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

## TL;DR

This study identifies a metabolic signaling loop in endometrial cancer that causes progesterone resistance and suggests resveratrol as a potential treatment.

## Contribution

The discovery of the OLR1/FOXM1/FGF19 axis as a driver of progesterone resistance in endometrial cancer.

## Key findings

- OxLDL activates the OLR1/FOXM1/FGF19 axis, promoting progesterone resistance in endometrial cancer.
- Resveratrol and its nanoformulation inhibit tumor growth by disrupting this signaling loop.
- Epithelial and fibroblast crosstalk is enriched in progesterone-resistant endometrial cancer tissues.

## 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.

It is revealed that a metabolic–stromal loop driven by oxLDL–OLR1–FOXM1–FGF19 signaling promotes progesterone resistance in endometrial cancer. OxLDL activates epithelial–fibroblast crosstalk, enhancing proliferation and hormonal insensitivity. Disruption of this circuit, especially with resveratrol, restores MPA sensitivity, highlighting a potential strategy to overcome hormone resistance via targeting tumor–fibroblast metabolic interactions.