Molecular mechanisms and translational implications in apoptosis, ferroptosis, pyroptosis, and cuproptosis of spermatogonial stem cells.

Spermatogonial stem cells (SSCs) are essential for male fertility because they form the cellular foundation for normal spermatogenesis. Here we address the regulatory mechanisms governing cell deaths of SSCs, e.g., apoptosis, ferroptosis, pyroptosis, and cuproptosis, including transcriptional and post-transcriptional regulation, RNA-binding proteins, and epigenetic modifications (e.g., non-coding RNAs). We systematically elucidate testicular microenvironment and signaling pathways in controlling SSC deaths, including mitochondrial signaling, death receptor signaling, PI3K/AKT/mTOR, MAPK, and WNT/β-catenin pathways. We also discuss the translational applications of targeting key pathways or remodeling the microenvironment to intervene in SSC deaths. We highlight the prospects and requirements to develop the advanced technologies, e.g., the long-term in vitro human primary SSC culture systems, single cell multi-omics, novel gene editing approaches with high safety and efficiency, and translating efficacy from basic research to clinical applications. The present review aims to provide new and overall insights into better understanding the molecular mechanisms underlying cell deaths of SSCs and the pathogenesis of non-obstructive azoospermia (NOA), which could offer novel strategies for precise treatment of male infertility.