Multi-omic analysis of androgen-deprived human testes reveals Sertoli cell regulation and niche reprogramming.

Testis development and male fertility depend on androgens, yet the mechanisms underlying their regulation of adult human testicular function remain poorly defined due to ethical and technical constraints. To address this, we leverage androgen-deprived adult human testes as a spontaneous model and construct a comprehensive multi-omics atlas integrating single-nucleus RNA sequencing, single-cell ATAC-seq, and spatial transcriptomics. Our analyses highlight androgen-regulated transcription factors critical for Sertoli cell function and identify Neuregulin 2 (NRG2) as an androgen-dependent niche factor secreted by Sertoli cells that promotes spermatogonial proliferation both in vivo and in vitro. We further observe that androgen deprivation triggers ectopic expression of the Sertoli cell marker WT1 in the testicular interstitium, reprogramming a subset of interstitial cells toward a Sertoli-like transcriptomic state. Together, these findings uncover molecular mechanisms of androgen regulation in the adult human testes and provide a valuable resource for advancing therapies for androgen-related infertility and reproductive disorders.