美国国立卫生研究院André Nussenzweig团队在研究中取得进展。他们开发出DNA修复驱动顺铂诱导的神经元死亡。该研究于2026年6月10日发表于国际一流学术期刊《细胞》杂志上。
这种脆弱性的出现是因为主题神经元具有低脱氧核苷三磷酸（dNTP）池。dNTPs最初在转录偶联NER中消耗，以解决转录阻断病变。当dNTP水平耗尽时，修复无法完成，导致双链断裂的积累，特别是在全球基因组NER期间。补充脱氧核苷或基因上调dNTP合成可恢复核苷酸池，保护神经元免于细胞死亡，并减少顺铂诱导的神经性疼痛。这些发现确定了有限的dNTP可用性是有丝分裂后细胞的关键脆弱性，并建议补充核苷作为减轻化疗诱导的神经毒性的潜在策略。
据悉，铂类药物是许多癌症的基础疗法，但通常会对有丝分裂后组织产生神经毒性，因此缺乏有效的干预措施。这一限制反映了对神经元对DNA损伤反应的不完全理解。研究团队发现核苷酸切除修复（NER）介导顺铂损伤在神经元中的去除；然而，与其在细胞分裂中的保护作用不同，NER在顺铂作用下促进神经元死亡。
附：英文原文
Title: DNA repair drives cisplatin-induced neuronal death
Author: William J. Nathan, Chuanyuan Chen, Rosy Sakr, Bruno Siqueira Mietto, Vincent van Batenburg, Jeroen van den Berg, Josette J. Wlaschin, Ferenc Livak, Elsa Callen, Nancy Wong, Eliza Y.H. Lloyd, Hanna Silberberg, Sushma Sharma, Raj Chari, Tzipporah Freeman, Baek Kim, Alexander van Oudenaarden, Alexander T. Chesler, Michael E. Ward, Lisa D. Boxer, Peter J. McHugh, Andrei Chabes, Claire E. Le Pichon, André Nussenzweig
Issue&Volume: 2026-06-10
Abstract: Platinum agents are cornerstone therapies for many cancers but often cause neurotoxicity in post-mitotic tissues, for which effective interventions are lacking. This limitation reflects an incomplete understanding of neuronal responses to DNA damage. We show that nucleotide excision repair (NER) mediates cisplatin lesion removal in neurons; however, unlike its protective role in dividing cells, NER promotes neuronal death in response to cisplatin. This vulnerability arises because neurons possess low deoxynucleoside triphosphate (dNTP) pools. dNTPs are initially consumed during transcription-coupled NER to resolve transcription-blocking lesions. As dNTP levels become depleted, repair fails to complete, leading to accumulation of double-strand breaks, particularly during global-genome NER. Supplementation with deoxynucleosides or genetic upregulation of dNTP synthesis restores nucleotide pools, protects neurons from cell death, and reduces cisplatin-induced neuropathic pain. These findings identify limited dNTP availability as a key vulnerability in post-mitotic cells and suggest nucleoside supplementation as a potential strategy to mitigate chemotherapy-induced neurotoxicity.
DOI: 10.1016/j.cell.2026.05.025
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00584-2