Metabolic syndrome promotes endometrial cancer by Oleic acid-mediated polyamine accumulation

Abstract Metabolic syndrome increases the risk of endometrial cancer development and progression, but the mechanism remains unclear. We find that polyamine metabolites are notably elevated in the sera and tumor tissues of endometrial cancer patients with metabolic syndrome. Oleic acid, one of the many components in hyperlipidemia, is the key factor for upregulating Ornithine Decarboxylase 1 (ODC1) (the rate-limiting enzyme in polyamine metabolism) and downstream polyamines. Mechanistically, Oleic acid binds to and stabilizes Homeobox B9 (HOXB9) by inhibiting the binding of HOXB9 to E3 ligase Praja2. Stable HOXB9 then competes with OAZ1 and combines with ODC1 to block ODC1 degradation. Targeting HOXB9 or ODC1 reduces polyamine levels and suppresses tumor growth/spread. Oleic acid-HOXB9-ODC1 stable cascading axis then is confirmed in patient tissues, and ODC1 inhibitors boost patient-derived tumor cells’ chemosensitivity. This study links fatty acids to polyamine buildup, reveals a mechanism for metabolic syndrome-driven endometrial cancer, and points to HOXB9 and ODC1 as potential therapeutic targets.