Lipid‐Driven OLR1/FOXM1/FGF19 Axis Orchestrates Crosstalk in an Epithelial‐Fibroblast Positive Feedback Promoting Progesterone Resistance in Endometrial Cancer

Abstract Progesterone resistance (ProR) remains a major obstacle in the conservative management of endometrial cancer (EC). Here, a metabolic‐stromal signaling loop centered on the OLR1/FOXM1/FGF19 axis is identified that drives progesterone resistance in EC. Single‐cell transcriptomic profiling first revealed a striking correlation between epithelial cells and fibroblasts in EC tissues with ProR. Tumor epithelial cells display profound alterations in lipid metabolism, whereas fibroblasts exhibited enhanced oxidative stress signatures. Clinical samples analyses indicated that oxidized low density lipoprotein (oxLDL), a product of LDL oxidation, is associated with adverse outcomes. The binding of oxLDL to its receptor OLR1 promoted the expression of FOXM1, a transcription factor that directly upregulates fibroblast growth factor 19 (FGF19). Immunofluorescence confirmed not only the spatial co‐localization of epithelial cells and fibroblasts but also the enrichment of OLR1 within epithelial compartments. Furthermore, treatment with the antioxidant resveratrol (RSV) and its nanoformulation (RSV‐NPs) markedly inhibited tumor growth in mice with lipid metabolic disorders, highlighting their potential to counteract progesterone resistance by disrupting this OLR1/FOXM1/FGF19 axis. This work highlights the therapeutic potential of targeting the tumor–stroma metabolic axis to increase progesterone sensitivity and improve outcomes in EC patients with fertility‐preserving demands.