ReviewBioMed research international2026
A Two-Hit Hypothesis for Chemotherapy-Induced Primary Ovarian Insufficiency in Asian Populations: A Population-Specific Mechanistic Framework Linking Genetic Susceptibility and Cytotoxic Stress via the PI3K-AKT-FOXO3 Axis.
Review in BioMed research international, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
1 citing paper in PubMed.
Corrections and comments
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Authors and funding
1 author.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As cancer incidence rises in Asian countries, chemotherapy remains central to treatment amid rapid population aging and declining fertility in most of them. These trends underscore concern over long-term reproductive health, as chemotherapy-induced ovarian toxicity and premature ovarian insufficiency (POI) emerge as major late effects with unclear population-specific susceptibility. This review examines chemotherapy-induced ovarian damage via the PI3K-AKT-FOXO3 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-specific 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-AKT-FOXO3 axis, ultimately accelerating follicular activation and depletion. A distinctive contribution of this review is the integration of longevity-associated genetic susceptibility with ovarian vulnerability, highlighting evidence suggesting that certain FOXO3 and PI3K-AKT pathway variants, reported to be more prevalent in several Asian populations, may influence susceptibility to chemotherapy-induced ovarian injury. This review proposes a two-hit hypothesis as a conceptual framework integrating currently available molecular, experimental, and population-based evidence while acknowledging that direct clinical validation remains limited. Within this framework, longevity-associated genetic predisposition affecting the PI3K-AKT-FOXO3 axis constitutes the first hit, whereas chemotherapy-induced cellular stress represents the second hit, together accelerating follicular burnout and increasing the risk of POI. This framework supports future evaluation of genotype-informed risk stratification, individualized fertility preservation strategies, and prospective validation in Asian cancer cohorts, with the ultimate goal of informing ethnicity-specific fertility preservation strategies and optimized chemotherapy protocols.
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Registered trials
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