HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reducton

Ovarian senescence impacts reproductive health and accelerates the overall aging process. Despite extensive research in this area there is still a dearth of effective therapeutic strategies. We here report the rejuvenating effects of HEP14, a natural activator of PKC pathway, on aged ovarian function. Further, we detail a method to fabricate HEP14-loaded PLGA microspheres designed for controlled and sustained drug release in vivo. Transcriptomic analysis revealed a significant overlap between the transcriptional profiles of HEP14-treated aged ovaries and those of adult ovaries, suggesting molecular rejuvenation process. Histopathological evaluations following treatment demonstrated that HEP14 not only enhances mitophagy but also exhibits antioxidative properties and promotes follicular regeneration. As a result, ovarian endocrine function was ultimately restored in aged mice, evident in raised serum levels of E2, AMH, Inhibin A/B and lowered FSH levels. In vitro studies further showcased restorative effect of HEP14 on enhancement of mitophagy and mitochondrial function by the activation of the PKC-ERK1/2 pathway in senescent GCs, which are integral to the action mechanism of HEP14. These findings pave the way for new therapeutic approaches for developing therapeutic strategies aimed at improving reproductive health in aging individuals. Overall design: To delve into the molecular mechanisms behind HEP14-driven ovarian function restoration in aged mice, we conducted a comparative transcriptomic analysis on ovaries from four groups of mice: young (7~8 weeks), adult (27~28 weeks), aged mice (73~74 weeks) treated with vehicle, and aged mice (73~74 weeks) treated with HEP14 (aged+HEP14 mice).