Unveiling the role of the PI3K/Akt signaling pathway in follicular development and non-malignant ovarian dysfunction: a comprehensive review

Phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) is an important signaling pathway that regulates cell survival, metabolism, and proliferation, with pivotal roles in key stages of follicular development, including primordial follicle activation, granulosa cell function, and oocyte maturation. Dysregulation of this pathway is closely related to follicular development disorders and decreased female fertility. This review synthesizes current knowledge on the regulatory mechanisms of the PI3K/Akt pathway in ovarian physiology and its dysregulation in non-malignant ovarian dysfunctions. It further examines how environmental pollutants disrupt this pathway to impair ovarian function and evaluates preclinical evidence for therapeutic interventions targeting this axis in models of polycystic ovary syndrome and premature ovarian insufficiency, including pharmacological agents, Traditional Chinese Medicine, and innovative techniques like ovarian tissue activation. While these findings highlight the pathway’s pivotal role and therapeutic potential, most evidence remains preclinical. Future translation to clinical practice requires addressing interspecies differences, advancing human studies, ensuring the safety of follicle-activating strategies, and developing targeted delivery systems to ultimately improve outcomes in female reproductive health.