Deer velvet antler peptides protect premature ovarian insufficiency by modulating CHK2-TAp63α signaling and gut microbiota

Premature ovarian insufficiency (POI) is a prevalent complication among childhood, adolescent, and young adult (CAYA) cancer survivors, yet lacks effective treatments. Here we show that therapeutic gavage of deer velvet antler peptides (DVAP) reversed the reduction of primordial follicles (PFs), enhanced fertility, and suppressed apoptosis in cyclophosphamide (CTX)-induced POI mice by modulating the gut microbiota and the CHK2-TAp63α signaling pathway. Prophylactic DVAP treatment similarly mitigated PF loss. Crucially, fecal microbiota transplantation (FMT) from DVAP-treated POI mice recapitulated the protective effects, while antibiotic-mediated gut microbiota depletion abolished DVAP’s therapeutic benefits, confirming gut microbiota as the primary mediator. Notably, DVAP reshaped the gut microbial composition by enriching Lactobacillus and Limosilactobacillus genera, both positively correlated with PF preservation. Furthermore, several phosphatidylinositol (PI) species in feces, including PI(18:0/PGF1α), PI(PGF1α/20:1(11Z)), and PI(PGF1α/20:2(11Z,14Z)) exhibited correlations with these enriched bacterial taxa. These results identify DVAP as a potential fertoprotective agent against POI via the gut–ovary axis.