OSBPL2-Mediated Lipid Transport Suppresses Stemness and Aggressiveness in Lung Cancer via Cholesterol Homeostasis and Lipid Droplet Regulation
Lung cancer remains the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of diagnoses. Lung cancer stem-like cells (LCSCs) drive metastasis, recurrence, and therapeutic failure, yet effective targeting strategies remain elusive. Oxysterol-binding protein-like 2 (OSBPL2/ORP2) is a lipid transport protein that localizes to lipid droplets (LDs) and regulates cholesterol homeostasis, but its role in lung cancer stemness has not been defined. Here, we demonstrate that OSBPL2 reduces cellular cholesterol content, as quantified by HPLC-MS, and inhibits lipid droplet accumulation in lung cancer cells. OSBPL2-mediated lipid transportation significantly suppressed tumor sphere formation, stemness marker expression (ALDH1A1, CD133, Nanog), and in vivo tumorigenesis and metastasis. In peritoneal carcinomatosis models using BALB/c mice (n=10 per group) injected with L-Osbpl2 or L-Vector transduced LLC cells (5×10^6 cells/100µL), OSBPL2 overexpression reduced metastatic tumor burden. Clinical specimen analysis revealed that OSBPL2 represses LCSC marker expression and its level negatively correlates with tumor stage progression and lymph node metastasis. These findings establish OSBPL2 as a critical regulator of lung cancer stemness through lipid metabolic reprogramming, offering a potential therapeutic target for aggressive NSCLC.