# Independent validation of lung adenocarcinoma prognostic risk scores incorporating cholesterol and estrogen metabolism related transcriptional biomarkers

## TL;DR

This study shows that combining cholesterol and estrogen metabolism gene scores improves lung cancer prognosis and predicts immunotherapy response.

## Contribution

A novel combined risk score integrating cholesterol and estrogen metabolism genes for LUAD prognosis and immunotherapy prediction is introduced.

## Key findings

- High Cholescore correlates with poor survival and immunosuppressive tumor environments.
- Estrogenscore independently predicts LUAD prognosis and interacts with Cholescore to worsen outcomes.
- Combining scores improves survival prediction accuracy and immunotherapy benefit estimation.

## Abstract

We investigated the prognostic significance of cholesterol metabolism-related genes (CMRGs) and estrogen metabolism-related genes (EMRGs) in lung adenocarcinoma (LUAD). Transcriptomic and clinical data from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases were analyzed. Iterative sure independence screening and least absolute shrinkage and selection operator (ISIS-LASSO) Cox regression identified prognostic CMRGs and EMRGs. Two risk scores—Cholescore and Estrogenscore—were constructed and validated. High Cholescore was associated with poor overall survival (OS), reduced immune infiltration, low immune checkpoint expression, and high tumor purity, suggesting an immunosuppressive tumor microenvironment. Estrogenscore also independently predicted LUAD prognosis. Mediation analysis revealed that estrogen-related pathways partially mediated the impact of cholesterol metabolism on prognosis. A significant interaction between Cholescore and Estrogenscore was identified, and patients with both high scores had the worst OS and lowest predicted immunotherapy benefit. Combining the two scores significantly improved the area under the curve (AUC) for 1–5 years OS prediction. These findings suggest that integrating cholesterol and estrogen metabolism signatures can improve LUAD prognostic stratification and provide molecular insights into tumor–immune interactions and immunotherapy response prediction.

The online version contains supplementary material available at 10.1038/s41598-025-22140-w.