulates human SSC proliferation and apoptosis through PLPP2, and abnormalities in these genes are associated with azoospermia

Background Non-obstructive azoospermia (NOA) is a severe form of male infertility characterized by the absence of sperm in the ejaculate due to impaired spermatogenesis. Spermatogonial stem cells (SSCs) play a crucial role in maintaining male fertility by ensuring continuous sperm production. However, the molecular mechanisms regulating SSC fate and their involvement in NOA remain largely unknown. Results In this study, we utilized single-cell RNA sequencing to analyze gene expression profiles in normal and NOA testes, revealing a significant downregulation of RGS14 in SSCs of NOA patients. We found that RGS14 interacts with GNAI3 and modulates SSC proliferation and apoptosis by regulating the expression of PLPP2 and the MAPK signaling pathway. Knockdown of RGS14 significantly inhibited SSC proliferation and increased apoptosis, effects that were partially rescued by overexpression of PLPP2. Additionally, both PLPP2 and GNAI3 were found to be significantly downregulated in NOA patients, correlating with the expression pattern of RGS14. Conclusions Our findings provide novel insights into the molecular mechanisms underlying SSC dysfunction in NOA. The dysregulation of RGS14, GNAI3, and PLPP2 may contribute to the pathogenesis of NOA. These results not only elucidate the role of RGS14 in SSC fate determination but also identify potential therapeutic targets for male infertility.