Metabolic rewiring at the obesity–estrogen–polyamine axis in endometrial cancer: emerging mechanisms and translational opportunities

Abstract

Endometrial cancer is one of the gynecologic malignancies most strongly associated with obesity, yet the biological basis of this association extends beyond excess adiposity as a risk factor. Obesity reshapes the endometrial ecosystem through peripheral estrogen excess, progesterone imbalance, insulin resistance, adipokine dysregulation, chronic inflammation, and activation of anabolic signaling pathways. These mechanisms converge on metabolic programs that support proliferation, invasion, immune remodeling, and treatment resistance. Polyamine metabolism is emerging as a potentially relevant but still incompletely validated layer of this biology. Ornithine decarboxylase 1, the rate-limiting enzyme in polyamine biosynthesis, is overexpressed in aggressive endometrial cancers and has been associated with recurrence and poor survival. Recent evidence further suggests that metabolic syndrome-associated oleic acid may stabilize homeobox B9, protect ornithine decarboxylase 1 from degradation, increase polyamine accumulation, and promote tumor progression. This Mini Review critically examines the obesity–estrogen–polyamine axis as an integrative framework linking endocrine dysfunction, inflammatory remodeling, lipid signaling, and proliferative metabolic rewiring in endometrial cancer. It also discusses biomarker opportunities, therapeutic vulnerabilities, and the translational gaps that must be addressed before this axis can inform precision oncology.