Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway.

Imatinib (IMA), a first-line tyrosine kinase inhibitor for hematologic neoplasms, has been demonstrated to potentially contribute to ovarian dysfunction and potential fertility impairment in premenopausal women following extended therapeutic regimens. As a bioactive flavonoid, quercetin (QUE) possesses diverse therapeutic effects, such as reducing oxidative stress, suppressing inflammation, and delaying aging. In our previous study, we demonstrated that QUE may mitigate IMA-induced ovarian damage, although the specific mechanism remained unclear. In this study, we employed an integrated approach combining network pharmacology with in vivo and in vitro experiments to demonstrate whether IMA induces excessive oxidative stress and mitophagy in ovarian granulosa cells, and further determine whether QUE exerts its protective effects through this pathway. We observed that IMA elevated levels of intracellular reactive oxygen species and mitochondrial superoxide, reduced mitochondrial membrane potential, and enhanced apoptosis in KGN cells. In addition, IMA induced the expression of mitophagy (Pink1 and Parkin) and autophagy (ATG5, P62, and LC3B) flow-related proteins in mice ovaries and KGN cells. Finally, we discovered that IMA activated the expression of p-JNK and c-JUN in both mice ovaries and KGN cells, while inhibited the phosphorylation of mTOR. QUE, reactive oxygen species inhibitor (N-Acetylcysteine) and JNK inhibitor (SP600125) played a restorative role to some extent. Our study establishes a theoretical foundation for the application of natural products in fertility preservation therapy for cancer patients.