2. Academic Validation
  3. Cistanoside F acts as a Monoacylglycerol Lipase inhibitor that synergizes the anti-tumor effect of 2-Arachidonoyl Glycerol on Bladder cancer

Cistanoside F acts as a Monoacylglycerol Lipase inhibitor that synergizes the anti-tumor effect of 2-Arachidonoyl Glycerol on Bladder cancer

  • Phytomedicine. 2025 Sep:145:157046. doi: 10.1016/j.phymed.2025.157046.
Yu-Jun Tan 1,  Yu-Shan Ren 1,  Jun-Lin Lv 2,  Peng Zhao 3,  Qi He 4,  Xue-Feng Lei 5,  Qing-Yue Liang 5,  He-Meng Zhang 5,  Shu-Fang Na 5,  Jing-Chun Yao 6,  Jie Li 7,  Yu-Heng Ma 8,  Gui-Cheng Dong 9
Affiliations

Affiliations

  • 1 College of Pharmacy, Inner Mongolia Medical University 010110, Hohhot, PR China.
  • 2 School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China.
  • 3 Baotou Teacher's College, Inner Mongolia University of Science and Technology 014030, Baotou, PR China.
  • 4 Department of Clinical Laboratory Medicine Center, Inner Mongolia Autonomous Region People's Hospital 010011, Hohhot, PR China.
  • 5 College of Life Sciences, Inner Mongolia Agricultural University 010011, Hohhot, PR China.
  • 6 State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co., Ltd 276000 Linyi, PR China.
  • 7 College of Pharmacy, Inner Mongolia Medical University 010110, Hohhot, PR China. Electronic address: lijie@bzmc.edu.cn.
  • 8 College of Pharmacy, Inner Mongolia Medical University 010110, Hohhot, PR China. Electronic address: 20120311@immu.edu.cn.
  • 9 College of Life Sciences, Inner Mongolia Agricultural University 010011, Hohhot, PR China. Electronic address: gcdhohhot@sohu.com.
PMID: 40645071 DOI: 10.1016/j.phymed.2025.157046
Abstract

Background: Bladder Cancer (BCa) remains clinically challenging due to high recurrence rates. As an endocannabinoid, 2-arachidonoylglycerol (2-AG) plays a pivotal role in regulating numerous physiological and pathological processes, including tumorigenesis. The maintenance of its levels in the biological system is essential for 2-AG to exert its biological functions. Therefore, inhibitors targeting the 2-AG metabolic enzyme, such as monoacylglycerol Lipase (MGLL), are considered promising for clinical application.

Methods: The cell viability assay, colony formation, cell migration, and invasion assay were used to demonstrate 2-AG's anti-proliferative and anti-metastatic effects in BCa cells, inversely correlated with MGLL expression. MGLL overexpression or knockdown confirmed its regulatory role in 2-AG efficacy. Transcriptomics identified LKB1 as a potential 2-AG target. From a medicinal-food compound library, the MGLL activity assay was used to discover Cistanoside F (CF) as a potent MGLL inhibitor.

Results: The in vitro experiments confirmed 2-AG's selective anti-proliferative and anti-metastatic effects in BCa cells, while MGLL attenuates the anti-tumor effect of 2-AG in BCa cells via metabolizing 2-AG into AA. In mechanism, 2-AG activated the LKB1-AMPKα-mTOR axis to suppress BCa progression. At non-cytotoxic concentrations (4-8 nM), CF enhanced 2-AG's effects in BCa cells by sustaining endogenous 2-AG levels through MGLL suppression. In vivo, CF synergized with 2-AG to significantly inhibit tumor growth and lung metastasis compared to 2-AG monotherapy.

Conclusion: These findings establish CF as a novel MGLL-targeting Adjuvant that amplifies 2-AG's anti-BCa efficacy via LKB1 pathway activation, providing dual therapeutic strategies: MGLL inhibition for 2-AG potentiation and LKB1 modulation for pathway-directed therapy.

Keywords

2-Arachidonoylglycerol; Bladder cancer; Cistanoside F; Monoacylglycerol lipase; Serine/threonine kinase 11; Tumor growth.

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