Dehydroepiandrosterone activates ADGRG2 to regulate chloride homeostasis and sperm motility via Gs-cAMP pathways.

Dehydroepiandrosterone (DHEA), a steroid hormone critical to reproductive health, is widely used to improve outcomes in assisted reproductive technologies, though its molecular targets and mechanisms remain incompletely defined. In our previous studies, we identified DHEA as a ligand for the male reproductive-related receptor ADGRG2 and elucidated the recognition mechanism between DHEA and ADGRG2 using Cryo-EM structure of ADGRG2 in complex with DHEA and Gs. However, it remains unclear whether DHEA acts as a physiological ligand for ADGRG2 to regulate its functions. Using ADGRG2-deficient mice and in vitro reconstitution assays, we demonstrated that DHEA activated the Gs signaling pathways of ADGRG2 in efferent ductal cells, which facilitated synergistic coupling with cystic fibrosis transmembrane conduction regulator (CFTR) to regulate chlorine homeostasis. Strikingly, ADGRG2 is selectively expressed in X chromosome-bearing (X) sperm, where DHEA enhances motility via a Gs-cAMP signaling axis. This functional bias enables efficient enrichment of X sperm through DHEA-induced motility enhancement, achieving 80.5% XX embryos in in vitro fertilization (IVF). These findings reveal ADGRG2-dependent mechanisms underlying male reproductive physiology and position DHEA-ADGRG2 axis as a promising therapeutic target for precision management of infertility and sex-controlled reproductive technologies.