Cholesterol metabolism in LUAD progression: GJB3 as a key target for cell‑based therapeutic interventions

Area of Science:

• Oncology
• Molecular Biology
• Metabolism

Background:

• Reprogramming of cholesterol metabolism is crucial in tumor development and progression.
• Lung adenocarcinoma (LUAD) is a significant form of lung cancer where metabolic alterations are increasingly recognized.

Purpose of the Study:

• To investigate the regulatory impact of cholesterol metabolism-related genes (CMRGs) in LUAD.
• To identify distinct patient clusters based on CMRGs and develop a predictive survival model.
• To explore the potential of CMRGs as biomarkers for prognosis and treatment response in LUAD.

Main Methods:

• Consensus clustering was applied to LUAD patient data based on CMRGs.
• Survival analysis and immune infiltration profiling were performed for identified clusters.
• A predictive model was built using LASSO regression on differentially expressed genes and validated independently.
• In vitro experiments assessed the functional role of the gene GJB3 in LUAD progression.

Main Results:

• Two distinct clusters of LUAD patients based on CMRGs were identified, differing in prognosis, biological pathways, and immune infiltration.
• A four-gene survival model demonstrated robust predictive accuracy across multiple datasets.
• The low-risk group predicted better immunotherapy response, while the high-risk group showed increased chemotherapy sensitivity.
• GJB3 knockdown inhibited LUAD cell proliferation and invasion, downregulating epithelial-mesenchymal transition markers.

Conclusions:

• Cholesterol metabolism-related genes are significant in LUAD pathogenesis and can define distinct patient subgroups.
• The developed survival model offers a promising tool for predicting prognosis and guiding personalized treatment strategies in LUAD.
• GJB3 plays a functional role in LUAD progression, suggesting its potential as a therapeutic target.