Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion–transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.

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OATP1B2 缺乏可防止紫杉醇诱导的神经毒性

紫杉醇是使用最广泛的抗癌药物之一，已知会引起剂量限制的外周神经毒性，其起始机制仍不清楚。在这里，我们将鼠溶质载体有机阴离子转运多肽 B2 (OATP1B2) 鉴定为紫杉醇诱导的神经毒性的介质。此外，使用已建立的测试来评估急性和慢性紫杉醇诱导的神经毒性，我们发现 OATP1B2 的基因或药理学敲除保护小鼠免受机械诱发的异常性疼痛、热痛觉过敏和数字最大动作电位幅度的变化。这种转运系统的功能被酪氨酸激酶抑制剂尼罗替尼通过非竞争机制抑制，而不会影响紫杉醇的抗癌特性。集体，