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

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-04-16 DOI:10.1016/j.taap.2025.117348

Jingyu Cao , Haotian Zhang , Chengbo Wang , Lihua He , Ya Li , Zimeng Wang , Xianxiao Li , Faisal Aziz , Minglei Yang , Xiangzhan Zhu

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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.

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去甲基化zeylastal通过调节mettl17介导的线粒体氧化磷酸化抑制骨肉瘤细胞增殖

摘要骨肉瘤（OS）是最常见的原发性骨恶性肿瘤，其特点是严重致残和致死，因此亟需更有效的治疗干预措施来改善临床疗效。据报道，去甲斑蝥素（DEM）是一种生物活性化合物，具有多种机制的抗肿瘤特性。然而，DEM对OS的具体作用尚未完全阐明。本研究表明，DEM 在体外和体内都能显著抑制 OS 细胞的增殖。从机理上讲，DEM 通过靶向已知的线粒体翻译调节因子 METTL17 来损害线粒体 OXPHOS，从而导致 ATP 生成减少。随后的研究发现，METTL17敲除可在OS中发挥强大的抗肿瘤作用，显著抑制体外细胞增殖和体内异种移植肿瘤生长。此外，过表达 METL17 能明显减轻 DEM 对细胞增殖的抑制作用，同时恢复 ATP 的产生和氧消耗率。这些研究结果表明，DEM通过靶向METTL17诱导线粒体功能障碍来阻碍OS的生长，从而为OS的治疗提供了一种新的治疗策略和潜在的分子靶点。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.