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索拉菲尼布通过RBM20介导的体和线粒体基因的替代拼接诱导心脏毒性

Songming Liu¹, Shanshan Yue², Yuxuan Guo³

¹Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.

Pharmacological research

|November 25, 2023

概括

索拉费尼布通过改变基因拼接而导致心脏损伤,特别是影响RBM20蛋白. 恢复RBM20水平可以逆转这些有害影响,为药物诱导的心脏毒性提供潜在的治疗方法.

科学领域:

心血管研究研究心血管研究
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

索拉菲尼布是一种氨酸激酶抑制剂,用于治疗晚期固体瘤,但会引起心脏毒性.
心脏毒性可能涉及对心脏功能至关重要的替代基因拼接.
替代拼接在索拉费尼布诱导的心脏毒性的作用尚未完全理解.

研究的目的:

调查替代拼接在索拉芬尼布诱导心脏毒性的作用.
为了确定受索拉费尼布治疗影响的特定基因和通路.
探索RBM20作为一个潜在的治疗目标.

主要方法:

用sorafenib治疗的老鼠心脏和人类心肌细胞的转录组分析.
替代拼接基因的验证及其功能影响.
在sorafenib治疗下评估RBM20表达及其标 (SLC25A3,FHOD3).

主要成果:

索拉芬尼在老鼠中诱导严重的心脏毒性,影响心脏功能和线粒体ATP产生.
包括RBM20目标在内的数百个基因表现出改变的拼接模式.
索拉芬尼抑制了RBM20的表达,导致SLC25A3和FHOD3的致病拼接成功能较差的胎儿异型.
升级RBM20逆转了这些拼接缺陷,改善了线粒体功能和细胞存活率.

结论:

通过RBM20失调调节的替代拼接是索拉芬尼布诱导心脏毒性的关键机制.
准RBM20提供了一种潜在的治疗策略,以减轻索拉芬尼心脏毒性.
这种依赖RBM20的途径可能与其他药物诱导的心脏毒性有关.

关键词:

替代拼接是一种替代拼接.心脏有毒性 - 心脏有毒性能量代谢能量代谢 FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3FHOD3 在RBM20中使用RBM20 在 SLC25A3 中,这种类型的瘤是sarcomere.索拉费尼布 (Sorafenib) 是一种

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