Inhibition of oogenic JNK prevents primary ovarian insufficiency and infertility induced by DNA-damaging anti-cancer agents

Current strategies preserving ovarian functions and fertility can be suboptimal due to concerns of feasibility, efficacy, or safety. Herein, we identify c-Jun N-terminal kinase (JNK) as a pivotal factor regulating the DNA damage response (DDR) signaling in oocytes of primordial follicles in response to DNA-damaging chemotherapy.

Using pharmacological inhibition of JNK and a mouse model with oocyte-specific deletion of JNK, together with bioinformatic, molecular, and computational approaches, we show that inhibition of oogenic JNK prevents chemotherapy-induced oocyte apoptosis and POI as well as preserve long-term reproductive cycles and fertility. Mechanistically, JNK is activated upon chemotherapy-induced DNA damage in oocytes of primordial follicles, which further activates the transcription factor TAp63α and triggers oocyte apoptosis. we further used a breast cancer mouse model to demonstrate that JNK inhibition preserves the ovarian reserve without interfering with the anti-cancer efficacy of chemotherapy.