Atorvastatin calcium alleviates 5-fluorouracil-induced intestinal damage by inhibiting cellular senescence and significantly enhances its antitumor efficacy

•It is the first time that 5-Fluorouracil(5-Fu) induced intestinal damage is associated with increased senescent cells and drug-induced inflammation, and Atorvastatincalcium can treat intestinal damage caused by 5-Fu.•Atorvastatincalcium relieves HIEC cells and the intestinal epithelium of mice senescence by inhibiting the mTORsignal pathway.•In vitro and in vivo, Atorvastatincalcium increases the sensitivity of 5-Fu to chemotherapy. And combination therapy significantly reduces the viability of HCT116 cells.•The combination of Atorvastatincalcium and 5-Fu inhibits the growth of tumors in CRC xenografts in null mice. 5-Fluorouracil (5-Fu) is the preferred drug in colorectal cancer treatment. Although 5-Fu treatment contributes to the increase in survival rates, long-term use of 5-Fu causes severe intestinal damage, eventually decreasing long-term survival. There is no standardtreatmentfor intestinal damage induced by 5-Fu. Our previous study found that 5-Fu-induced intestinal damage was connected to an increase in senescent cells, and antiaging drugs could relieve some adverse side effects caused by 5-Fu. Hence, it is essential to discover novel, potential antiaging therapeutic drugs for 5-Fu side effect treatment. According to the current study, Atorvastatincalcium (Ator) alleviated cellular senescence in human intestinal epithelial cells (HUVECs) and human umbilical vein endothelial cells (HIECs) caused by oxidative stress and 5-Fu. 5-Fu resulted in an increase in SA-β-Gal-positive cells, synchronously increased expression of aging-related proteins (p16), aging-related genes (p53, p21), and the senescence-associated secretory phenotype (SASP: IL-1β, IL-6, TNF-α), while Atorvastatincalcium (Ator) reversed the increase in these indicators. In the BALB/c mouse model, we confirmed that intestinal damage caused by 5-Fu is related to the increase in senescent cells and drug-induced inflammation, with the therapeutic effects of Ator. In addition, Ator increased the sensitivity of 5-Fu to chemotherapy in vitro and in vivo. Combination therapy significantly reduced HCT116 cell viability. Furthermore, Ator and 5-Fu present a cooperative effect on preventing the growth of tumors in CRC xenograft nude mice. In conclusion, our study demonstrates the value of Ator for treating intestinal damage. Moreover, Ator combined with 5-Fu increased the antitumor ability in CRC cells. Additionally, we provide a novel therapeutic protocol for CRC.