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These trends underscore concern over long\u2010term reproductive health, as chemotherapy\u2010induced ovarian toxicity and premature ovarian insufficiency (POI) emerge as major late effects with unclear population\u2010specific susceptibility. This review examines chemotherapy\u2010induced ovarian damage via the PI3K\u2010AKT\u2010FOXO3 signaling axis, a key regulator of follicular quiescence, stress responses, and ovarian longevity. Evidence was synthesized from human studies, experimental models, and mechanistic investigations to develop this population\u2010specific conceptual framework. Chemotherapy initiates DNA damage and oxidative stress, which subsequently activate interconnected pathways involving mitochondrial dysfunction, dysregulated autophagy, apoptosis, ferroptosis, inflammatory signaling, and dysregulation of the PI3K\u2010AKT\u2010FOXO3 axis, ultimately accelerating follicular activation and depletion. A distinctive contribution of this review is the integration of longevity\u2010associated genetic susceptibility with ovarian vulnerability, highlighting evidence suggesting that certain FOXO3 and PI3K\u2010AKT pathway variants, reported to be more prevalent in several Asian populations, may influence susceptibility to chemotherapy\u2010induced ovarian injury. This review proposes a two\u2010hit hypothesis as a conceptual framework integrating currently available molecular, experimental, and population\u2010based evidence while acknowledging that direct clinical validation remains limited. Within this framework, longevity\u2010associated genetic predisposition affecting the PI3K\u2010AKT\u2010FOXO3 axis constitutes the first hit, whereas chemotherapy\u2010induced cellular stress represents the second hit, together accelerating follicular burnout and increasing the risk of POI. This framework supports future evaluation of genotype\u2010informed risk stratification, individualized fertility preservation strategies, and prospective validation in Asian cancer cohorts, with the ultimate goal of informing ethnicity\u2010specific fertility preservation strategies and optimized chemotherapy protocols.<\/jats:p>","DOI":"10.1155\/bmri\/2340719","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T09:39:28Z","timestamp":1784972368000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Two\u2010Hit Hypothesis for Chemotherapy\u2010Induced Primary Ovarian Insufficiency in Asian Populations: A Population\u2010Specific Mechanistic Framework Linking Genetic Susceptibility and Cytotoxic Stress via the PI3K\u2010AKT\u2010FOXO3 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