卡培他滨与5-氟尿嘧啶疗效相当，但其骨髓抑制等毒性更低，近年广泛应用于结直肠癌等癌症的治疗。然而临床报道卡培他滨引起严重的周围神经系统（PNS）毒性限制其临床应用，目前的研究还未阐明卡培他滨影响哪类神经细胞以及调控的关键靶点和分子机制。我们的前期研究发现卡培他滨引起的PNS毒性主要与施万细胞损伤相关，DJ-1可能是参与其毒性的关键蛋白，且卡培他滨引起Cul3 Neddylation修饰程度增加和Keap1/Nrf2通路转录因子Nrf2核转位减少。本项目将进一步明确卡培他滨对施万细胞的损伤，确定DJ-1在其毒性损伤中的关键作用，深入阐明Cul3 Neddylation修饰在DJ-1介导卡培他滨损伤施万细胞中的分子事件，以及其对Keap1/Nrf2通路的调控机制。此研究旨在明确卡培他滨引起PNS毒性的作用特点，丰富DJ-1调控Keap1/Nrf2的分子机制，为防治这类毒性提供新靶点和新思路。

Capecitabine is widely used in colorectal cancer and other tumor treatments in recent years, which has equal efficacy to 5-fluorouracil and lower bone marrow suppression. However, many clinical cases have reported that capecitabine caused severe peripheral neurotoxicity, which limited its clinical use. It is still unclear that which type of nerve cells are affected by capecitabine, and the regulation of key targets and molecular mechanisms remain unknown. Our previous study found that PNS toxicity caused by capecitabine was mainly associated with Schwann cell injury, and DJ-1 may be the key protein involved in it. Capecitabine caused an increase in Cul3 Neddylation and a decrease in Keap1/Nrf2 signaling pathway transcription factor Nrf2 nuclear translocation. In current study, we will further investigate the Schwann cell injury caused by capecitabine, the key role of DJ-1 in Schwann cells damage, the effect of Cul3 Neddylation on DJ-1-mediated capecitabine toxicity, and the regulation of the Keap1/Nrf2 signaling pathway by DJ-1. This study aims to clarify the mechanism of capecitabine-induced peripheral neurotoxicity, enrich the molecular mechanism of DJ-1 regulating Keap1/Nrf2 signaling pathway, and provide potential targets and new ideas for the prevention and treatment of such toxicity.