5-Fluorouracil (5-FU) is used as a standard first-line drug for colorectal cancer malignancy (CRC), but it brings a series of side effects such as severe diarrhea and intestinal damage. Our previous study found that a large number of senescent cells increased while 5-Fu induced intestinal damage, and anti-senescence drugs can alleviate its side effects of inflammatory damage. Oleanolic acid (OA) is a common pentacyclic triterpenoid mainly derived from food fungi and medicinal plants, and studies have shown that it mainly possesses hepatoprotective, enzyme-lowering, anti-inflammatory, and anti-tumor effects. But its role in senescence is still unclear. In the present study, we demonstrated for the first time that OA ameliorated 5-Fu-induced human umbilical vein endothelial cells (HUVECs) and human normal intestinal epithelial cells (NCM460) in a 5-Fu-induced cellular senescence model by decreasing the activity of SA-β-gal-positive cells, and the expression of senescence-associated proteins (p16), senescence-associated genes (p53 and p21), and senescence-associated secretory phenotypes (SASPs: IL-1β, IL-6, IL-8, IFN-γ and TNF-α). Meanwhile, in this study, in a BALB/c mouse model, we demonstrated that 5-FU induced intestinal inflammatory response and injury, which was also found to be closely related to the increase of senescent cells, and that OA treatment was effective in ameliorating these adverse phenomena. Furthermore, our in vivo and in vitro studies showed that OA could alleviate senescence by inhibiting mTOR. In colon cancer cell models, OA also enhanced the ability of 5-FU to kill HCT116 cells and SW480 cells. Overall, this study demonstrates for the first time the potential role of OA in counteracting the side effects of 5-FU chemotherapy, providing a new option for the treatment of colorectal cancer to progressively achieve the goal of high efficacy and low toxicity of chemotherapy.

5-氟尿嘧啶（5-FU）被用作结直肠癌恶性肿瘤（CRC）的标准一线药物，但它带来了严重腹泻和肠道损伤等一系列副作用。我们前期的研究发现，5-Fu引起肠道损伤的同时，衰老细胞大量增加，而抗衰老药物可以减轻其炎症损伤的副作用。齐墩果酸（OA）是一种常见的五环三萜类化合物，主要来源于食用真菌和药用植物，研究表明其主要具有保肝、降酶、抗炎、抗肿瘤等作用。但其在衰老中的作用仍不清楚。在本研究中，我们首次证明，在 5-Fu 诱导的细胞衰老模型中，OA 通过降低活性来改善 5-Fu 诱导的人脐静脉内皮细胞 (HUVEC) 和人正常肠上皮细胞 (NCM460) SA-β-gal 阳性细胞的表达，以及衰老相关蛋白 (p16)、衰老相关基因（p53 和 p21）和衰老相关分泌表型（SASP：IL-1β、IL-6、IL -8、IFN-γ 和 TNF-α）。同时，在这项研究中，我们在BALB/c小鼠模型中证明了5-FU诱导肠道炎症反应和损伤，这也与衰老细胞的增加密切相关，并且OA治疗可以有效改善肠道炎症反应和损伤。这些不良现象。此外，我们的体内和体外研究表明，OA可以通过抑制mTOR来缓解衰老。在结肠癌细胞模型中，OA还增强了5-FU杀死HCT116细胞和SW480细胞的能力。 总体而言，本研究首次证明了OA在对抗5-FU化疗副作用中的潜在作用，为结直肠癌的治疗提供了新的选择，逐步实现化疗高效低毒的目标。