Single-Cell Transcriptomics Identifies Fibroblast-Associated Transcriptional Patterns and Candidate Therapeutic Targets in the Comorbidity of Non-Small Cell Lung Cancer and Obesity.

BACKGROUND/

INTRODUCTION

Obesity acts as a critical modifiable risk factor for non-small cell lung cancer (NSCLC), while the key cellular and molecular drivers mediating their comorbid association remain poorly defined. Single-cell RNA sequencing (scRNA-seq) enables precise resolution of cell-specific transcriptomic features, making it an optimal tool for uncovering inter-disease regulatory patterns.

MATERIALS AND

METHODS

scRNA-seq datasets for NSCLC (GSE198099, 2 tumor/2 normal samples) and obesity (GSE214982, 5 obese/4 lean samples) were obtained from GEO and processed using Seurat (v5.x). Cell types were annotated by SingleR and validated with canonical lineage markers. Intercellular communication was inferred using CellChat (v2.x) with the human ligand-receptor database. Shared differentially expressed genes (DEGs) were identified and validated by bulk RNA-seq (GSE21933 and GSE55200). Functional enrichment, protein-protein interaction network, and drug-gene interaction analyses were integrated to identify repurposable FDA-approved agents.

RESULTS

Common cell remodeling patterns were observed across both diseases. Cell-cell communication analysis revealed that fibroblasts exhibited prominent outgoing and incoming signaling in both NSCLC and obese adipose tissues, predominantly through collagen, fibronectin, and CXCL12 pathways that target endothelial and immune cells. A total of 160 upregulated and 494 downregulated shared DEGs were identified; after stringent bulk RNA-seq validation, nine high-confidence candidates were retained, including CALCRL, NPR1, and TMEM100. These genes were enriched in endothelial differentiation, cell adhesion, and inflammatory signaling cascades.

DISCUSSION: The shared transcriptional features may point to a conserved stromal-vascular remodeling axis underlying the epidemiological link between obesity and NSCLC. The fibroblast-centered signaling patterns observed in both tissues suggest a common microenvironmental response, though functional studies are required to establish causality.

CONCLUSION

This dual scRNA-seq-based analysis suggests that fibroblasts may function as a conserved signaling hub and highlights 9 candidate genes and several FDA-approved agents warranting further functional validation for comorbidity management in obesity- associated NSCLC.