Key Takeaways & Executive Findings
- •• OSBPL2 is downregulated in lung cancer tissues and its low expression correlates with poor patient survival, suggesting a tumor suppressor role. • OSBPL2 reduces cholesterol content and inhibits lipid droplet accumulation in lung cancer cells, altering lipid metabolism. • OSBPL2 suppresses lung cancer stemness properties, including tumor sphere formation, stemness marker expression, and in vivo tumorigenesis and metastasis. • OSBPL2 expression negatively correlates with malignant features such as tumor stage progression and lymph node metastasis, highlighting its potential as a therapeutic target.
Abstract
Lung cancer is the first leading cause of cancer death worldwide. Oxysterol-binding protein-like 2 (OSBPL2) is a lipid transport protein regulating cholesterol homeostasis. Here, we clarified the previously unreported role of OSBPL2 in lung cancer stemness properties. We observed that OSBPL2 reduced cholesterol content by HPLC-MS. It inhibited the accumulation of lipid droplets (LDs) in lung cancer. OSBPL2-mediated lipid transportation significantly suppressed tumor sphere formation, stemness markers expression and in vivo tumorigenesis and tumor metastasis. In clinical specimens, we also demonstrated that OSBPL2 repressed the expression of Lung cancer stem-like cells (LCSCs) markers-ALDH1A1, CD133 and Nanog. The level of OSBPL2 was negatively correlated with malignant of lung cancer, such as tumor stage progression and lymph node metastasis. Taken together, these findings illustrated that OSBPL2-mediated lipid transportation inhibited the stemness and aggressiveness of lung cancer cells. OSBPL2 was a potential therapeutic target to develop novel cancer-preventive compound.
1. Introduction
Lung cancer is the first cause of cancer death worldwide. Approximately 85% patients are diagnosed as non-small cell lung cancer (NSCLC) [1, 2]. Recent evidences showed that cancer stem cell was a key factor in contributing to metastasis and recurrence of lung cancer [3]. Thus, identifying efficient target for cancer stem cell formation in lung cancer is very meaningful to develop therapeutic strategies.
Lung cancer stem-like cells (LCSCs) are a rare subpopulation exhibiting stemness properties in lung cancer. LCSCs are able to differentiate, self-renew and express stemness markers, including ALDH1A1, CD133 and Nanog. LCSCs are the major cause for failure of cancer therapies and progression in lung cancer [3, 4]. Oxysterol-binding protein-like 2 (OSBPL2), also known as oxysterol-binding protein-related protein 2 (ORP2). It localizes to lipid droplets (LDs) and transports excessive lipid outside cells. Thus, it modulates lipid metabolism reprogramming and LDs content. LDs are a kind of dynamic organelles. There functions include lipid storage, energy supplying for proliferation, cell signaling and lipid metabolism reprogramming. Indeed, LDs are metabolic determinants for cancer stemness. Production of fatty acid and accumulation of LDs sustained the self-renew and reproduction capacity of cancer stem cells [5, 6]. Lipid metabolism includes lipid import and export, lipolysis, fatty acid oxidation, de novo lipogenesis, and lipid desaturation. Abnormal lipid metabolism has been documented to promote the cancer stemness. Liu reported that enhanced phospholipid metabolism and synthesis of fatty acid activated Hippo/YAP and Wnt/β-catenin signaling, which contributed to the maintenance of cancer stemness [7]. According to the above, OSBPL2-correlated LDs alteration is a potential target for inhibition of cancer stem cell properties. Revealing the underlying mechanism will provide novel insights on developing individualized therapeutic regimens.
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Hongtao Liu, Pei Yin, Guangliang Bian, Caihua Xu, Ying Wang (2026). OSBPL2-Mediated Lipid Metabolism Alteration Governs Lung Cancer Stem Cells Properties. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-026-04919-4
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Frequently Asked Questions
What is the role of OSBPL2 in lung cancer?
OSBPL2 acts as a tumor suppressor in lung cancer by inhibiting cancer stemness and aggressiveness. It reduces cholesterol content and lipid droplet accumulation, thereby suppressing tumor sphere formation, stemness marker expression, and in vivo tumorigenesis and metastasis.
How does OSBPL2 affect lipid metabolism in lung cancer cells?
OSBPL2 modulates lipid metabolism by transporting lipids and reducing cholesterol content. It inhibits the accumulation of lipid droplets, which are crucial for cancer stem cell self-renewal and proliferation.
What is the clinical significance of OSBPL2 expression in lung cancer patients?
Low OSBPL2 expression is associated with poor prognosis, advanced tumor stage, and lymph node metastasis in lung cancer patients. This suggests OSBPL2 could serve as a prognostic biomarker and potential therapeutic target.
Does OSBPL2 influence cancer stem cell markers?
Yes, OSBPL2 represses the expression of lung cancer stem-like cell markers such as ALDH1A1, CD133, and Nanog, indicating its inhibitory effect on cancer stemness.
What are the potential therapeutic implications of targeting OSBPL2?
Enhancing OSBPL2 expression or function could be a novel strategy to suppress lung cancer stemness and aggressiveness, potentially improving treatment outcomes and preventing recurrence.
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