2. Academic Validation
  3. Demethylzeylasteral inhibits osteosarcoma cell proliferation by regulating METTL17-mediated mitochondrial oxidative phosphorylation

Demethylzeylasteral inhibits osteosarcoma cell proliferation by regulating METTL17-mediated mitochondrial oxidative phosphorylation

  • Toxicol Appl Pharmacol. 2025 Jun:499:117348. doi: 10.1016/j.taap.2025.117348.
Jingyu Cao 1,  Haotian Zhang 2,  Chengbo Wang 1,  Lihua He 1,  Ya Li 3,  Zimeng Wang 4,  Xianxiao Li 5,  Faisal Aziz 6,  Minglei Yang 7,  Xiangzhan Zhu 8
Affiliations

Affiliations

  • 1 Institute of Pediatric Medicine, Henan Province Children's Disease Clinical Medical Research Centre, Henan Children's Hospital, Zhengzhou Children's Hospital, Children's Hospital Affiliated of Zhengzhou University, Zhengzhou, China.
  • 2 Guangdong Provincial Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 3 Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury; Henan Provincial Outstanding Overseas Scientists Chronic Liver Injury Workshop, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 4 The Department of Pharmacology and Cancer, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 5 Accident and Emergency Care Department, Henan Province Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
  • 6 The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
  • 7 The Department of Orthopedic Oncology, The Second Affiliated Hospital of Naval Medical University, Shanghai, China. Electronic address: ymlsmmu@163.com.
  • 8 Institute of Pediatric Medicine, Henan Province Children's Disease Clinical Medical Research Centre, Henan Children's Hospital, Zhengzhou Children's Hospital, Children's Hospital Affiliated of Zhengzhou University, Zhengzhou, China; School of Life Sciences, Zhengzhou University, Zhengzhou, China; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China. Electronic address: zhuxiangzhan999@163.com.
PMID: 40250487 DOI: 10.1016/j.taap.2025.117348
Abstract

Osteosarcoma (OS) represents the most common primary bone malignancy, characterized by substantial disability and mortality, thereby underscoring the critical need for more effective therapeutic interventions to improve clinical outcomes. Demethylzeylasteral (DEM) is a bio-active compound has been reported for its anti-tumor properties through various mechanisms. Nonetheless, the specific effects of DEM on OS have yet to be fully elucidated. This study demonstrated that DEM significantly inhibited OS cell proliferation both in vitro and in vivo. Mechanistically, DEM impairs mitochondrial OXPHOS by targeting METTL17, a known regulator of mitochondrial translation, resulting in reduced ATP production. Subsequent investigations revealed that METTL17 knockdown exerts potent anti-tumor effects in OS, significantly suppressing both in vitro cell proliferation and in vivo xenograft tumor growth. Furthermore, METL17 overexpression significantly alleviated the inhibitory effects of DEM on cell proliferation, while restoring ATP production and oxygen consumption rates. These findings suggest that DEM impedes OS growth by inducing mitochondrial dysfunction through targeting METTL17, thereby highlighting a novel therapeutic strategy and potential molecular target for OS treatment.

Keywords

Demethylzeylasteral; METTL17; Osteosarcoma; Oxidative Phosphorylation; Proliferation.

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