Science China Life Sciences recently published research from the team of Professor Jinpeng Sun, Professor Xiao Yu, and Professor Zhao Yang from Shandong University, and Researcher Hui Lin from Peking University Health Science Center. The study systematically elucidates how dehydroepiandrosterone (DHEA, commonly known as the "youth hormone") rapidly regulates sperm motility and reproductive tract ion homeostasis via its membrane receptor ADGRG2.
DHEA is one of the most abundant circulating steroid hormones in the human body and is commonly used in assisted reproduction to improve ovarian reserve function. However, its direct target and rapid regulatory mechanisms remain unclear. Previous work by the team resolved the cryo-EM structure of the DHEA-ADGRG2–Gs complex, confirming DHEA as a specific agonist of ADGRG2 ( Nat Chem Biol , 2022), and developed an allosteric nanobody that enhances this binding, alleviating testicular inflammation and improving reproductive function ( Nat Chem Biol , 2025). The current study further investigated whether DHEA regulates male reproductive function under physiological conditions via ADGRG2.
Regarding ion regulation, the authors found that DHEA activated ADGRG2 in efferent ductule epithelial cells and enhanced CFTR chloride channel current activity via the Gs signaling pathway, thereby regulating the chloride ion and fluid microenvironment necessary for sperm maturation.
In terms of sperm function, the study confirmed that ADGRG2 was specifically expressed in the midpiece of X chromosome-bearing sperm. DHEA significantly improved the motion parameters and survival rate of sperm from wild-type mice by activating the ADGRG2–Gs–cAMP–PKA signaling pathway. This effect was completely abolished in ADGRG2-deficient mice and was independent of CFTR or intracellular calcium signaling. The study also found that activating ADGRG2 with DHEA could enrich X chromosome-bearing sperm in vitro , although the authors note that various balancing mechanisms present in natural conception may attenuate such bias.
In summary, this study reveals that DHEA, as an endogenous ligand of ADGRG2, rapidly regulates sperm motility via the Gs–cAMP–PKA signaling pathway and modulates reproductive tract ion homeostasis by enhancing ADGRG2–CFTR functional coupling. This discovery not only clarifies a novel mechanism of DHEA in male reproduction but also provides a potential target for the precise intervention of male infertility and sex-controlled reproductive technologies.
See the article:
Dehydroepiandrosterone activates ADGRG2 to Regulate Chloride Homeostasis and Sperm Motility via Gs-cAMP Pathways
Science China Life Sciences