神经元ALAS2/5-ala轴通过BACH1/NRF2通路减轻化疗引起的神经毒性
Wen-Yuan Zhang1,2, Qian-Qian Wei1,2, Tao Zhang3,4
1Department of Pharmacy, Zhongshan City People's Hospital, Zhongshan, China.
British journal of pharmacology
|February 7, 2026
概括
化疗药物多克索鲁比 (DOX) 通过降低5 - 氨基诺列武林酸合成酶2 (ALAS2) 和5 - 氨基诺列武林酸 (5-ALA) 来损害大脑细胞. 恢复这种途径可以防止神经毒性.
科学领域:
- 神经科学是一个神经科学.
- 在瘤学瘤学.
- 生物化学 生物化学
背景情况:
- 化疗,包括多克索鲁比辛 (DOX),在癌症治疗中仍然至关重要.
- 神经毒性是一种重要的副作用,限制了化疗的疗效.
- 了解化疗诱导的神经毒性机制对于开发支持性疗法至关重要.
研究的目的:
- 为了识别小鼠海马体中受多克索鲁比 (DOX) 影响的关键分子通路.
- 调查5 - 氨基诺氨酸合成酶2 (ALAS2) 和5 - 氨基诺氨酸 (5-ALA) 轴在DOX诱导的神经毒性的作用.
- 探索针对ALAS2/5-ALA通路进行神经保护的潜力.
主要方法:
- 对DOX治疗的小鼠海马体进行了全面的转录和代谢分析.
- 在体外和体内验证已识别的机制.
- 使用斑马鱼模型来评估神经保护作用.
主要成果:
- doxorubicin (DOX) 治疗降低了ALAS2/5-ALA轴的下调,特别是在海马神经元中.
- 缺少ALAS2导致对氧化损伤的敏感性增加,并增强了BACH1的稳定性,抑制了NRF2的活动.
- 给予5-ALA或ALAS2过度表达,通过恢复血水平,促进BACH1降解和增强NRF2活性,从而防止DOX诱导的神经毒性.
结论:
- 揭示了一种涉及ALAS2/5-ALA轴调节BACH1/NRF2通路的新型内源性神经保护机制.
- ALAS2/5-ALA轴在细胞氧化还原稳定和神经元保护免受化疗引起的损伤方面发挥着至关重要的作用.
- 5-ALA显示出用于减轻化疗相关神经毒性的重新用途的潜力.
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