5-氟尿嘧啶（5-FU）是结直肠癌患者的常规有效药物，是综合化疗和辅助化疗的重要组成部分。化疗性肠黏膜炎（CIM）是由5-FU引起的严重副作用，导致癌症治疗失败并影响患者的生活质量。5-FU诱导的CIM机制与5-FU诱导的正常细胞衰老有关。靶向Janus激酶（JAK）的抑制剂Peficitinib治疗炎症性疾病，包括类风湿关节炎、银屑病和炎症性肠病。然而，Peficitinib在CIM中的治疗作用和潜在机制尚不清楚。我们研究的主要目标是研究Peficitinib对5-FU诱导的衰老和肠道损伤在人脐静脉内皮细胞（HUVEC）、人肠上皮细胞（HIEC）和BABL/C小鼠中的作用。结果显示，5-FU通过诱导衰老和增加炎症和氧化应激引起肠道损伤。Peficitinib通过减少衰老β-半乳糖苷酶（SA-β-gal）活性和衰老指标蛋白（p53、p21、p16）的水平来缓解衰老。此外，Peficitinib逆转了5-FU引起的衰老相关分泌表型（SASP）表达的变化。此外，5-FU引起的炎症因子和氧化应激指标的释放被Peficitinib逆转。此外，Peficitinib与5-FU的联合使用增强了5-FU在两种结直肠癌细胞系（HCT116细胞和SW620细胞）中的抗癌治疗意图。总之，Peficitinib通过缓解衰老、减少炎症积累和氧化应激以及增强5-FU的抗肿瘤活性来缓解黏膜炎。版权所有©2023 Elsevier B.V。保留所有权利。

5-Fluorouracil (5-FU) is a conventional and effective drug for colorectal cancer patients, and it is an important part of combined chemotherapy and adjuvant chemotherapy. Chemotherapy intestinal mucositis (CIM) is a severe side effect caused by 5-FU that, induces cancer treatment failure and affects patients' quality of life. The mechanism of 5-FU-induced CIM is related to normal cell senescence induced by 5-FU. Peficitinib, a Janus Kinase (JAK) inhibitor, treats inflammatory disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. However, the therapeutic role and underlying mechanism of peficitinib in CIM remain unclear. The main objective of our research was to investigate the effects of peficitinib on 5-FU-induced senescence and intestinal damage in human umbilical vein endothelial (HUVEC) cells, human intestinal epithelial (HIEC) cells and BABL/C mice. The results showed that 5-FU caused intestinal damage by inducing aging and increasing inflammation and oxidative stress. Peficitinib alleviated aging by reducing senescence-beta-galactosidase (SA-β-gal) activity and the protein levels of aging indicators (p53, p21, p16). Moreover, peficitinib reversed the changes in senescence-associated secretory phenotype (SASP) expression caused by 5-FU. Besides, 5-FU induced release of inflammatory factors and oxidative stress indicators was reversed by peficitinib. Additionally, the combination of peficitinib and 5-FU reinforced the anticancer curative intent of 5-FU in two colorectal cancer cell lines (HCT116 cells and SW620 cells). In conclusion, peficitinib alleviates mucositis by alleviating aging, reducing inflammatory accumulation and oxidative stress and enhancing the antitumor activity of 5-FU.Copyright © 2023 Elsevier B.V. All rights reserved.