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Biochemical pathways linking adiposity, diet, and endometrial carcinogenesis
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DOI：10.1016/j.biochi.2026.03.008.png)
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Abstract
En 中文
Endometrial cancer (EC) arises from a convergence of metabolic, endocrine, and inflammatory disturbances largely driven by excess adiposity and diet-induced biochemical reprogramming. This review synthesizes molecular evidence linking adipose-derived estrogen excess, insulin/IGF-1 activation of PI3K/AKT/mTOR and RAS/MAPK pathways, adipokine imbalance, and NF-kappa B-dependent inflammation to EC initiation and progression. Mechanistic studies demonstrate that aromatase-mediated estradiol production in hypertrophic adipose tissue activates proliferative estrogen receptor-dependent transcriptional programs, potentiated by alterations in chromatin remodeling. Hyperinsulinemia and IGF-1 signaling independently accelerate mitogenesis and inhibit apoptosis by reinforcing anabolic metabolism and suppressing key tumor-suppressive checkpoints. Obesity-associated shifts in adipokines, including increased leptin/JAK2-STAT3 activity and reduced adiponectin/AMPK signaling, further amplify epithelial-mesenchymal transition, chronic inflammation, and metabolic stress. Additional emerging pathways, including riboflavin/FAD-dependent redox regulation and Ca 2+ signaling dysregulation, reveal metabolic vulnerabilities such as enhanced LSD1 activity, FSP1-mediated ferroptosis resistance, and IP3R-driven endoplasmic reticulum stress that may support precision-targeted interventions. Dietary exposures modulate these biochemical networks bidirectionally: sucrose-rich ultra-processed foods intensify insulin resistance and inflammation, whereas Mediterranean and plantforward dietary patterns attenuate insulin/IGF-1 activity, reduce systemic inflammation, improve estrogen metabolism, and enrich phytochemicals, such as glucosinolate-derived isothiocyanates, with detoxifying and epigenetic effects. Integrating biochemical biomarkers, including insulin, IGF-1, leptin, adiponectin, hs-CRP, and estrogen metabolites, provides a systems-level framework for identifying individuals at elevated risk and guiding metabolic, nutritional, and lifestyle interventions. Overall, the biochemical architecture of EC underscores a central role for diet-modifiable metabolic and inflammatory pathways in carcinogenesis and survivorship, offering promising avenues for prevention and personalized metabolic health strategies. (c) 2026 Elsevier B.V. and Soci & eacute;t & eacute; Fran & ccedil;aise de Biochimie et Biologie Mol & eacute;culaire (SFBBM). All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Keywords:
Adipokines
Adiposity
Endometrial cancer
Inflammation
Insulin-IGF-1 signaling
Mediterranean diet
Riboflavin/FAD metabolism
Ultra-processed foods
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